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BackgroundUnderstanding the predictors of metabolic disorders in persons with HIV/HCV coinfection post-HCV therapy is crucial for improving patient outcomes. Since immune checkpoint proteins are usually upregulated in these persons with HIV/HCV coinfection, we aimed to evaluate the association between plasma immune checkpoint proteins at baseline (before HCV therapy) and metabolic disturbances during the follow-up (about 5 years after successful HCV treatment) in persons with HIV/HCV coinfection.MethodsWe performed a retrospective study on 80 persons with HIV/HCV coinfection with advanced fibrosis or cirrhosis who cleared HCV infection after successful HCV therapy and were followed for about 5 years after completion of HCV treatment. Plasma samples were collected at baseline. Immune checkpoint proteins were analyzed using a Luminex 200™ analyzer. Outcomes were the development of a metabolic event (type 2 diabetes mellitus and/or dyslipidemia) and the change in Triglycerides and glucose (TyG) index.ResultsDuring follow-up, 21 (26%) patients developed metabolic events (type 2 diabetes mellitus/dyslipidemia), and 29 (46.0%) patients had an increase in TyG during the follow-up. Low baseline values of BTLA and LAG-3, two immune checkpoint proteins, were associated with the development of metabolic events (aAMR = 0.69 and aAMR = 0.71, respectively) and with increases in TyG values (aAMR = 0.72 and aAMR = 0.70, respectively). In addition, other immune checkpoint proteins were also inversely associated with increases in TyG.ConclusionWe discovered that low plasma levels of BTLA and LAG-3 before HCV therapy significantly correlate with an increased risk of developing metabolic disorders after treatment.

Background: Despite effective antiretroviral therapy, people with HIV (PWH) experience persistent systemic inflammation and increased morbidity and mortality. Modulating the gut microbiome through fecal microbiota transplantation (FMT) represents a novel therapeutic strategy. We aimed to evaluate proteomic changes in inflammatory pathways following repeated, low-dose FMT versus placebo., Methods: This double-masked, placebo-controlled pilot study assessed the proteomic impacts of weekly FMT versus placebo treatment over 8 weeks on systemic inflammation in 29 PWH receiving stable antiretroviral therapy (ART). Three stool donors with high Faecalibacterium and butyrate profiles were selected, and their individual stools were used for FMT capsule preparation. Proteomic changes in 345 inflammatory proteins in plasma were quantified using the proximity extension assay, with samples collected at baseline and at weeks 1, 8, and 24. Concurrently, we characterized shifts in the gut microbiota composition and annotated functions through shotgun metagenomics. We fitted generalized additive models to evaluate the dynamics of protein expression. We selected the most relevant proteins to explore their correlations with microbiome composition and functionality over time using linear mixed models., Results: FMT significantly reduced the plasma levels of 45 inflammatory proteins, including established mortality predictors such as IL6 and TNF-α. We found notable reductions persisting up to 16 weeks after the final FMT procedure, including in the expression of proteins such as CCL20 and CD22. We identified changes in 46 proteins, including decreases in FT3LG, IL6, IL10RB, IL12B, and IL17A, which correlated with multiple bacterial species. We found that specific bacterial species within the Ruminococcaceae, Succinivibrionaceae, Prevotellaceae families, and the Clostridium genus, in addition to their associated genes and functions, were significantly correlated with changes in inflammatory markers., Conclusions: Targeting the gut microbiome through FMT effectively decreased inflammatory proteins in PWH, with sustained effects. These findings suggest the potential of the microbiome as a therapeutic target to mitigate inflammation-related complications in this population, encouraging further research and development of microbiome-based interventions. Video Abstract., (© 2024. The Author(s).)

