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OBJECTIVES: The aim of the study was to investigate whether lamivudine (3TC) or emtricitabine (FTC) use following detection of M184V/I is associated with better virological outcomes. METHODS: We identified people with viruses harbouring the M184V/I mutation in UK multicentre data sets who had treatment change/initiation within 1 year. We analysed outcomes of viral suppression (

This study assessed the likelihood of referral for liver transplantation assessment in a prospective cohort of patients co-infected with HIV and hepatitis B or C with complications of cirrhosis. There were 141 co-infected patients from 11 UK centres with at least one complication of cirrhosis recorded (either decompensation or hepatocellular carcinoma) out of 772 identified with cirrhosis and/or HCC. Only 23 of these 141 (16.3%) were referred for liver transplantation assessment, even though referral is recommended for co-infected patients after the first decompensation episode.

Background We describe a patient copresenting with epilepsia partialis continua, tuberculosis, and hemophagocytic lymphohistiocytosis. To our knowledge, this is the first documented case of this triad. Case presentation A 54-year-old black South African woman presented to a hospital in Scotland with an acute history of right-sided facial twitching, breathlessness, and several months of episodic night sweats. Clinical examination revealed pyrexia and continuous, stereotyped, right-sided facial contractions. These worsened with speech and continued through sleep. A clinical diagnosis of epilepsia partialis continua was made, and we provide a video of her seizures. Computed tomographic imaging of the chest and serous fluid analyses were consistent with a diagnosis of disseminated Mycobacterium tuberculosis. An additional diagnosis of hemophagocytic lymphohistiocytosis was made following the identification of pancytopenia and hyperferritinemia in peripheral blood, with hemophagocytosis evident in bone marrow investigation. We provide images of her hematopathology. The patient was extremely unwell and was hospitalized for 6 months, including two admissions to the intensive care unit for ventilatory support. She was treated successfully with high doses of antiepileptic drugs (benzodiazepines, levetiracetam, and phenytoin) and 12 months of oral antituberculosis therapy, and she underwent chemotherapy with 8 weeks of etoposide and dexamethasone for hemophagocytic lymphohistiocytosis, followed by 12 months of cyclosporine and prednisolone. Conclusions This combination of pathologies is unusual, and this case report helps educate clinicians on how such a patient may present and be managed. A lack of evidence surrounding the coexpression of this triad may represent absolute rarity, underdiagnosis, or incomplete case ascertainment due to early death caused by untreated tuberculosis or hemophagocytic lymphohistiocytosis. Further research is needed. Electronic supplementary material The online version of this article (10.1186/s13256-019-2092-x) contains supplementary material, which is available to authorized users.

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Objective: Model trajectories of viral load measurements from time of starting combination antiretroviral therapy (cART), and use the model to predict whether patients will achieve suppressed viral load (Design: Prospective cohort study including HIV-positive adults (UK Collaborative HIV Cohort Study).Methods: Eligible patients were antiretroviral naive and started cART after 1997. Random effects models were used to estimate viral load trends. Patients were randomly selected to form a validation dataset with those remaining used to fit the model. We evaluated predictions of suppression using indices of diagnostic test performance.Results: Of 9562 eligible patients 6435 were used to fit the model and 3127 for validation. Mean log(10) viral load trajectories declined rapidly during the first 2 weeks post-cART, moderately between 2 weeks and 3 months, and more slowly thereafter. Higher pretreatment viral load predicted steeper declines, whereas older age, white ethnicity, and boosted protease inhibitor/non-nucleoside reverse transcriptase inhibitors based cART-regimen predicted a steeper decline from 3 months onwards. Specificity of predictions and the diagnostic odds ratio substantially improved when predictions were based on viral load measurements up to the 4-month visit compared with the 2 or 3-month visits. Diagnostic performance improved when suppression was defined by two consecutive suppressed viral loads compared with one.Conclusions: Viral load measurements can be used to predict if a patient will be suppressed by 6-month post-cART. Graphical presentations of this information could help clinicians decide the optimum time to switch treatment regimen during the first months of cART. Copyright (C) 2016 Wolters Kluwer Health, Inc. All rights reserved.

