Red de Investigación en Sida

BACKGROUND: Cardiovascular disease (CVD) is the worldwide leading cause of morbidity and mortality. An early risk detection of apparently healthy people before CVD onset has clinical relevance in the prevention of cardiovascular events. We evaluated the association between the product of fasting plasma glucose and triglycerides (TyG index) and CVD. MATERIAL AND METHODS: A total of 5014 patients of the Vascular Metabolic CUN cohort (VMCUN cohort) were followed up during a median period of 10 years. We used a Cox proportional-hazard ratio with repeated measures to estimate the risk of incidence of CVD across quintiles of the TyG index, calculated as ln[fasting triglycerides (mg/dL) × fasting plasma glucose (mg(dL)/2], and plotted a receiver-operating characteristics (ROC) curve to compare a prediction model fitted on the variables used in the Framingham risk score, a new model containing the Framingham variables with the TyG index, and the risk of coronary heart disease. RESULTS: A higher level of TyG index was significantly associated with an increased risk of developing CVD independent of confounding factors with a value of 2·32 (95% CI: 1·65-3·26) for those in the highest quintile and 1·52 (95% CI: 1·07-2·16) for those in the fourth quintile. The areas under the curve (AUC) of the ROC plots were 0·708 (0·68-0·73) for the Framingham model and 0·719 (0·70-0·74) for the Framingham + TyG index model (P = 0·014). CONCLUSIONS: The TyG index, a simple measure reflecting insulin resistance, might be useful to early identify individuals at a high risk of developing a cardiovascular event.

The purpose of this study was to document the genetic diversity of human immunodeficiency virus type 1 (HIV-1) in the Democratic Republic of Congo (DRC; formerly Zaire). A total of 247 HIV-1-positive samples, collected during an epidemiologic survey conducted in 1997 in three regions (Kinshasa [the capital], Bwamanda [in the north], and Mbuyi-Maya [in the south]), were genetically characterized in the env V3-V5 region. All known subtypes were found to cocirculate, and for 6% of the samples the subtype could not be identified. Subtype A is predominant, with prevalences decreasing from north to south (69% in the north, 53% in the capital city, and 46% in the south). Subtype C, D, G, and H prevalences range from 7 to 9%, whereas subtype F, J, K, and CRF01-AE strains represent 2 to 4% of the samples; only one subtype B strain was identified. The highest prevalence (25%) of subtype C was in the south, and CRF01-AE was seen mainly in the north. The high intersubtype variability among the V3-V5 sequences is the most probable reason for the low (45%) efficiency of subtype A-specific PCR and HMA (heteroduplex mobility assay). Eighteen (29%) of 62 samples had discordant subtype designations between env and gag. Sequence analysis of the entire envelope from 13 samples confirmed the high degree of diversity and complexity of HIV-1 strains in the DRC; 9 had a complex recombinant structure in gp160, involving fragments of known and unknown subtypes. Interestingly, the unknown fragments from the different strains did not cluster together. Overall, the high number of HIV-1 subtypes cocirculating, the high intrasubtype diversity, and the high numbers of possible recombinant viruses as well as different unclassified strains are all in agreement with an old and mature epidemic in the DRC, suggesting that this region is the epicenter of HIV-1 group M.

We performed an observational analysis of prospectively collected data on 1,474 adult patients who were hospitalized for community-acquired pneumonia; 1,169 patients were under 80 years of age and 305 (21%) patients were over 80 years ("very elderly"). Mean patient ages were 60 years in the former group and 85 years in the latter group. Severely immunosuppressed patients and nursing-home residents were not included. Comorbidities significantly associated with older age were chronic obstructive pulmonary disease, chronic heart disease, and dementia. The most common causative organism was Streptococcus pneumoniae (23% in both groups). Aspiration pneumonia was more frequent in the very elderly (5% in younger patients versus 10% in the very elderly); Legionella pneumophila (8% in younger patients versus 1% in the very elderly) and atypical agents (7% in younger patients versus 1% in the very elderly) were rarely recorded in the very elderly. While very elderly patients complained less frequently of pleuritic chest pain, headache, and myalgias, they were more likely to have absence of fever and altered mental status on admission. No significant differences were observed between groups as regards incidence of classic bacterial pneumonia syndrome (60% versus 59%) in 343 patients with pneumococcal pneumonia. The development of inhospital complications (26% in younger versus 32% in very elderly patients) as well as early mortality (2% in younger versus 7% in very elderly patients) and overall mortality (6% in younger versus 15% very elderly patients) were significantly higher in very elderly patients. Acute respiratory failure and shock/multiorgan failure were the most frequent causes of death, especially of early mortality. Factors independently associated with 30-day mortality in the very elderly were altered mental status on admission (odds ratio, 3.69), shock (odds ratio, 10.69), respiratory failure (odds ratio, 3.50), renal insufficiency (odds ratio, 5.83), and Gram-negative pneumonia (odds ratio, 20.27).