Background: Our aim was to analyze the effects of a multicomponent exercise program (MEP) on frailty and physical performance in older adults with HIV (OAWH) since exercise can reverse frailty in the older population overall, but there is no data for OAWH., Methods: A prospective longitudinal study with intervention and control group was designed. Sedentary adults 50 or over with and without HIV were included. The intervention was a 12-week home-based MEP. Dependent variables were frailty (frailty phenotype), physical performance (Senior Fitness Test), muscle mass (ASMI) by bioimpedance. Pre- and postintervention measurements were analyzed using McNemar's test for categorical variables and the Wilcoxon signed-rank test for quantitative variables., Results: 40 OAWH and 20 OA without HIV. The median age was 56.5 years. 23.3% were women. The prevalence of frailty was 6.6% with no frail HIV-negative participants. Three of the four frail HIV-participants transitioned two (50%) from frail to prefrail and one (25%) to robust after the MEP. In participants with an adherence ≥50%, physical performance was significantly improved [basal vs. 12 week]: upper extremity strength [13 (13-15) vs. 16 (15-19), p = 0.0001], lower extremity strength [13 (11-16) vs. 15 (13-16), p = 0.004], aerobic endurance [62 (55-71) vs. 66 (58-80), p = 0.005]. Participants with low adherence experienced a significant worsening in ASMI [8.35 (7.44-9.26) vs. 7.09 (6.08-8.62), p = 0.03]., Conclusion: A 12-week MEP enhances frailty by increasing robustness in OAWH, and improves physical performance, and preserves muscle mass in older adults with good adherence to the MEP independently of HIV status., Competing Interests: FB reports research grant from MSD, non-financial support from Nestlé, and personal fees from ViiV Healthcare, Gilead, AMGEN, UCB, Grünenthal, Abbott, Vegenat, and Nestlé. MS-C reports research grant from Gilead, educational grants from MSD, Gilead, and ViiV Healthcare, and personal fees and non-financial support from Gilead. PR reports grants and personal fees from Gilead and personal fees from ViiV Healthcare and Abbvie. BV-B reports grants from Nutricia, and personal fees from Abbott nutrition, and Fresenius Kabi. EM reports conference attendance support from Gilead and ViiV Healthcare. JM-S reports personal fees from ViiV Healthcare, Janssen, Gilead, and MSD, non-financial support from ViiV Healthcare, Jannsen, and Gilead, and research grants from Gilead. FD has received research grants or honoraria for lectures or for participation in advisory boards from Gilead, ViiV-Healthcare, and unrestricted grants from ViiV Healthcare and Gilead. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Brañas, Díaz-Álvarez, Fernández-Luna, Vásquez-Brolen, García-Molina, Moreno, Ryan, Martínez-Sanz, Luna, Martínez, Dronda and Sánchez-Conde.)

Metabolic-dysfunction-associated fatty liver disease (MAFLD) is a comorbidity that generally increases in people living with HIV (PLWH). This condition is usually accompanied by persistent inflammation and premature immune system aging. In this prospective cohort study, we describe a straightforward methodology for quantifying biomarkers of aging, such as DNA methylation and telomere length, in PLWH and in the context of another relevant condition, such as MAFLD. Fifty-seven samples in total, thirty-eight from PLWH and nineteen from non-PLWH participants with or without MAFLD, were obtained and subjected to DNA extraction from peripheral blood mononuclear cells (PBMCs). Global DNA methylation and telomere length quantification were performed using an adapted enzyme-linked immunosorbent assay (ELISA) and qPCR, respectively. The quantification results were analysed and corrected by clinically relevant variables in this context, such as age, sex, and metabolic syndrome. Our results show an increased association of these biomarkers in PLWH regardless of their MAFLD status. Thus, we propose including the quantification of these age-related factors in studies of comorbidities. This will allow a better understanding of the effect of comorbidities of HIV infection and MAFLD and prevent their effects in these populations in the future., (© 2023. BioMed Central Ltd., part of Springer Nature.)

HIV infection is considered a scenario of accelerated aging. Previous studies have suggested a link between aging, frailty, and gut dysbiosis, but there is a knowledge gap regarding the HIV population. Our objective was to compare the fecal bacteriome of older people with HIV (PWH) and non-HIV controls, and to assess potential links between gut dysbiosis and frailty. A total of 36 fecal samples (24 from PWH and 12 from non-HIV controls) were submitted to a metataxonomic analysis targeting the V3-V4 hypervariable region of the 16S rRNA gene. High-quality reads were assembled and classified into operational taxonomic units. Alpha diversity, assessed using the Shannon index, was higher in the control group than in the HIV group ( p < 0.05). The relative abundance of the genus Blautia was higher in the HIV group ( p < 0.001). The presence of Blautia was also higher in PWH with depression ( p = 0.004), whereas the opposite was observed for the genus Bifidobacterium ( p = 0.004). Our study shows shifts in the composition of the PWH bacteriome when compared to that of healthy controls. To our knowledge, this is the first study suggesting a potential link between depression and gut dysbiosis in the HIV population.