Background: Antiretrovirals (ARVs) affect bone density and turnover, but their effect on risk of fractures and osteonecrosis of the femoral head is less understood. We investigated if exposure to ARVs increases the risk of both bone outcomes. Methods: EuroSIDA participants were followed to assess fractures and osteonecrosis. Poisson regression identified clinical, laboratory and demographic predictors of either bone outcome. Ever, current, and cumulative exposures to ARVs were assessed. Results: During 86118 PYFU among 11820 included persons (median age 41y, 75% male, median baseline CD4 440/mm3, 70.4% virologically suppressed), there were 619 fractures (incidence/1000 PYFU 7.2; 95% CI 6.6-7.7) and 89 osteonecrosis (1.0; 0.8-1.3). Older age, white race, lower BMI, IV drug use, lower baseline CD4, HCV coinfection, prior osteonecrosis, prior fracture, cardiovascular disease, and recent non-AIDS cancer (last 12 months) were associated with fractures. After adjustment, persons who had ever used tenofovir disoproxil fumarate (TDF) (1.40; 1.15-1.70) or who were currently on TDF (1.25; 1.05-1.49) had higher incidence of fractures. There was no association between cumulative exposure to TDF and fractures (1.08/5 y exposure; 0.94-1.25). No other ARV was associated with fractures (all P > .1). Risk of osteonecrosis was associated with white race, lower nadir CD4, prior osteonecrosis, prior fracture, and prior AIDS. After mutual adjustment, no ARV was associated with osteonecrosis. Conclusions: In human immunodeficiency virus (HIV) infection, host factors, HIV-specific variables, and comorbidities contribute to risk of fractures and osteonecrosis. Exposure to TDF, but not other ARVs, was an independent risk factor for fractures. info:eu-repo/semantics/publishedVersion

Objective: The objective of this study is to estimate life expectancies of HIV-positive patients conditional on response to antiretroviral therapy (ART). Methods: Patients aged more than 20 years who started ART during 2000–2010 (excluding IDU) in HIV clinics contributing to the UK CHIC Study were followed for mortality until 2012. We determined the latest CD4+ cell count and viral load before ART and in each of years 1–5 of ART. For each duration of ART, life tables based on estimated mortality rates by sex, age, latest CD4+ cell count and viral suppression (HIV-1 RNA

© 2016 The Author(s)The central nervous system has been proposed as a sanctuary site where HIV can escape antiretroviral control and develop drug resistance. HIV-1 RNA can be at higher levels in CSF than plasma, termed CSF/plasma discordance. We aimed to examine whether discordance in CSF is associated with low level viraemia (LLV) in blood. In this MRC-funded multicentre study, we prospectively recruited patients with LLV, defined as one or more episode of unexplained plasma HIV-1 RNA within 12 months, and undertook CSF examination. Separately, we prospectively collected CSF from patients undergoing lumbar puncture for a clinical indication. Patients with durable suppression of viraemia and no evidence of CNS infection were identified as controls from this group. Factors associated with CSF/plasma HIV-1 discordance overall were examined. One hundred fifty-three patients were recruited across 13 sites; 40 with LLV and 113 undergoing clinical lumbar puncture. Seven of the 40 (18 %) patients with LLV had CSF/plasma discordance, which was significantly more than 0/43 (0 %) with durable suppression in blood from the clinical group (p = 0.005). Resistance associated mutations were shown in six CSF samples from discordant patients with LLV (one had insufficient sample for testing), which affected antiretroviral therapy at sampling in five. Overall discordance was present in 20/153 (13 %) and was associated with nadir CD4 but not antiretroviral concentrations in plasma or CSF. CSF/plasma discordance is observed in patients with LLV and is associated with antiretroviral resistance associated mutations in CSF. The implications for clinical practice require further investigation.