OBJECTIVE: To investigate the virological and immunological impact of a structured treatment interruption (STI) in a cohort of HIV-1 chronically infected patients with a further long-lasting effective virus suppression. METHODS: Twelve HIV-1 chronically infected adults who had maintained viral suppression (< 20 copies/ml) for more than 2 years, as well as a CD4:CD8 ratio > 1 for a median time of 22 months, were included in the study. Participants interrupted their antiretroviral treatment during a maximum period of 30 days or until a viral load rebound > 3000 copies/ml was detected. The same prior antiretroviral regimen was resumed after STI. Kinetics of plasma viral rebound was evaluated every 2 days during the treatment interruption period. Flow cytometry and cell proliferation assays were performed before and after STI. Genotypic resistance was assessed at the time of treatment resumption. RESULTS: No adverse events occurred during the interruption period. In two patients no viral rebound was detected after 30 days of treatment interruption. In the remaining 10 patients, viral load became detectable (> 20 copies/ml) at a median time of 14 days after treatment interruption. Afterwards, viral load increased exponentially with a mean t1/2 of 1.6 days. Treatment was successfully resumed in all patients. No resistance-conferring mutations associated with the pre-interruption antiretroviral regimen were detected. The percentage of CD4 and CD8 lymphocytes did not vary during the STI period; however, the level of expression of T-cell activation antigen CD38 on CD8 T cells increased significantly in response to viral rebound. Four patients gained T-helper cell responses to recall antigens (tuberculin and tetanus toxoid), two of who developed an HIV-specific response to p24. CONCLUSIONS: STI in chronically HIV-1-infected patients is not associated with reductions in CD4 T lymphocytes or to clinical complications in this group of patients after 2 years of effective plasma viral suppression. Viral load rebounds in most but not all patients, without evidence of selection of resistance-conferring mutations. Thereafter, viraemia can be effectively controlled by antiretroviral agent reintroduction. HIV-specific T-helper cell responses may be achieved after one cycle of treatment interruption suggesting some degree of immune-stimulation. These data do not discard consecutive cycles of STI as a therapeutic strategy to boost HIV-specific immunity in order to maintain viral replication under effective control.

Chimeric antigen receptor T (CAR-T) cell therapies have transformed the treatment of relapsed/refractory (R/R) B-cell malignancies and multiple myeloma by redirecting activated T cells to CD19- or BCMA-expressing tumor cells. However, this approach has yet to be approved for acute myeloid leukemia (AML), the most common acute leukemia in adults and the elderly. Simultaneously, CAR-T cell therapies continue to face significant challenges in the treatment of solid tumors. The primary challenge in developing CAR-T cell therapies for AML is the absence of an ideal target antigen that is both effective and safe, as AML cells share most surface antigens with healthy hematopoietic stem and progenitor cells (HSPCs). Simultaneously targeting antigen expression on both AML cells and HSPCs may result in life-threatening on-target/off-tumor toxicities such as prolonged myeloablation. In addition, the immunosuppressive nature of the AML tumor microenvironment has a detrimental effect on the immune response. This review begins with a comprehensive overview of CAR-T cell therapy for cancer, covering the structure of CAR-T cells and the history of their clinical application. It then explores the current landscape of CAR-T cell therapy in both hematologic malignancies and solid tumors. Finally, the review delves into the specific challenges of applying CAR-T cell therapy to AML, highlights ongoing global clinical trials, and outlines potential future directions for developing effective CAR-T cell-based treatments for relapsed/refractory AML.