Background: To understand the effects of frailty, geriatric syndromes, and comorbidity on quality of life and mortality in older adults with HIV (OAWH)., Methods: Cross-sectional study of the FUNCFRAIL multicenter cohort. The setting was outpatient HIV-Clinic. OAWH, 50 year or over were included. We recorded sociodemographic data, HIV infection-related data, comorbidity, frailty, geriatric syndromes (depression, cognitive impairment, falls and malnutrition), quality of life (QOL) and the estimated risk of all-cause 5-year mortality by VACS Index. Association of frailty with geriatric syndromes and comorbidity was evaluated using the Cochran-Mantel-Haenszel test., Results: Seven hundred ninety six patients were included. 24.7% were women, mean age was 58.2 (6.3). 14.7% were 65 or over. 517 (65%) patients had ≥3 comorbidities, ≥ 1 geriatric syndrome and/or frailty. There were significant differences in the estimated risk of mortality [(frailty 10.8%) vs. (≥ 3 comorbidities 8.2%) vs. (≥ 1 geriatric syndrome 8.2%) vs. (nothing 6.2%); p = 0.01] and in the prevalence of fair or poor QOL [(frailty 71.7%) vs. (≥ 3 comorbidities 52%) vs. (≥ 1 geriatric syndrome 58.4%) vs. (nothing 51%); p = 0.01]. Cognitive impairment was significantly associated to mortality (8.7% vs. 6.2%; p = 0.02) and depression to poor QOL [76.5% vs. 50%; p = 0.01]., Conclusions: Frailty, geriatric syndromes, and comorbidity had negative effects on mortality and QOL, but frailty had the greatest negative effect out of the three factors. Our results should be a wake-up call to standardize the screening for frailty and geriatric syndromes in OAWH in the clinical practice., Trial Registration: NCT03558438., (© 2023. The Author(s).)

People living with HIV-1 and HTLV-2 concomitantly show slower CD4 + T cell depletion and AIDS progression, more frequency of the natural control of HIV-1, and lower mortality rates. A similar beneficial effect of this infection has been reported on HCV coinfection reducing transaminases, increasing the spontaneous clearance of HCV infection and delaying the development of hepatic fibrosis. Given the critical role of CD8 + T cells in controlling HIV-1 infection, we analysed the role of CD8 + T cell-mediated cytotoxic activity in coinfected individuals living with HIV-1. One hundred and twenty-eight individuals living with HIV-1 in four groups were studied: two groups with HTLV-2 infection, including individuals with HCV infection (N = 41) and with a sustained virological response (SVR) after HCV treatment (N = 25); and two groups without HTLV-2 infection, including individuals with HCV infection (N = 25) and with a sustained virological response after treatment (N = 37). We found that CD8 + T cell-mediated HIV-1 inhibition in vitro was higher in individuals with HTLV-2. This inhibition activity was associated with a higher frequency of effector memory CD8 + T cells, higher levels of granzyme A and granzyme B cytolytic enzymes, and perforin. Hence, cellular and soluble cytolytic factors may contribute to the lower HIV-1 pre-ART viral load and the HIV-1 proviral load during ART therapy associated with HTLV-2 infection. Herein, we confirmed and expanded previous findings on the role of HTLV-2 in the beneficial effect on the pathogenesis of HIV-1 in coinfected individuals.

Background: People in their fifties with HIV are considered older adults, but they appear not to be a homogeneous group., Objective: To evaluate the differences among older adults with HIV according to their chronological age and the year of HIV diagnosis., Methods: Cross-sectional study of the FUNCFRAIL cohort. Patients 50 or over with HIV were included and were stratified by both chronological age and the year of HIV diagnosis: before 1996 (long-term HIV survivors [LTHS]) and after 1996. We recorded sociodemographic data, HIV-related factors, comorbidities, frailty, physical function, other geriatric syndromes, and quality of life (QOL)., Results: We evaluated 801 patients. Of these, 24.7% were women, 47.0% were LTHS, and 14.7% were 65 or over. Of the 65 or over patients, 73% were diagnosed after 1996. Higher rates of comorbidities among LTHS were found, being the more prevalent: COPD, history of cancer, osteoarthritis, depression, and other psychiatric disorders while the more prevalent among the 65 or over patients were: hypertension, diabetes, dyslipidemia, cancer, and osteoarthritis. LTHS showed a significantly worse QOL. There were no differences by the year of HIV diagnosis regarding frailty and functional impairment (SPPB <10) but they were more than twice as prevalent in the 65 or over patients compared to the other chronological age groups., Conclusions: A LTHS and a 65 or over person are both "older adults with HIV," but their characteristics and requirements differ markedly. It is mandatory to design specific approaches focused on the real needs of the different profiles., Competing Interests: The authors have declared that no competing interests exist.