Objective HIV-1 genetic variability may influence antiretroviral therapy (ART) outcomes. The study aim was to determine the impact of polymorphisms in regions known to harbor major nonnucleoside reverse transcriptase inhibitor (NNRTI) resistance mutations (codons 90-108, 135-138, 179-190, 225-348) on virologic responses to first-line NNRTI-based ART. Methods Reverse transcriptase sequences from ART-naive individuals who commenced efavirenz (EFV) or nevirapine (NVP) with at least two nucleos(t)ide reverse transcriptase inhibitors (NRTIs) without major drug resistance mutations were analyzed. The impact of polymorphisms on week 4 viral load decrease and time to virologic failure was measured over a median 97 weeks. Results Among 4528 patients, most were infected with HIV-1 subtype B (67%) and commenced EFV-based ART (84%). Overall, 2598 (57%) had at least one polymorphism, most frequently at codons 90, 98, 101, 103, 106, 135, 138, 179, and 238. Virologic failure rates were increased in patients with two (n = 597) or more than two (n = 72) polymorphisms [adjusted hazard ratio 1.43; 95% confidence interval (CI) 1.07-1.92; P = 0.016]. Polymorphisms associated with virologic failure occurred at codons 90 (mostly V90I), 98 (mostly A98S), and 103 (mostly K103R), with adjusted hazard ratios of 1.78 (1.15-2.73; P = 0.009), 1.55 (1.16-2.08; P = 0.003), and 1.75 (1.00-3.05: P = 0.049), respectively. Polymorphisms at codon 179, especially V179D/E/T, predicted reduced week 4 responses (P = 0.001) but not virologic failure. Conclusion The occurrence of multiple polymorphisms, though uncommon, was associated with a small increase in the risk of NNRTI treatment failure; significant effects were seen with polymorphisms at codon 90, 98, and 103. The mechanisms underlying the slower suppression seen with V179D/E/T deserve further investigation.

Background To combat the pandemic of human immunodeficiency virus 1 (HIV-1), a successful vaccine will need to cope with the variability of transmissible viruses. Human hosts infected with HIV-1 potentially harbour many viral variants but very little is known about viruses that are likely to be transmitted, or even if there are viral characteristics that predict enhanced transmission in vivo. We show for the first time that genetic divergence consistent with a single transmission event in vivo can represent several years of pre-transmission evolution. Results We describe a highly unusual case consistent with a single donor transmitting highly related but distinct HIV-1 variants to two individuals on the same evening. We confirm that the clustering of viral genetic sequences, present within each recipient, is consistent with the history of a single donor across the viral env, gag and pol genes by maximum likelihood and Bayesian Markov Chain Monte Carlo based phylogenetic analyses. Based on an uncorrelated, lognormal relaxed clock of env gene evolution calibrated with other datasets, the time since the most recent common ancestor is estimated as 2.86 years prior to transmission (95% confidence interval 1.28 to 4.54 years). Conclusion Our results show that an effective design for a preventative vaccine will need to anticipate extensive HIV-1 diversity within an individual donor as well as diversity at the population level.

BACKGROUND: Although HIV treatment guidelines recommend highly active antiretroviral therapy (HAART) initiation before reaching a CD4 count of 200 cells/mm3, many people in resource-rich settings, and a substantial proportion in resource-limited settings, present at levels

