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Objectives Lipoatrophy is a long-term adverse effect of some antiretrovirals that affects quality of life, compromises adherence and may limit the clinical impact of HIV treatments. This paper explores the effect of tenofovir/emtricitabine ( TDF/ FTC) on the amount of limb fat in patients with virological suppression. Methods A randomized, prospective clinical trial was performed to compare continuation on a zidovudine/lamivudine ( ZDV/3TC)-based regimen with switching to a TDF/ FTC-based regimen in terms of the effect on limb fat mass as assessed by DEXA over a 72-week period. Results Eighty patients were included (39 in the TDF/ FTC arm and 41 in the ZDV/3 TC arm) and 73 completed the study (37 and 36, respectively). In the switch arm, limb fat increased by a median of 540 g from baseline ( P = 0.022), while in the ZDV/3TC arm it decreased by a median of 379 g ( P = 0.112; p between groups = 0.007). Subjects with baseline limb fat ≤ 7200 g, previous time on ZDV > 5 years or a body mass index > 25 kg/m2 experienced higher limb fat gains than other subjects, and these differences were statistically significant. Haemoglobin increased by a median of 1.0 g/d L in the TDF/ FTC arm ( P < 0.001) and remained unchanged in the ZDV/3TC arm (p between groups = 0.0002). There were no significant differences between groups in other secondary endpoints (body weight, total body and trunk fat content, total body bone mineral density, laboratory parameters, CD4 cell count and viral load). Conclusions Switching from a ZDV/3TC-based to a TDF/ FTC-based regimen led to a statistically significant improvement in limb fat, in contrast to the progressive loss of limb fat in subjects continuing ZDV/3TC. [ABSTRACT FROM AUTHOR]

Objective This paper presents the final analysis of once-daily darunavir/ritonavir ( DRV/r) vs. lopinavir/ritonavir ( LPV/r) in treatment-naïve HIV-1-infected adults. Methods ARTEMIS ( AntiRetroviral Therapy with TMC114 ExaMined In naïve Subjects; NCT00258557) was a randomized, open-label, phase- III, 192-week trial. Patients were stratified by baseline HIV-1 RNA and CD4 count, and randomized to once-daily DRV/r 800/100 mg or LPV/r 800/200 mg total daily dose (either once or twice daily) plus tenofovir/emtricitabine. Results Of 689 randomized patients receiving treatment ( DRV/r: 343; LPV/r: 346), 85 and 114 patients in the DRV/r and LPV/r arms, respectively, had discontinued by week 192. Noninferiority was shown in the primary endpoint of virological response ( HIV-1 RNA < 50 copies/ mL) [ DRV/r: 68.8%; LPV/r: 57.2%; P < 0.001; intent to treat ( ITT)/time to loss of virological response; estimated difference in response 11.6% (95% confidence interval 4.4-18.8%)]. Statistical superiority in virological response of DRV/r over LPV/r was demonstrated for the primary endpoint ( P = 0.002) and for the ITT non-virological-failure-censored analysis (87.4% vs. 80.8%, respectively; P = 0.040). No protease inhibitor ( PI) primary mutations developed and only low levels of nucleoside reverse transcriptase inhibitor ( NRTI) resistance developed in virological failures in both groups. Significantly fewer discontinuations because of adverse events were observed with DRV/r (4.7%) than with LPV/r (12.7%; P = 0.005). Grade 2-4 treatment-related diarrhoea was significantly less frequent with DRV/r than with LPV/r (5.0% vs. 11.3%, respectively; P = 0.003). DRV/r was associated with smaller median increases in total cholesterol and triglyceride levels than LPV/r. Changes in low- and high-density lipoprotein cholesterol were similar between groups. Similar increases in aspartate aminotransferase and alanine aminotransferase for DRV/r and LPV/r were observed. Conclusion Over 192 weeks, once-daily DRV/r was noninferior and statistically superior in virological response to LPV/r, with a more favourable gastrointestinal profile, demonstrating its suitability for long-term use in treatment-naïve patients. [ABSTRACT FROM AUTHOR]

Introduction: CD4/CD8 ratio is a marker of immune activation in HIV infection and has been associated with neurocognitive performance during chronic infection, but little is known about the early phases. The aim of this study was to examine the relationship between blood CD4/CD8 ratio and central nervous system endpoints in primary HIV infection (PHI) before and after antiretroviral treatment (ART). Methods: This was a retrospective analysis of the Primary Infection Stage CNS Events Study (PISCES) cohort. We longitudinally assessed blood and cerebrospinal fluid (CSF) markers of inflammation, immune activation and neuronal injury, and neuropsychological testing performance (NPZ4, an average of three motor and one processing speed tests, and a summarized total score, NPZ11, including also executive function, learning and memory) in ART‐naïve participants enrolled during PHI. Spearman correlation and linear mixed models assessed the relationships between the trajectory of CD4/CD8 ratio over time and neurocognitive performance, blood and CSF markers of immune activation and neuronal injury. Results: In all, 109 PHI participants were enrolled. The mean CD4/CD8 ratio decreased with longer time from infection to starting treatment (p < 0.001). Every unit increase in NPZ4 score was independently associated with a 0.15 increase in CD4/CD8 ratio (95% CI: 0.002–0.29; p = 0.047), whereas no correlation was found between CD4/CD8 ratio and NPZ11. Among the cognitive domains, only a change in processing speed was correlated with CD4/CD8 ratio over time (p = 0.03). The trajectory of the CD4/CD8 ratio was negatively correlated with change in CSF neurofilament light chain (p = 0.04). Conclusions: The trajectory of CD4/CD8 ratio was independently associated with motor/psychomotor speed performance, suggesting that immune activation is involved in brain injury during the early stages of the infection. [ABSTRACT FROM AUTHOR]