While changes in microbiome composition have been associated with HIV, the effect of diet and its potential impact on inflammation remains unclear. Methods: Twenty-seven people living with HIV (PWH) on antiretroviral therapy (ART) were studied. A comprehensive dietary analysis was performed and two types of dietary patterns were determined. We explored the associations of each dietary pattern with gut microbiota and plasma inflammatory biomarkers. Results: We appreciated two dietary patterns, Mediterranean-like (MEL) and one Western-like (WEL). Compared to participants with the WEL pattern, participants with MEL pattern showed higher abundance of Lachnospira (p-value = 0.02) and lower levels of the inflammatory biomarkers D-dimer (p-value = 0.050) and soluble TNF-alpha receptor 2 (sTNFR2) (p-value = 0.049). Men who have sex with men (MSM) with MEL pattern had lower abundance of Erysipelotrichaceae (p-value < 0.001) and lower levels of D-dimer (p-value = 0.026) than MSM with WEL pattern. Conclusion: MEL pattern favours Lachnospira abundance, and protects against Erysipelotrichaceae abundance and higher levels of the inflammatory biomarkers D-dimer and sTNFR2, precursors of inflammatory processes in HIV-infected patients. Our study contributes to understanding the determinants of a healthier diet and its connections with gut microbiota and inflammation.

Objectives: The World Health Organization recommends routinely screening HIV-infected patients with CD4 + T-cell counts <100/μL for cryptococcal infection to prevent cryptococcal meningitis (CM), based on studies in Sub-Saharan Africa where the prevalence of positive cryptococcal antigen (CrAg+) is ≥ 3% in this subgroup. Data about such prevalence in Spain are unavailable and rare in other European countries. Thus, the Spanish AIDS Study Group guidelines do not recommend routinely screening. We aim to determine the prevalence and outcomes of cryptococcal infection in this subgroup of patients in Spain., Methods: We determined CrAg using a lateral flow assay in banked plasma from participants in the cohort of the Spanish AIDS Research Network. Eligible patients had CD4 + T-cell counts ≤100/μL at the time of plasma collection and a follow-up >4 weeks, unless they died., Results: We included 576 patients from June 2004 to December 2017. Of these, 43 were CrAg+ for an overall prevalence of 7.5%. There were no differences depending on birthplace. The CrAg+ was independently associated with a higher mortality at eight weeks (hazard ratio (HR) 5.36, 95% confidence interval (CI) 1.46-19.56) and 6 months (HR 3.12, 95% CI 1.19-8.21). CM was reported in 10 of the 43 CrAg+ patients. There were no cases among negatives. Five patients had CM when the plasma was collected and five developed it during the follow-up. The number of subjects needed to screen to anticipate the diagnosis of one CM case was 114., Conclusions: The CrAg+ prevalence among HIV-infected patients with CD4 + T-cell counts ≤100/μL diagnosed in Spain, both immigrants and native-born Spanish, is >7%. Consequently, the Spanish AIDS Study Group guidelines have to be updated and recommend routine screening for cryptococcal infection in these patients. Future studies should explore whether this recommendation could be firmly applied to other European populations., (Copyright © 2020 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Changes in the microbiota have been linked to persistent inflammation during treated HIV infection. In this pilot double-blind study, we study 30 HIV-infected subjects on antiretroviral therapy (ART) with a CD4/CD8 ratio < 1 randomized to either weekly fecal microbiota capsules or placebo for 8 weeks. Stool donors were rationally selected based on their microbiota signatures. We report that fecal microbiota transplantation (FMT) is safe, not related to severe adverse events, and attenuates HIV-associated dysbiosis. FMT elicits changes in gut microbiota structure, including significant increases in alpha diversity, and a mild and transient engraftment of donor's microbiota during the treatment period. The greater engraftment seems to be achieved by recent antibiotic use before FMT. The Lachnospiraceae and Ruminococcaceae families, which are typically depleted in people with HIV, are the taxa more robustly engrafted across time-points. In exploratory analyses, we describe a significant amelioration in the FMT group in intestinal fatty acid-binding protein (IFABP), a biomarker of intestinal damage that independently predicts mortality. Gut microbiota manipulation using a non-invasive and safe strategy of FMT delivery is feasible and deserves further investigation. Trial number: NCT03008941.