Selection of protease mutations on antiretroviral therapy (ART) including a ritonavir-boosted protease inhibitor (PI) has been reported infrequently. Scarce data exist from long-term cohorts on resistance incidence or mutational patterns emerging to different PIs.We studied UK patients receiving lopinavir/ritonavir as their first PI, either while naive to ART or having previously received non-PI-based ART. Virological failure was defined as viral load ≥ 400 copies/mL after previous suppression400 copies/mL, or failure to achieve400 copies/mL during the first 6 months. pol sequences whilst failing lopinavir or within 30 days after stopping were analysed. Major and minor mutations (IAS-USA 2008-after exclusion of polymorphisms) were considered. Predicted susceptibility was determined using the Stanford HIVdb algorithm.Three thousand and fifty-six patients were followed for a median (IQR) of 14 (6-30) months, of whom 811 (27%) experienced virological failure. Of these, resistance test results were available on 291 (36%). One or more protease mutations were detected in 32 (11%) patients; the most frequent were I54V (n = 12), M46I (n = 11), V82A (n = 7) and L76V (n = 3). No association with viral subtype was evident. Many patients retained virus predicted to be susceptible to lopinavir (14, 44%), tipranavir (26, 81%) and darunavir (27, 84%).This study reflects the experience of patients in routine care. Selection of protease gene mutations by lopinavir/ritonavir occurred at a much higher rate than in clinical trials. The mutations observed showed only partial overlap with those previously identified by structural chemistry models, serial cell culture passage and genotype-phenotype analyses. There remained a low degree of predicted cross-resistance to other widely used PIs.

BACKGROUND: The clinical relevance of mutations in the connection subdomain and the ribonuclease (RNase) H domain of HIV-1 reverse transcriptase (RT) is uncertain.METHODS: The risk of virological failure to nonnucleoside RT inhibitor (NNRTI)-based antiretroviral therapy (ART) was evaluated in NNRTI-naive patients who started NNRTIs in the EuroSIDA study after July 1997 according to preexisting substitutions in the connection subdomain and the RNase H domain of HIV-1 RT. An observed association between A376S and virological failure was further investigated by testing in vitro NNRTI susceptibility of single site-directed mutants and patient-derived recombinant viruses. Enzymatic assays also determined the effects of A376S on nevirapine and template-primer binding to HIV-1 RT.RESULTS: Virological failure occurred in 142 of 287 (49%) individuals: 77 receiving nevirapine (67%) and 65 receiving efavirenz (38%) (P < .001). Preexisting A376S was associated with an increased risk of virological failure to nevirapine (relative hazard [RH] = 10.4; 95% confidence interval [CI], 2.0-54.7), but it did not affect efavirenz outcome the same way (RH = 0.5; 95% CI, 0.1-2.2) (P value for interaction = .013). A376S conferred selective low-level nevirapine resistance in vitro, and led to greater affinity for double-stranded DNA.CONCLUSIONS: The A376S substitution in the connection subdomain of HIV-1 RT causes selective nevirapine resistance and confers an increased risk of virological failure to nevirapine-based ART.

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.

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.

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

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.

Background: HIV cohort collaborations, which pool data from diverse patient cohorts, have provided key insights into outcomes of antiretroviral therapy (ART). However, the extent of, and reasons for, between-cohort heterogeneity in rates of AIDS and mortality are unclear. Methods: We obtained data on adult HIV-positive patients who started ART from 1998 without a previous AIDS diagnosis from 17 cohorts in North America and Europe. Patients were followed up from 1 month to 2 years after starting ART. We examined between-cohort heterogeneity in crude and adjusted (age, sex, HIV transmission risk, year, CD4 count and HIV-1 RNA at start of ART) rates of AIDS and mortality using random-effects meta-analysis and meta-regression. Results: During 61 520 person-years, 754/38 706 (1.9%) patients died and 1890 (4.9%) progressed to AIDS. Between-cohort variance in mortality rates was reduced from 0.84 to 0.24 (0.73 to 0.28 for AIDS rates) after adjustment for patient characteristics. Adjusted mortality rates were inversely associated with cohorts' estimated completeness of death ascertainment [excellent: 96-100%, good: 90-95%, average: 75-89%; mortality rate ratio 0.66 (95% confidence interval 0.46-0.94) per category]. Mortality rate ratios comparing Europe with North America were 0.42 (0.31-0.57) before and 0.47 (0.30-0.73) after adjusting for completeness of ascertainment. Conclusions: Heterogeneity between settings in outcomes of HIV treatment has implications for collaborative analyses, policy and clinical care. Estimated mortality rates may require adjustment for completeness of ascertainment. Higher mortality rate in North American, compared with European, cohorts was not fully explained by completeness of ascertainment and may be because of the inclusion of more socially marginalized patients with higher mortality risk. © The Author 2012; all rights reserved.