Objectives Viral load ( VL) monitoring is recommended, but seldom performed, in resource-constrained countries. RV288 is a US President's Emergency Plan for AIDS Relief ( PEPFAR) basic programme evaluation to determine the proportion of patients on treatment who are virologically suppressed and to identify predictors of virological suppression and recovery of CD4 cell count. Analyses from Uganda are presented here. Methods In this cross-sectional, observational study, patients on first-line antiretroviral therapy ( ART) (efavirenz or nevirapine + zidovudine/lamivudine) from Kayunga District Hospital and Kagulamira Health Center were randomly selected for a study visit that included determination of viral load ( HIV-1 RNA), CD4 cell count and clinical chemistry tests. Subjects were recruited by time on treatment: 6-12, 13-24 or > 24 months. Logistic regression modelling identified predictors of virological suppression. Linear regression modelling identified predictors of CD4 cell count recovery on ART. Results We found that 85.2% of 325 subjects were virologically suppressed (viral load < 47 HIV-1 RNA copies/ml). There was no difference in the proportion of virologically suppressed subjects by time on treatment, yet CD4 counts were higher in each successive stratum. Women had higher median CD4 counts than men overall (406 vs. 294 cells/μL, respectively; P < 0.0001) and in each time-on-treatment stratum. In a multivariate logistic regression model, predictors of virological suppression included efavirenz use [odds ratio ( OR) 0.47; 95% confidence interval ( CI) 0.22-1.02; P = 0.057], lower cost of clinic visits ( OR 0.815; 95% CI 0.66-1.00; P = 0.05), improvement in CD4 percentage ( OR 1.06; 95% CI 1.014-1.107; P = 0.009), and care at Kayunga vs. Kangulamira ( OR 0.47; 95% CI 0.23-0.92; P = 0.035). In a multivariate linear regression model of covariates associated with CD4 count recovery, time on highly active antiretroviral therapy ( ART) ( P < 0.0001), patient satisfaction with care ( P = 0.038), improvements in total lymphocyte count ( P < 0.0001) and haemoglobin concentration ( P = 0.05) were positively associated, whereas age at start of ART ( P = 0.0045) was negatively associated with this outcome. Conclusions High virological suppression rates are achievable on first-line ART in Uganda. The odds of virological suppression were positively associated with efavirenz use and improvements in CD4 cell percentage and total lymphocyte count and negatively associated with the cost of travel to the clinic. CD4 cell reconstitution was positively associated with CD4 count at study visit, time on ART, satisfaction with care at clinic, haemoglobin concentration and total lymphocyte count and negatively associated with age. [ABSTRACT FROM AUTHOR]

Objectives The accuracy and precision of glomerular filtration rate ( GFR) estimating equations based on plasma creatinine ( GFRcr), cystatin C ( GFRcys) and the combination of these markers ( GFRcr-cys) have recently been assessed in HIV-infected individuals. We assessed the associations of GFR, estimated by these three equations, with clinical events in HIV-infected individuals. Methods We compared the associations of baseline GFRcr, GFRcys and GFRcr-cys [using the Chronic Kidney Disease Epidemiology Collaboration ( CKD-EPI) equations] with mortality, cardiovascular events ( CVEs) and opportunistic diseases ( ODs) in the Strategies for the Management of Antiretroviral Therapy ( SMART) study. We used Cox proportional hazards models to estimate unadjusted and adjusted hazard ratios per standard deviation ( SD) change in GFR. Results A total of 4614 subjects from the SMART trial with available baseline creatinine and cystatin C data were included in this analysis. Of these, 99 died, 111 had a CVE and 121 had an OD. GFRcys was weakly to moderately correlated with HIV RNA, CD4 cell count, high-sensitivity C-reactive protein, interleukin-6, and D-dimer, while GFRcr had little or no correlation with these factors. GFRcys had the strongest associations with the three clinical outcomes, followed closely by GFRcr-cys, with GFRcr having the weakest associations with clinical outcomes. In a model adjusting for demographics, cardiovascular risk factors, HIV-related factors and inflammation markers, a 1- SD lower GFRcys was associated with a 55% [95% confidence interval ( CI) 27−90%] increased risk of mortality, a 21% (95% CI 0−47%) increased risk of CVE, and a 22% (95% CI 0−48%) increased risk of OD. Conclusions Of the three CKD-EPI GFR equations, GFRcys had the strongest associations with mortality, CVE and OD. [ABSTRACT FROM AUTHOR]