The incidence of classical Hodgkin lymphoma (cHL) in the HIV-1 setting has increased 5-25-fold compared to that observed in the general population. This study aimed to determine whether selected micro RNAs (miRs) and other soluble biomarkers and cellular subsets are dysregulated in cHL and could be used as biomarkers. This was a retrospective and longitudinal matched case-control study of 111 Caucasian, HIV-1-infected adult individuals, including 37 individuals with cHL and 74 with no type of cancer. Immunovirological data, plasma exosome-derived miR-16, miR-20a, miR-21, miR-221, miR-223, miR-106a, miR-185, miR-23, miR-30d, miR-222, miR-146a and miR-324, plasma IL-6, sCD14, sCD27, sCD30, sIL-2R, TNFR1, and cell phenotyping of T and B lymphocytes and natural killer (NK) cells were analyzed. Before cHL diagnosis, miR-20a, miR-21, and sCD30 were higher in cHL ( p = 0.008, p = 0.009 and p = 0.042, respectively), while miR-16 was down-regulated ( p = 0.040). miR-20a and miR-21 were independently associated with cHL ( p = 0.049 and p = 0.035, respectively). The combination of miR-20a and miR-21 showed a good AUC value of 0.832 with a moderate likelihood ratio positive (LR+) value of 5.6 and a slight likelihood ratio negative (LR-) value of 0.23. At cHL diagnosis, miR-20a, miR-21 and miR-324 were overexpressed in cHL ( p = 0.005, p = 0.024, and p = 0.001, respectively), while miR-223, miR-16, miR-185 and miR-106a were down regulated ( p = 0.042, p = 0.007, p = 0.006, and p = 0.002, respectively). In addition, sCD14, sCD27, sCD30 and IL2R levels were higher in these individuals ( p = 0.038, p = 0.010, p = 0.030, p = 0.006, respectively). miR-20a was independently associated with cHL ( p = 0.011). The diagnostic value of miR-20a showed good AUC value of 0.754 ( p = 0.074) with a slight LR+ value of 2 and a slight LR- of 0.25. After chemotherapy, miR-20a was higher in those individuals who had an adverse outcome ( p < 0.001), while sCD14 and sCD30 were higher ( p < 0.001). A specific signature of miRs and cytokines associated with a subsequent cHL diagnosis was found in this study, especially miR-20a and miR-21. Also, another biomarker signature was found at cHL diagnosis, with a relevant discriminant disease value for miR-20a. Of note, miR-20a expression was higher in those individuals who had an adverse clinical outcome after chemotherapy.

Introduction: HIV testing guidelines are poorly implemented in most clinical settings. The best screening strategy and healthcare scenario are still unknown. The aim of our study is to evaluate the impact of a structured HIV testing intervention (DRIVE), compared to HIV testing as routinely performed in clinical practice, in two different clinical settings: a primary care center and an emergency department., Methods: Prospective evaluation of an HIV testing strategy in two clinical settings from the same healthcare area. The DRIVE program included trained nurse practitioners to perform the screening, a questionnaire to assess the risk of exposure and HIV indicator conditions (RE&IC), and rapid HIV tests. The main variables between the DRIVE program and clinical practice were the absolute number of newly diagnosed HIV infections and testing coverage., Results: The DRIVE program included 5,329 participants, of which 51.2% reported at least one positive answer in the questionnaire. The estimated HIV testing coverage was significantly higher in the DRIVE program than in the routine clinical practice (7.17% vs. 0.96%, p < 0.001), and was better in the primary care center than in the emergency department with the two strategies. Twenty-two HIV-positive people were identified, with a rate of 8.6‰ in the emergency department vs. 2.2‰ in the primary care center (p = 0.001). A higher rate of new HIV diagnoses was found in the DRIVE program compared to routine clinical practice (29.6 vs. 3.1 per 100,000 patients attended; p < 0.001)., Conclusions: An easy-to-implement, structured intervention increased the absolute number of new HIV diagnoses and HIV tests, compared to routine clinical practice., Competing Interests: Santiago Moreno has been involved in speaking activities and has received grants for research from Abbott, Boehringer&Ingelheim, Bristol-Myers Squibb, Gilead, Glaxo Smith Kline, Janssen Cilag, Merck Sharp&Dohme, Pfizer, Roche, and Schering Plough. María Jesús Pérez Elias has done consulting work for Abbvie, Boehringer Ingelheim, ViiV Healthcare, Gilead Sciences, and Janssen Cilag; she has received fellowships for clinical research from ViiV Healthcare, Gilead Sciences, Janssen, and Merck-Sharp & Dome, and has received financial compensation for being a speaker at events funded by Gilead Sciences, Janssen Cilag, Merck-Sharp & Dome and ViiV Healthcare. The other authors declare that they have no competing interests. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