The novel pandemic influenza A (H1H1) 2009 virus spread rapidly around the world in 2009. The paucity of prospective international epidemiologic data on predictors of clinical outcomes with pandemic (H1N1) 2009 virus infection stimulated the INSIGHT network, an international network of community and hospital-based investigators, to commence two worldwide clinical observational studies to describe pandemic (H1N1) 2009 virus activity. The purpose of these two studies was to estimate the percent of adult patients with illness due to laboratory-confirmed pandemic (H1N1) 2009 virus infection that experience clinically significant outcomes and to study factors related to these outcomes. Enrollment commenced in October 2009 and will continue until August 2011: as of the end of 2010, 62 sites in 14 countries in Australasia (12 sites), Europe (37) and North America (13) have enrolled 1365 adult patients, with 1049 enrollments into the FLU 002 outpatient study and 316 into the FLU 003 hospitalization study. These in progress INSIGHT influenza observational studies may act as a model for obtaining epidemiological, clinical and laboratory information in future international disease outbreaks.

Summary Background Whether people living with HIV who have not received antiretroviral therapy (ART) and have high CD4 cell counts have higher mortality than the general population is unknown. We aimed to examine this by analysis of pooled data from industrialised countries. We merged data on demographics, CD4 cell counts, viral-load measurements, hepatitis C co-infection status, smoking status, date of death, and whether death was AIDS-related or not from 23 European and North American cohorts. We calculated standardised mortality ratios (SMRs) standardised by age, sex, and year, stratifying by risk group. Data were included for patients aged 20-59 years who had at least one CD4 count greater than 350 cells per μL while ART naive. All pre-ART CD4 counts greater than 350 cells per μL from January, 1990, to December, 2004, were included. We investigated mortality for four risk groups - men who have sex with men, heterosexual people, injecting drug users, and those at other or unknown risk. The association between CD4 cell count and death rate was investigated by use of Poisson regression methods. Data were analysed for 40 830 patients contributing 80 682 person-years of follow-up. Of 419 deaths, 401 were used in the SMR analysis: 100 men who have sex with men (SMR 1·30, 95 CI 1·06-1·58); 68 heterosexual people (2·94, 2·28-3·73); 203 injecting drug users (9·37, 8·13-10·75); and 30 in the other or unknown risk category (4·57, 3·09-6·53). Compared with CD4 counts of 350-499 cells per μL, death rate was lower in patients with counts of 500-699 cells per μL (adjusted rate ratio 0·77, 95 CI 0·61-0·95) and counts of 700 cells per μL (0·66, 0·52-0·85). In HIV-infected ART-naive patients with high CD4 cell counts, death rates were raised compared with the general population. In men who have sex with men this was modest, suggesting that a substantial proportion of the increased risk in other groups is due to confounding by other factors. Even though the increased risk is small, new studies of potential benefits of ART in this group are merited. European Commission, FP6. European AIDS Treatment Network (NEAT). Project number LSHP-CT-2006-037570.

Objectives: Chronic kidney disease (CKD) in HIV-positive persons might be caused by both HIV and traditional or non-HIV-related factors. Our objective was to investigate long-term exposure to specific antiretroviral drugs and CKD. Design: A cohort study including 6843 HIV-positive persons with at least three serum creatinine measurements and corresponding body weight measurements from 2004 onwards. Methods: CKD was defined as either confirmed (two measurements >= 3 months apart) estimated glomerular filtration rate (eGFR) of 60 ml/min per 1.73 m(2) or below for persons with baseline eGFR of above 60 ml/min per 1.73 m(2) or confirmed 25% decline in eGFR for persons with baseline eGFR of 60 ml/min per 1.73 m(2) or less, using the Cockcroft-Gault formula. Poisson regression was used to determine factors associated with CKD. Results: Two hundred and twenty-five (3.3%) persons progressed to CKD during 21 482 person-years follow-up, an incidence of 1.05 per 100 person-years follow-up [95% confidence interval (CI) 0.91-1.18]; median follow-up was 3.7 years (interquartile range 2.8-5.7). After adjustment for traditional factors associated with CKD and other confounding variables, increasing cumulative exposure to tenofovir [incidence rate ratio (IRR) per year 1.16, 95% CI 1.06-1.25, P