The hypothalamic peptide, nesfatin-1, derived from the precursor NEFA/nucleobindin 2 (NUCB2), was recently identified as anorexigenic signal, acting in a leptin-independent manner. Yet its participation in the regulation of other biological functions gated by body energy status remains unexplored. We show herein that NUCB2/nesfatin-1 is involved in the control of female puberty. NUCB2/nesfatin mRNA and protein were detected at the hypothalamus of pubertal female rats, with prominent signals at lateral hypothalamus (LHA), paraventricular (PVN), and supraoptic (SON) nuclei. Hypothalamic NUCB2 expression raised along pubertal transition, with detectable elevations of its mRNA levels at LHA, PVN, and SON, and threefold increase of its total protein content between late-infantile and peripubertal periods. Conditions of negative energy balance, such as 48 h fasting or sustained subnutrition, decreased hypothalamic NUCB2 mRNA and/or protein levels in pubertal females. At this age, central administration of nesfatin-1 induced modest but significant elevations of circulating gonadotropins, whose magnitude was notably augmented in conditions of food deprivation. Continuous intracerebroventricular infusion of antisense morpholino oligonucleotides (as-MONs) against NUCB2 along pubertal maturation, which markedly reduced hypothalamic NUCB2 protein content, delayed vaginal opening and decreased ovarian weights and serum luteinizing hormone (LH) levels. In contrast, in adult female rats, intracerebroventricular injection of nesfatin did not stimulate LH or follicle-stimulating hormone secretion; neither did central as-MON infusion alter preovulatory gonadotropin surges, despite suppression of hypothalamic NUCB2. In sum, our data are the first to disclose the indispensable role of NUCB2/nesfatin-1 in the central networks driving puberty onset, a function that may contribute to its functional coupling to energy homeostasis.

BACKGROUND: Mineral metabolism parameters may play a role in the survival of patients with chronic kidney disease (CKD). METHODS: In the CORES Study, we analysed the association between calcium, phosphorus and PTH and mortality (all-cause and cardiovascular) in 16 173 haemodialysis (HD) patients over 18 years from six Latin American countries, who underwent haemodialysis up to 54 months. Unadjusted, case-mix-adjusted and time-dependent multivariable-adjusted hazard ratio (HR) of death were calculated for categories of serum albumin-corrected calcium (Ca(Alb)), phosphorus and PTH using as 'reference values' the range in which the lowest death rate was observed. Age, gender, vitamin D treatment, diabetes, vintage, vascular access, weight, blood pressure and laboratory variables (serum albumin, haemoglobin, creatinine, ferritin and Kt/V) were used as confounding variables. RESULTS: Low (<9.5 mg/dL) and high (>10.5 mg/dL) Ca(Alb) increased the HR for all-cause mortality. Low (<9.0 mg/dL) Ca(Alb) increased the HR for cardiovascular mortality. High phosphorus (>5.5 mg/dL) increased the HR for both all-cause and cardiovascular mortality. Low phosphorus (<4.0 and <3.0 mg/dL) increased the HR for both all-cause and cardiovascular mortality. Furthermore, low (<150 pg/mL) and high (>500 and >300 pg/mL) PTH increased the HR for both all-cause and cardiovascular mortality. In addition, only phosphorus >6.0 mg/dL increased the HR for cardiovascular hospitalizations. No effect was observed with Ca(Alb) or PTH. CONCLUSIONS: In summary, in 16,173 HD patients, elevated and reduced serum levels of albumin-corrected calcium, phosphorus and PTH levels were associated with increments in all-cause mortality. Similar results were obtained when only cardiovascular mortality was analysed.