In 1986, a new syndrome was described in Taiwan secondary to hypervirulent K. pneumoniae (hvKP), and its main feature was the ability to cause severe infection in young and immunocompetent hosts. Their virulence is explained by the efficient acquisition of iron and an increase in capsule production, which confer the characteristic hypermucoviscous phenotype. Most of these cases have been described in Asia and subsequently spread to America and Europe, where their prevalence is much lower. We present four cases of bacteremia and liver abscesses secondary to hypervirulent K. pneumoniae, two of them associated with endophthalmitis . K. pneumoniae isolates recovered from two of the patients belonged to capsular serotype K1 (genes wzx&#95;K1 and magA ), while the other two were K2 (gene wzy&#95;K2 ). Both of the K1 isolates were classified into a ST23, and isolates of serotype K2 belonged to the ST375 and ST881 clones. In Europe, hvKP isolates are less frequently recovered, mostly associated with Asian citizens or travelers, which was not the case in our patients. K1 capsular serotype is a major cause of primary liver abscess and secondary septic embolus, and K2 is associated with secondary liver abscess. Although these hypervirulent variants usually affect immunocompetent patients as in our cases, diabetes mellitus is a major risk factor for the most invasive cases, with concomitant poor prognosis. Identification of hypervirulent K. pneumoniae serotypes K1 and K2 should be considered as part of the microbiological diagnosis of community-acquired liver abscess due to their clinical implications.

Aim: To evaluate the association between DNA methylation and frailty in the HIV-infected population and to investigate the usefulness of assessing frailty as a clinical marker to identify age acceleration., Methods: Frailty was assessed according to Fried's frailty phenotype. DNA methylation was analyzed in 10 frail patients, and compared with 10 robust control patients, all with HIV. Predicted age was inferred using the Weidner's formula. Age acceleration was assessed using the difference between predicted and chronological age., Results: HIV-infected frail patients had significantly higher biological predicted ages than chronological ages (mean acceleration: 10.3 years; p = 0.012)., Conclusions: We link age acceleration and frailty in an older HIV population. Frailty could be used in this population for implementing specific clinical approaches.

Background: In Spain, migrants are disproportionately affected by HIV and experience high rates of late diagnosis. We investigated barriers to health care access among migrants living with HIV (MLWH) in Spain., Methods: Cross sectional electronic survey of 765 adult HIV-positive migrants recruited within 18 health care settings between July 2013 and July 2015. We collected epidemiological, demographic, behavioral and clinical data. We estimated the prevalence and risk factors of self-reported barriers to health care using multivariable logistic regression., Results: Of those surveyed, 672 (88%) had information on health care access barriers: 23% were women, 63% from Latin America and Caribbean, 14% from Sub-Saharan Africa and 15% had an irregular immigration status. Men were more likely to report barriers than women (24% vs. 14%, P = 0.009). The main barriers were: lengthy waiting times for an appointment (9%) or in the clinic (7%) and lack of a health card (7%). Having an irregular immigration status was a risk factor for experiencing barriers for both men (OR: (4.0 [95%CI: 2.2-7.2]) and women (OR: 10.5 [95%CI: 3.1-34.8]). Men who experienced racial stigma (OR: 3.1 [95%CI: 1.9-5.1]) or food insecurity (OR: 2.1 [95%CI: 1.2-3.4]) were more likely to report barriers. Women who delayed treatment due to medication costs (6.3 [95%CI: 1.3-30.8]) or had a university degree (OR: 5.8 [95%CI: 1.3-25.1]) were more likely to report barriers., Conclusion: Health care barriers were present in one in five5 MLWH, were more common in men and were associated to legal entitlement to access care, perceived stigma and financial constraints.