Udgivelsesdato: 2009-Sep-15 BACKGROUND: Activation and coagulation biomarkers were measured within the Strategies for Management of Antiretroviral Therapy (SMART) trial. Their associations with opportunistic disease (OD) in human immunodeficiency virus (HIV)-positive patients were examined. METHODS: Inflammatory (high-sensitivity C-reactive protein [hsCRP], interleukin-6 [IL-6], amyloid-A, and amyloid-P) and coagulation (D-dimer and prothrombin-fragment 1+2) markers were determined. Conditional logistic regression analyses were used to assess associations between these biomarkers and risk of OD. RESULTS: The 91 patients who developed an OD were matched to 182 control subjects. Patients with an hsCRP level > or =5 microg/mL at baseline had a 3.5 higher odds of OD (95% confidence interval [CI], 1.5-8.1) than did those with an hsCRP level or =3 pg/mL at baseline had a 2.4 higher odds of OD (95% CI, 1.0-5.4) than did those with an IL-6 level or =5 microg/mL (compared with a level or =6 mg/L (compared with a level or =3 pg/mL (compared with a level

Udgivelsesdato: 2008-Nov-12 BACKGROUND: Interruption of a non-nucleoside reverse transcriptase inhibitor (NNRTI)-regimen is often necessary, but must be performed with caution because NNRTIs have a low genetic barrier to resistance. Limited data exist to guide clinical practice on the best interruption strategy to use. METHODS: Patients in the drug-conservation arm of the Strategies for Management of Antiretroviral Therapy (SMART) trial who interrupted a fully suppressive NNRTI-regimen were evaluated. From 2003, SMART recommended interruption of an NNRTI by a staggered interruption, in which the NNRTI was stopped before the NRTIs, or by replacing the NNRTI with another drug before interruption. Simultaneous interruption of all antiretrovirals was discouraged. Resuppression rates 4-8 months after reinitiating NNRTI-therapy were assessed, as was the detection of drug-resistance mutations within 2 months of the treatment interruption in a subset (N = 141). RESULTS: Overall, 601/688 (87.4%) patients who restarted an NNRTI achieved viral resuppression. The adjusted odds ratio (95% confidence interval) for achieving resuppression was 1.94 (1.02-3.69) for patients with a staggered interruption and 3.64 (1.37-9.64) for those with a switched interruption compared with patients with a simultaneous interruption. At least one NNRTI-mutation was detected in the virus of 16.4% patients with simultaneous interruption, 12.5% patients with staggered interruption and 4.2% patients with switched interruption. Fewer patients with detectable mutations (i.e. 69.2%) achieved HIV-RNA of 400 copies/ml or less compared with those in whom no mutations were detected (i.e. 86.7%; P = 0.05). CONCLUSION: In patients who interrupt a suppressive NNRTI-regimen, the choice of interruption strategy may influence resuppression rates when restarting a similar regimen. NNRTI drug-resistance mutations were observed in a relatively high proportion of patients. These data provide additional support for a staggered or switched interruption strategy for NNRTI drugs.