Seventy-seven subjects infected with human immunodeficiency virus were randomized to switch from protease inhibitor (PI) therapy to nevirapine therapy (group A; n=26) or to efavirenz therapy (group B; n=25) or to continue PI therapy (group C; n=26). At month 12, viral suppression had been maintained in 96% of patients in group A, 92% of patients in group B, and 92% of patients in group C. A significant increase in the CD4(+) level was observed in all 3 groups. In group A, lipid profiles improved, whereas levels of gamma-glutamiltransferase and alanine aminotransferase significantly increased; 1 subject interrupted treatment because of hepatotoxicity. In group B, an increase in gamma-glutamiltransferase levels was also observed, and 3 patients interrupted treatment because of central nervous system symptoms. Two patients in group C withdrew therapy. Quality of life significantly improved for groups A and B. In patients receiving effective PI-based therapy, the replacement of the PI with either nevirapine or efavirenz is safe and virologically effective.

BACKGROUND: Low bone mineral density (BMD) is an emerging metabolic condition in HIV-infected patients; however, data on progression of this disease are scarce. METHODS: We studied 671 patients with at least one dual-energy X-ray absorptiometry scan (391 of them ≥2 scans) to determine the prevalence and progression of BMD and establish related factors. Linear regression and logistic polytomic regression were used for the cross-sectional study and mixed effects and generalized estimating equations were used for the longitudinal study. RESULTS: Osteopenia and osteoporosis were diagnosed in 47.5 and 23%, respectively. Progression to bone demineralization was observed in 28% of the patients over a median of 2.5 years (12.5% progressed to osteopenia and 15.6% to osteoporosis). In the 105 patients with at least 5 years of follow-up, progression was 47% (18% to osteopenia; 29% to osteoporosis). Factors associated with bone loss and progression were age [odds ratio (OR) 1.07; 95% confidence interval (CI) 1.05-1.08; P < 0.0001], male sex (OR 2.23; 95% CI 1.77-2.8; P < 0.0001), low body mass index (OR 1.14; 95% CI 1.11-1.17; P < 0.0001), time on protease inhibitor (OR 1.18; 95% CI 1.12-1.24; P < 0.0001), time on tenofovir (OR 1.08; 95% CI 1.03-1.14; P < 0.0019), and current use of protease inhibitors (OR 1.64; 95% CI 1.35-2.04; P < 0.0001). CONCLUSIONS: Our results show a high prevalence of and considerable progression to osteopenia/osteoporosis in our cohort. Our findings support the importance of applying adequate strategies to prevent bone demineralization and of close monitoring of BMD in HIV-infected patients, specifically in at-risk patients who are taking antiretrovirals that affect bone mineralization.

BACKGROUND: Liver damage is frequently seen in HIV-positive subjects, often resulting from coinfection with hepatitis B and/or C viruses (HCV), alcohol abuse, etc. However, the etiology of liver disease still remains unknown for a small subset of individuals. METHODS: Cryptogenic liver disease (CLD) was defined as persistently elevated aminotransferases levels in the absence of hepatitis C and/or B viruses replication and of other common causes of liver disease (alcohol, medications, etc). We identified cases initially meeting this definition by examining all HIV-positive subjects attended during the year 2004 in 2 large HIV clinics in Spain. Their clinical charts were retrospectively reviewed, and their assessment completed when needed to rule out other less frequent causes of liver disease. The stage of liver fibrosis was assessed by liver biopsy and/or elastography. To assess which factors could be associated with CLD, HIV-positive controls were chosen and matched by age, gender, and CD4 status. RESULTS: CLD was diagnosed in 17 (0.5%) out of 3200 HIV-positive patients. Their mean age was 43 years, 82.4% were male, and 76% had acquired HIV through homosexual relationships. The mean time from HIV diagnosis was >15 years, and all patients had been exposed to antiretroviral therapy. Nevirapine, stavudine, and didanosine were the drugs more frequently used by this subset of patients. None of them had liver function test abnormalities before initiating antiretroviral therapy. Advanced liver fibrosis (F3-F4 Metavir scores) was recognized in 10 (58.8%) individuals, and 9 (52.9%) had developed symptomatic liver complications, including ascites (8), portal thrombosis (6), variceal bleeding (5), and encephalopathy (2). In the case-control analysis, prolonged didanosine exposure was the only independent predictor of developing CLD in this population. CONCLUSIONS: CLD is an uncommon condition in HIV-positive individuals and might be associated with prolonged didanosine exposure. It may evolve causing severe liver complications, with variceal bleeding and portal thrombosis being particularly frequent.