Maraviroc is a CCR5 antagonist used in the treatment of HIV-1 infection. We and others have suggested that maraviroc could reactivate latent HIV-1. To test the latency-reversing potential of maraviroc and the mechanisms involved, we performed a phase II, single-center, open-label study in which maraviroc was administered for 10 days to 20 HIV-1-infected individuals on suppressive antiretroviral therapy (EudraCT registration no. 2012-003215-66). All patients completed full maraviroc dosing and follow-up. The primary endpoint was to study whether maraviroc may reactivate HIV-1 latency, eliciting signaling pathways involved in the viral reactivation. An increase in HIV-1 transcription in resting CD4 + T cells, estimated by levels of HIV-1 unspliced RNA, was observed. Moreover, activation of the NF-κB transcription factor was observed in these cells. To elucidate the mechanism of NF-κB activation by maraviroc, we have evaluated in HeLa P4 C5 cells, which stably express CCR5, whether maraviroc could be acting as a partial CCR5 agonist, with no other mechanisms or pathways involved. Our results show that maraviroc can induce NF-κB activity and that NF-κB targets gene expression by CCR5 binding, since the use of TAK779, a CCR5 inhibitor, blocked NF-κB activation and functionality. Taking the results together, we show that maraviroc may have a role in the activation of latent virus transcription through the activation of NF-κB as a result of binding CCR5. Our results strongly support a novel use of maraviroc as a potential latency reversal agent in HIV-1-infected patients. IMPORTANCE HIV-1 persistence in a small pool of long-lived latently infected resting CD4 + T cells is a major barrier to viral eradication in HIV-1-infected patients on antiretroviral therapy. A potential strategy to cure HIV-1-infection is the use of latency-reversing agents to eliminate the reservoirs established in resting CD4 + T cells. As no drug has been shown to be completely effective so far, the search for new drugs and combinations remains a priority for HIV cure. We examined the ability of maraviroc, a CCR5 antagonist used as an antiretroviral drug, to activate latent HIV-1 in infected individuals on antiretroviral therapy. The study showed that maraviroc can activate NF-κB and, subsequently, induce latent HIV-1-transcription in resting CD4 + T cells from HIV-1-infected individuals on suppressive antiretroviral therapy. Additional interventions will be needed to eliminate latent HIV-1 infection. Our results suggest that maraviroc may be a new latency-reversing agent to interfere with HIV-1 persistence during antiretroviral therapy., (Copyright © 2018 American Society for Microbiology.)

Background and Objectives: HIV patients have seen accelerated ageing. Our objective was to determine the prevalence of frailty, to evaluate factors associated with frailty and to evaluate physical function in older HIV-infected adults., Design: this was a cross-sectional study., Setting: outpatient clinics of two public university hospitals in Madrid (Spain)., Methods: frailty was defined according to the criteria of Fried: shrinking, weakness, poor endurance and energy, slowness and low physical activity level, being frail those who met at least three criteria, prefrail one or two criteria and robust when they met no criteria. Physical function was assessed using standardised methods., Results: we evaluated 117 HIV-infected patients. Mean age was 61.3 ([standard deviation] 6.87) years. All patients were on antiretroviral therapy. Median current CD4+ T-cell count was 638 (144-1871) cells/μl, and median CD4/CD8 ratio was 0.79 (0.00-3.62). The prevalence of frailty was 15.4%, and that of prefrailty was 52.1%. In the multivariate analyses depressive symptoms (OR [95% CI], 9.20 [2.17-39.05]) and CD4/CD8 ratio (OR 0.11 [0.02-0.61]) were associated with frailty. Even though 100% of the patients were able to walk and perform basic activities of daily life independently, functional impairment was high (20% slow gait and 55% Short Physical Performance Battery ≤9)., Conclusions: HIV-infected patients aged ≥55 years have a high prevalence of frailty and a high burden of functional impairment. Optimal management of this population requires close collaboration between infectious diseases specialists and geriatricians., (© The Author 2017. Published by Oxford University Press on behalf of the British Geriatrics Society.All rights reserved. For permissions, please email: journals.permissions@oup.com)