Udgivelsesdato: 2008-Apr-15 BACKGROUND: The SMART study randomized 5,472 human immunodeficiency virus (HIV)-infected patients with CD4+ cell counts >350 cells/microL to intermittent antiretroviral therapy (ART; the drug conservation [DC] group) versus continuous ART (the viral suppression [VS] group). In the DC group, participants started ART when the CD4+ cell count was or= 6 months (n=228) were analyzed. The following clinical outcomes were assessed: (i) opportunistic disease (OD) or death from any cause (OD/death); (ii) OD (fatal or nonfatal); (iii) serious non-AIDS events (cardiovascular, renal, and hepatic disease plus non-AIDS-defining cancers) and non-OD deaths; and (iv) the composite of outcomes (ii) and (iii). RESULTS: A total of 477 participants (228 in the DC group and 249 in the VS group) were followed (mean, 18 months). For outcome (iv), 21 and 6 events occurred in the DC (7 in ART-naive participants and 14 in those who had not received ART for >or= 6 months) and VS (2 in ART-naive participants and 4 in those who had not received ART for 6 months) groups, respectively. Hazard ratios for DC vs. VS by outcome category were as follows: outcome (i), 3.47 (95% confidence interval [CI], 1.26-9.56; p=.02); outcome (ii), 3.26 (95% CI, 1.04-10.25; p=.04); outcome (iii), 7.02 (95% CI, 1.57-31.38; p=.01); and outcome (iv), 4.19 (95% CI, 1.69-10.39; p=.002 ). CONCLUSIONS: Initiation of ART at CD4+ cell counts >350 cells/microL compared with

Human immunodeficiency virus (HIV)-infected CD8 lymphocytes have been reported in vivo, but the mechanism of infection remains unclear. Experiments using the thy/hu mouse model support export of intrathymically infected CD8 precursors, while recent in vitro data suggest that mature CD8 lymphocytes upregulate CD4 upon activation (generating a CD8brightCD4dimphenotype) and are susceptible to HIV infection. To determine whether these mechanisms operate in vivo and to assess their relative importance in the generation of circulating HIV-infected CD8 lymphocytes, we quantified HIV long terminal repeat (LTR) DNA in CD8+CD4−and CD8brightCD4dimlymphocytes isolated from HIV-infected individuals by fluorescence-activated cell sorting. HIV infection of CD8 lymphocytes was demonstrated in 17 of 19 subjects, with a significant inverse relationship between level of infection and CD4 lymphocyte count (R= −0.73;P< 0.001). The level of HIV infection of CD8brightCD4dimlymphocytes was significantly higher (median, 1,730 HIV LTR copies/106cells;n= 9) than that of CD8+CD4−lymphocytes (undetectable in seven of nine individuals;P< 0.01) and approached that of CD4 lymphocytes from the same individuals (median, 3,660 HIV LTR copies/106cells). CD8brightCD4dimlymphocytes represented 0.8 to 3.3% of total CD8 lymphocytes and were most prevalent in the memory subset. Thus, HIV-infected CD8 lymphocytes commonly circulate in HIV-infected individuals and are generated through infection of activated CD8 lymphocytes rather than through export of intrathymically infected precursors. The high level of infection of CD8brightCD4dimlymphocytes could have a direct role in the decline in CD8 lymphocyte function that accompanies HIV disease progression.

There is increasing evidence that a wider range of lymphoid cell types other than CD4(+) T helper lymphocytes are infected with HIV-1 in vivo, including CD8 lymphocytes, natural killer cells, and reticulodendritic cells. Each potentially contributes to the reservoir of infected cells that resist antiviral treatment and to the impairment of immune responses in AIDS. By quantitative PCR for HIV proviral sequences we have now obtained evidence for substantial infection of gammadelta lymphocytes, contributing 3-45% of the proviral load in peripheral blood. A large proportion of gammadelta lymphocytes constitutively expressed the chemokine receptors CCR5 and CXCR4, with evidence for marked up-regulation of CD8 in samples from HIV-infected individuals, corresponding to an activated phenotype. That gammadelta lymphocytes might be susceptible to HIV infection was investigated using in vitro infectivity assays of recombinant HIV-expressing green fluorescent protein, followed by flow cytometry. gammadelta, CD4, and CD8 lymphocytes were each productively infected, with gammadelta lymphocytes showing the greatest susceptibility. For each cell type, blocking assays with an anti-CD4 monoclonal antibody indicated that entry was CD4-dependent.