BACKGROUND: Numerous studies have shown that baseline drug resistance patterns may influence the outcome of antiretroviral therapy. Therefore, guidelines recommend drug resistance testing to guide the choice of initial regimen. In addition to optimizing individual patient management, these baseline resistance data enable transmitted drug resistance (TDR) to be surveyed for public health purposes. The SPREAD program systematically collects data to gain insight into TDR occurring in Europe since 2001. METHODS: Demographic, clinical, and virological data from 4140 antiretroviral-naive human immunodeficiency virus (HIV)-infected individuals from 26 countries who were newly diagnosed between 2008 and 2010 were analyzed. Evidence of TDR was defined using the WHO list for surveillance of drug resistance mutations. Prevalence of TDR was assessed over time by comparing the results to SPREAD data from 2002 to 2007. Baseline susceptibility to antiretroviral drugs was predicted using the Stanford HIVdb program version 7.0. RESULTS: The overall prevalence of TDR did not change significantly over time and was 8.3% (95% confidence interval, 7.2%-9.5%) in 2008-2010. The most frequent indicators of TDR were nucleoside reverse transcriptase inhibitor (NRTI) mutations (4.5%), followed by nonnucleoside reverse transcriptase inhibitor (NNRTI) mutations (2.9%) and protease inhibitor mutations (2.0%). Baseline mutations were most predictive of reduced susceptibility to initial NNRTI-based regimens: 4.5% and 6.5% of patient isolates were predicted to have resistance to regimens containing efavirenz or rilpivirine, respectively, independent of current NRTI backbones. CONCLUSIONS: Although TDR was highest for NRTIs, the impact of baseline drug resistance patterns on susceptibility was largest for NNRTIs. The prevalence of TDR assessed by epidemiological surveys does not clearly indicate to what degree susceptibility to different drug classes is affected.

BACKGROUND: Efavirenz has been associated with neuropsychiatric disorders, although little is known about its long-term toxicity. OBJECTIVE: To assess neuropsychiatric disorders and their relation to efavirenz plasma levels as well as quality of life, psychologic status, and adherence in HIV-infected patients on long-term efavirenz-based antiretroviral therapy. METHODS: Cross-sectional study comparing 60 patients on an efavirenz-based approach (EFV group) and 60 patients on a protease inhibitor-containing regimen (PI group) for at least 1 year. Adverse events, efavirenz plasma levels, quality of life, psychologic status, and adherence were assessed. RESULTS: The mean time on treatment was 91.1 +/- 39.5 weeks in the EFV group and 119.9 +/- 67.4 weeks in the PI group. Mild dizziness, sadness, mood changes, irritability, lightheadedness, nervousness, impaired concentration, abnormal dreams, and somnolence were reported more frequently in the EFV group than in the PI group (P < 0.05). Forty-nine of 60 patients presented with therapeutic efavirenz plasma levels (range: 1.0-4.0 mg/L). Efavirenz plasma levels were similar in subjects with and without neuropsychiatric disorders. No significant differences were found between the EFV group and the PI group regarding quality of life and psychologic status. Sixty percent of patients in the EFV group and 55% in the PI group reported adherence >/=95%. CONCLUSIONS: Mild and clinically tolerable neuropsychiatric disorders may persist in patients after a mean of 2 years using an efavirenz-based approach. Quality of life and psychologic status remained good in both study groups. Interventions to enhance long-term adherence should be applied in clinical practice.