Objectives As socioeconomic factors may impact the risk of chronic kidney disease ( CKD), we evaluated the incidence and risk factors of incident CKD among an HIV-infected cohort with universal access to health care and minimal injecting drug use ( IDU). Methods Incident CKD was defined as an estimated glomerular filteration rate (eGFR) <60 ml/min/1.73 m2 for ≥ 90 days. eGFR was calculated using the Chronic Kidney Disease Epidemiology Collaboration ( CKD-EPI) equation. Rates were calculated per 1000 person-years ( PY). Associations with outcomes were assessed using two separate Cox proportional hazard models, adjusting for baseline and time-updated covariates. Results Among 3360 participants [median age 29 years; 92% male; 44% African American ( AA)] contributing 23 091 PY of follow-up, 116 developed incident CKD [5.0/1000 PY; 95% confidence interval ( CI) 4.2-6.0/1000 PY]. The median first eGFR value was 97.0 mL/min/1.73 m2 [interquartile range ( IQR) 85.3-110.1 mL/min/1.73 m2]. Baseline factors associated with CKD included older age, lower CD4 count at HIV diagnosis [compared with CD4 count ≥ 500 cells/μL, hazard ratio ( HR) 2.1 (95% CI 1.2-3.8) for CD4 count 350-499 cells/μL; HR 3.6 (95% CI 2.0-6.3) for CD4 count 201-349 cells/μL; HR 4.3 (95% CI 2.0-9.4) for CD4 count ≤ 200 cells/μL], and HIV diagnosis in the pre-highly active antiretroviral therapy ( HAART) era. In the time-updated model, low nadir CD4 counts, diabetes, hepatitis B, hypertension and less HAART use were also associated with CKD. AA ethnicity was not associated with incident CKD in either model. Conclusions The low incidence of CKD and the lack of association with ethnicity observed in this study may in part be attributable to unique features of our cohort such as younger age, early HIV diagnosis, minimal IDU, and unrestricted access to care. Lower baseline CD4 counts were significantly associated with incident CKD, suggesting early HIV diagnosis and timely introduction of HAART may reduce the burden of CKD. [ABSTRACT FROM AUTHOR]

Objectives Antiretroviral therapy reduces mortality and morbidity in HIV-infected individuals most markedly when initiated early, before advanced immunodeficiency has developed. Late presentation for diagnosis and care remains a significant challenge. To guide public health interventions effectively it is crucial to describe the factors associated with late presentation. Methods Case surveillance data for all individuals newly diagnosed with HIV infection in Germany in the years 2001-2010 and data for the years 1999-2010 from the German Clinical Surveillance of HIV Disease ( ClinSurv) cohort study, a large multicentre observational study, were analysed. Factors associated with late presentation ( CD4 count < 350 cells/ μL or clinical AIDS) were assessed using descriptive statistics and multivariable logistic regression methods. Results Among 22 925 eligible patients in the national surveillance database, 49.5% were late presenters for HIV diagnosis. Among 6897 treatment-naïve patients in the ClinSurv cohort, 58.1% were late presenters for care. Late presenters for care were older (median 42 vs. 39 years for early presenters), more often heterosexuals from low-prevalence countries (18.1% vs. 15.5%, respectively) and more often migrants (18.2% vs. 9.7%, respectively; all P < 0.005). The probability of late presentation was >65% throughout the observation period in migrants. The probability of late presentation for care clearly decreased in men who have sex with men ( MSM) from 60% in 1999 to 45% in 2010. Conclusions In Germany, the numbers of late presenters for HIV diagnosis and care remain high. The probability of late presentation for HIV diagnosis seems to be particularly high for migrants. These results argue in favour of targeted test promotion rather than opt-out screening. Late presentation for care seems to be an additional problem after HIV diagnosis. [ABSTRACT FROM AUTHOR]

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In the USA, women, racial/ethnic minorities and persons who acquire HIV infection through heterosexual intercourse represent an increasing proportion of HIV-infected persons, and yet are frequently underrepresented in clinical trials. We assessed the demographic predictors of trial participation in antiretroviral-naïve patients. Methods Patients were characterized as trial participants if highly active antiretroviral therapy (HAART) was initiated within a clinical trial. Prevalence ratios (PRs) were obtained using binomial regression. Results Between 1996 and 2006, 30% of 738 treatment-naïve patients initiated HAART in a clinical trial. Trial participation rates for men who have sex with men (MSM), heterosexual men, and women were respectively 36.5, 29.6 and 24.3%. After adjustment for other factors, heterosexual men appeared less likely to participate in trials compared with MSM [PR 0.79, 95% confidence interval (CI) 0.57, 1.11], while women were as likely to participate as MSM (PR 0.97, 95% CI 0.68, 1.39). The participation rate in Black patients (25.9%) was lower compared with non-Black patients (37.5%) (adjusted PR 0.80, 95% CI 0.60, 1.06). Conclusions In our clinical setting, gender did not appear to impact participation in HIV treatment trials, but Black patients were slightly less likely to participate in these trials. Considering the substantial proportion of HIV-infected patients who are Black, future trials need to consider strategies to incorporate such underrepresented populations. [ABSTRACT FROM AUTHOR]