There is increasing evidence that CD8 lymphocytes may represent targets for infection by human immunodeficiency virus type 1 (HIV-1) in vivo whose destruction may contribute to the loss of immune function underlying AIDS. HIV-1 may infect thymic precursor cells destined to become CD4 and CD8 lymphocytes and contribute to the numerical decline in both subsets on disease progression. There is also evidence for the induction of CD4 expression and susceptibility to infection by HIV-1 of CD8 lymphocytes activated in vitro. To investigate the relationship between CD8 activation and infection by HIV-1 in vivo, activated subsets of CD8 lymphocytes in peripheral blood mononuclear cells (PBMCs) of HIV-seropositive individuals were investigated for CD4 expression and HIV infection. Activated CD8 lymphocytes were identified by expression of CD69, CD71, and the human leukocyte antigen (HLA) class II, the β-chain of CD8, and the RO isoform of CD45. CD4+and CD4−CD8 lymphocytes, CD4 lymphocytes, other T cells, and non-T cells were purified using paramagnetic beads, and proviral sequences were quantified by PCR using primers from the long terminal repeat region. Frequencies of activated CD8 lymphocytes were higher in HIV-infected study subjects than in seronegative controls, and they frequently coexpressed CD4 (mean frequencies on CD69+, CD71+, and HLA class II+cells of 23, 37, and 8%, respectively, compared with 1 to 2% for nonactivated CD8 lymphocytes). The level of CD4 expression of the double-positive population approached that of mature CD4 lymphocytes. That CD4 expression renders CD8 cell susceptible to infection was indicated by their high frequency of infection in vivo; infected CD4+CD8 lymphocytes accounted for between 3 and 72% of the total proviral load in PBMCs from five of the eight study subjects investigated, despite these cells representing a small component of the PBMC population (

To investigate the mechanism and functional significance of infection of CD8+lymphocytes by human immunodeficiency virus type 1 (HIV-1) in vivo, we determined frequencies of infection, proviral conformation, and genetic relationships between HIV-1 variants infecting naive (CD45RA+) and memory (CD45RO+) peripheral blood CD4+and CD8+lymphocytes. Infection of CD3+CD8+CD45RA+cells was detected in 9 of 16 study subjects at frequencies ranging from 30 to 1,400 proviral copies/106cells, more frequently than CD3+CD8+lymphocytes expressing the RO isoform of CD45 (n= 2, 70 and 260 copies /106cells). In agreement with previous studies, there was no evidence for a similar preferential infection of CD4+naive lymphocytes. Proviral sequences in both CD4+and CD8+lymphocyte subsets were complete, as assessed by quantitation using primers from the long terminal repeat region spanning the tRNA primer binding site. In six of the seven study subjects investigated, variants infecting CD8+lymphocytes were partially or completely genetically distinct in the V3 region from those recovered from CD4+lymphocytes and showed a greater degree of compartmentalization than observed between naive and memory subsets of CD4+lymphocytes. In two study subjects, arginine substitutions at position 306, associated with use of the chemokine coreceptor CXCR4, were preferentially found in CD4 lymphocytes. These population differences may have originated through different times of infection rather than necessarily indicating a difference in their biological properties. The preferential distribution of HIV-1 in naive CD8+lymphocytes indeed suggests that infection occurred early in T-lymphocyte ontogeny, such as during maturation in the thymus. Destruction of cells destined to become CD8+lymphocytes may be a major factor in the decline in CD8+lymphocyte frequencies and function on disease progression and may contribute directly to the observed immunodeficiency in AIDS.

3 observations d'intoxication par le paracetamol (tentatives de suicide), presentant toutes les caracteristiques de l'hepatite virale «non-A-non-B». Mort de coma hepatique