BACKGROUND: Although antiretroviral therapy improves immune response, some human immunodeficiency virus-infected patients present unsatisfactory CD4 T cell recovery despite achieving viral suppression, resulting in increased morbidity and mortality. METHODS: Cross-sectional, case-control study to characterize the mechanism and to identify predictive factors of poor immune response. We included 230 patients who were receiving highly active antiretroviral therapy and who had a viral load <50 copies/mL for >2 years; 95 were "discordant" (case patients; CD4 T cell count always <350 cells/microL), and 135 were "concordant" (control subjects). Activation markers, CD4 T cell death (necrosis, intrinsic apoptosis, and extrinsic apoptosis), and caspase-3 were measured. Clinical parameters, particularly antiretroviral combinations, were correlated with immune recovery. RESULTS: Discordant patients showed higher levels of activation markers, mainly in CD4 T cells (p < .001), and higher rates of spontaneous cell death (P < .001). Rates of activation and rates of CD4 T cell death (mainly by intrinsic apoptosis) were the best predictive factors for immune recovery, along with nadir CD4 T cell count. Patients who were receiving a protease inhibitor-based regimen were more likely to be discordant and showed higher rates of activation (P= .011), higher rates of CD4 T cell death (P = .033), and a lower nadir CD4 T cell count (P < .001). Multivariate analysis, however, ruled out any effect of protease inhibitors on immune recovery. No differences were observed between the use of tenofovir-emtricitabine (Truvada) and the use of abacavir-lamivudine (Kivexa). CONCLUSIONS: CD4 T cell apoptosis by the intrinsic pathway represents the determinant mechanism of the unsatisfactory immune recovery and should be targeted to manage therapy for discordant patients. The predictive value of low nadir CD4 T cell count for a poor immune recovery led us to consider starting antiretroviral therapy earlier. No differences were observed among antiretrovirals in terms of immune recovery.

BACKGROUND: Patterns of cause-specific mortality in individuals infected with human immunodeficiency virus type 1 (HIV-1) are changing dramatically in the era of antiretroviral therapy (ART). METHODS: Sixteen cohorts from Europe and North America contributed data on adult patients followed from the start of ART. Procedures for coding causes of death were standardized. Estimated hazard ratios (HRs) were adjusted for transmission risk group, sex, age, year of ART initiation, baseline CD4 count, viral load, and AIDS status, before and after the first year of ART. RESULTS: A total of 4237 of 65 121 (6.5%) patients died (median, 4.5 years follow-up). Rates of AIDS death decreased substantially with time since starting ART, but mortality from non-AIDS malignancy increased (rate ratio, 1.04 per year; 95% confidence interval [CI], 1.0-1.1). Higher mortality in men than women during the first year of ART was mostly due to non-AIDS malignancy and liver-related deaths. Associations with age were strongest for cardiovascular disease, heart/vascular, and malignancy deaths. Patients with presumed transmission through injection drug use had higher rates of all causes of death, particularly for liver-related causes (HRs compared with men who have sex with men: 18.1 [95% CI, 6.2-52.7] during the first year of ART and 9.1 [95% CI, 5.8-14.2] thereafter). There was a persistent role of CD4 count at baseline and at 12 months in predicting AIDS, non-AIDS infection, and non-AIDS malignancy deaths. Lack of viral suppression on ART was associated with AIDS, non-AIDS infection, and other causes of death. CONCLUSIONS: Better understanding of patterns of and risk factors for cause-specific mortality in the ART era can aid in development of appropriate care for HIV-infected individuals and inform guidelines for risk factor management.

We assessed the impact of an efavirenz-containing regimen versus a protease inhibitor-containing regimen on quality of life, emotional status, and adherence of HIV-1-infected patients. In addition, we sought to define the adverse events associated with these treatments, with a special focus on central nervous system disorders in the efavirenz treatment group. This prospective, randomized, two-arm, controlled study included 100 patients for whom initial treatment with a protease inhibitor-containing regimen failed. Patients were randomized to start treatment with two nucleoside retrotranscriptase inhibitors plus efavirenz (group 1; 51 patients) or two nucleoside retrotranscriptase inhibitors plus one or more new protease inhibitors (group 2; 49 patients). Quality of life was assessed by a five-point item adapted from the HIV questionnaire of the Medical Outcomes Study, emotional status was evaluated by the Profile of Mood State questionnaire, and patients self-reported adherence. Data were analyzed by both an as-treated method and an intention-to-treat-last observation carried forward method. Patients in group 1 reported the following findings at week 4: dizziness (66%), abnormal dreaming (48%), light-headedness (37%), and difficulty sleeping (35%). At week 24, dizziness (13%; p <.001), abnormal dreaming (18%; p =.002), light-headedness (13%; p =.01), difficulty sleeping (7%; p =.001), and nervousness (13%; p =.01) decreased in these patients. Irritability, abnormal dreaming, and nervousness persisted at week 48 in 13%, 10%, and 8% of group 1 patients, respectively. Patients in group 2 reported the following findings at week 4: light-headedness (8%), dizziness (5%), difficulty sleeping (4%), nervousness (4%), and headaches (3%). Patients in group 2 reported the following findings at week 48: difficulty sleeping (4%), nervousness (3%), headaches (3%), and light-headedness (2%). In group 1, quality of life (p <.001) and emotional status (week 48; p =.004) improved, both of which were better than those in group 2 (p =.001). Both groups maintained high levels of medication adherence, and no significant differences in the number of patients who had viral loads of <200 copies/mL at week 48 were found (78% of group 1 patients vs. 85% of group 2 patients; p = not significant). At week 48, the mean CD4 cell count +/- SD was 497 +/- 224/mm3 in group 1 and 539 +/- 298/mm3 in group 2 (p = not significant). Despite similar immunologic and virologic outcomes, a second-line efavirenz-containing regimen improved quality of life of HIV-1-infected patients compared with a second-line protease inhibitor-containing regimen. However, close follow-up of patients receiving treatment with efavirenz-based regimens is recommended, especially for those with previous emotional disturbances due to central nervous system disorders in the short term and those with persistence of a low percentage of these disorders in the long term.

BACKGROUND: It is unknown if tenofovir disoproxil fumarate (TDF), which is often coformulated with the lipid-neutral emtricitabine (FTC), has a lipid-lowering effect. METHODS: We performed a randomized, crossover, double-blind, placebo-controlled clinical trial on human immunodeficiency virus type 1 (HIV-1)-infected subjects with HIV-1 RNA < 50 copies/mL during ≥6 months on stable darunavir/ritonavir (800/100 mg once daily) or lopinavir/ritonavir (400/100 mg twice daily) monotherapy, fasting total cholesterol (TC) ≥200 mg/dL or low-density lipoprotein cholesterol (LDL-c) ≥130 mg/dL, and no lipid-lowering drugs. In arm 1, TDF/FTC was added for 12 weeks, followed by 12 weeks of placebo (washout) and 12 additional weeks of placebo (placebo period). Subjects in arm 2 added placebo for 12 weeks (placebo period) followed by TDF/FTC for 12 weeks and placebo for 12 additional weeks (washout). The primary endpoint was change in median fasting TC levels. RESULTS: Of 46 subjects enrolled, 56% received darunavir/ritonavir and 44% lopinavir/ritonavir. Exposure to TDF/FTC reduced TC from 234 to 205 mg/dL (P < .001), LDL-c from 155 to 128 mg/dL (P < .001), and high-density lipoprotein cholesterol (HDL-c) from 50.3 to 44.5 mg/dL (P < .001). It also decreased the proportion of subjects with fasting TC ≥200 mg/dL from 86.7% to 56.8% (P = .001), and LDL-c ≥130 mg/dL from 87.8% to 43.9% (P < .001). After 12 weeks, TDF/FTC exposure was associated with lower TC and LDL-c levels than placebo (P = .001 and P = .002, respectively). The TC/HDL-c ratio and triglyceride levels did not change with TDF/FTC exposure. CONCLUSIONS: Coformulated TDF/FTC has an intrinsic lipid-lowering effect, likely attributable to TDF. CLINICAL TRIALS REGISTRATION: NCT01458977.

Drosophila telomeres do not have typical telomerase repeats. Instead, two families of non-LTR retrotransposons, HeT-A and TART, maintain telomere length by occasional transposition to the chromosome ends. Despite the work on Drosophila telomeres, its evolutionary origin remains controversial. Herein we describe a novel telomere-specific retroelement that we name TAHRE (Telomere-Associated and HeT-A-Related Element). The structure of the three telomere-specific elements indicates a common ancestor. These results suggest that preexisting transposable elements were recruited to perform the cellular function of telomere maintenance. A recruitment similar to that of a retrotransposal reverse transcriptase has been suggested as the common origin of telomerases.

Dolutegravir is a novel integrase strand-transfer inhibitor that displays potent in vitro activity and a remarkably different resistance profile. Its robust pharmacokinetic/pharmacodynamic properties - long plasma t1/2, high plasma inhibition quotient, and slow dissociation rate from the integrase complex - suggest it should present a high barrier to resistance development. This has been confirmed in pivotal phase III studies of initial therapy, with none out of 1,118 treated individuals selecting resistance-associated mutations at the integrase or reverse transcriptase. In integrase-naive subjects with virological failure, a rescue intervention with dolutegravir has shown significantly higher rates of virological suppression than raltegravir, as well as significantly lower rates of selection of resistance both at the integrase and against the optimized background. Unexpectedly, a mutation rarely selected in this scenario (R263K) induces a fitness cost that prevents HIV-1 from evading drug pressure, and accumulation of further secondary mutations does not occur and has not been able to compensate the replication capacity deficit in the aftermath of the appearance of a single drug resistance mutation. Therefore, both in vitro and in vivo, it leads the virus to a previously unnoticed evolutionary pathway with low chances to develop resistance to both dolutegravir and other families of antiretrovirals present in the background. This high genetic barrier to resistance development in early stages of antiretroviral treatment can help preserve future treatment options in patients who fail antiretroviral therapy.

OBJECTIVES: To estimate mortality rates and prognostic factors in HIV-positive patients who started combination antiretroviral therapy between 1996-1999 and survived for more than ten years. METHODS: We used data from 18 European and North American HIV cohort studies contributing to the Antiretroviral Therapy Cohort Collaboration. We followed up patients from ten years after start of combination antiretroviral therapy. We estimated overall and cause-specific mortality rate ratios for age, sex, transmission through injection drug use, AIDS, CD4 count and HIV-1 RNA. RESULTS: During 50,593 person years 656/13,011 (5%) patients died. Older age, male sex, injecting drug use transmission, AIDS, and low CD4 count and detectable viral replication ten years after starting combination antiretroviral therapy were associated with higher subsequent mortality. CD4 count at ART start did not predict mortality in models adjusted for patient characteristics ten years after start of antiretroviral therapy. The most frequent causes of death (among 340 classified) were non-AIDS cancer, AIDS, cardiovascular, and liver-related disease. Older age was strongly associated with cardiovascular mortality, injecting drug use transmission with non-AIDS infection and liver-related mortality, and low CD4 and detectable viral replication ten years after starting antiretroviral therapy with AIDS mortality. Five-year mortality risk was <5% in 60% of all patients, and in 30% of those aged over 60 years. CONCLUSIONS: Viral replication, lower CD4 count, prior AIDS, and transmission via injecting drug use continue to predict higher all-cause and AIDS-related mortality in patients treated with combination antiretroviral therapy for over a decade. Deaths from AIDS and non-AIDS infection are less frequent than deaths from other non-AIDS causes.

CRANIum, a cross-sectional epidemiology study in Western Europe and Canada, was conducted to describe and compare the prevalence of a positive screen for neurocognitive impairment (NCI), depressive symptoms, and anxiety in an HIV-positive population either receiving combination antiretroviral therapy (cART) or who were naive to antiretroviral therapy (ART). HIV-positive patients ≥18 years of age attending a routine medical follow-up visit and able to complete the designated screening tools were eligible for study inclusion. The Brief Neurocognitive Screen was used to assess NCI; depressive and anxiety symptoms were assessed using the Hospital Anxiety and Depression Scale. The evaluable patient population (N = 2863) included 1766 men (61.7%) and 1096 (38.3%) women. A total of 1969 patients were cART-experienced (68.8%), and 894 were ART-naive (31.2%). A positive screen for NCI was found in 41.5% of patients (cART-experienced, 42.5%; ART-naive, 39.4%; p = 0.12). A positive screen for depressive symptoms was found in 15.7% of patients (cART-experienced, 16.8%; ART-naive, 13.3%; p = 0.01), whereas 33.3% of patients screened positive for anxiety (cART-experienced, 33.5%; ART-naive, 32.8%; p = 0.71). A greater percentage of women compared with men screened positive for NCI (51.78% vs. 35.1%; p < 0.0001) and depressive symptoms (17.9% vs. 14.3%; p = 0.01). These data suggest that neurocognitive and mood disorders remain highly prevalent in HIV-infected patients. Regular mental health screening in this population is warranted.