The aim of our study was to develop a Spanish-structured HIV risk of exposure and indicator conditions (RE&IC) questionnaire. People attending to an emergency room or to a primary clinical care center were offered to participate in a prospective, 1 arm, open label study, in which all enrolled patients filled out our developed questionnaire and were HIV tested. Questionnaire accuracy, feasibility, and reliability were evaluated.Valid paired 5329 HIV RE&IC questionnaire and rapid HIV tests were performed, 69.3% in the primary clinical care center, 49.6% women, median age 37 years old, 74.9% Spaniards, 20.1% Latin-Americans. Confirmed hidden HIV infection was detected in 4.1%, while HIV RE&IC questionnaire was positive in 51.2%. HIV RE&IC questionnaire sensitivity was 100% to predict HIV infection, with a 100% negative predictive value. When considered separately, RE or IC items sensitivity decreases to 86.4% or 91%, and similarly their negative predictive value to 99.9% for both of them. The majority of people studied, 90.8% self-completed HIV RE&IC questionnaire. Median time to complete was 3 minutes. Overall HIV RE&IC questionnaire test-retest Kappa agreement was 0.82 (almost perfect), likewise for IC items 0.89, while for RE items was lower 0.78 (substantial).A feasible and reliable Spanish HIV RE&IC self questionnaire accurately discriminated all non-HIV-infected people without missing any HIV diagnoses, in a low prevalence HIV infection area. The best accuracy and reliability were obtained when combining HIV RE&IC items.

Altered interplay between gut mucosa and microbiota during treated HIV infection may possibly contribute to increased bacterial translocation and chronic immune activation, both of which are predictors of morbidity and mortality. Although a dysbiotic gut microbiota has recently been reported in HIV+ individuals, the metagenome gene pool associated with HIV infection remains unknown. The aim of this study is to characterize the functional gene content of gut microbiota in HIV+ patients and to define the metabolic pathways of this bacterial community, which is potentially associated with immune dysfunction. We determined systemic markers of innate and adaptive immunity in a cohort of HIV-infected individuals on successful antiretroviral therapy without comorbidities and in healthy non-HIV-infected subjects. Metagenome sequencing revealed an altered functional profile, with enrichment of the genes involved in various pathogenic processes, lipopolysaccharide biosynthesis, bacterial translocation, and other inflammatory pathways. In contrast, we observed depletion of genes involved in amino acid metabolism and energy processes. Bayesian networks showed significant interactions between the bacterial community, their altered metabolic pathways, and systemic markers of immune dysfunction. This study reveals altered metabolic activity of microbiota and provides novel insight into the potential host-microbiota interactions driving the sustained inflammatory state in successfully treated HIV-infected patients.

We analyzed the effect of interferon α (IFN-α) and ribavirin (RBV) therapy on cell-associated human T-lymphotropic virus type 2 (HTLV-2) DNA in HIV-1-coinfected patients receiving antiretroviral therapy. Sixty-one patients under suppressive antiretroviral therapy were included: 37 with hepatitis C virus (HCV) infection, 15 with sustained virologic response (N = 10), relapse (N = 2), or with nonresponse (N = 3) after IFN-α/RBV treatment, and 9 with spontaneous HCV RNA clearance. Patients who were treated with IFN-α/RBV or had spontaneous HCV clearance had lower level of cell-associated HTLV-2 DNA (P = 0.022 and P = 0.040, respectively). Both IFN-alpha treatment and the ability to spontaneously clear HCV infection seem to reduce cell-associated HTLV-2 DNA in HIV-1-coinfected patients.

Objectives: The absence of direct clinical symptoms clearly associated to HTLV-2 infection may partially explain an underestimate of the real HTLV-2 prevalence rate and its effects in patients concurrently infected with HIV-1 and hepatitis C virus (HCV). Hence, to date, the influence of HTLV-2 on hepatic fibrosis has been poorly studied., Design: Retrospective study to clarify the influence of HTLV-2 infection in HCV infection and hepatic fibrosis among patients co-infected with HIV-1., Methods: This is a comparative cohort study including 39 HTLV-2-HIV-1-HCV co-infected patients and 42 HIV-1-HCV co-infected patients conducted in a tertiary care hospital. They were evaluated for transaminase levels, hepatic fibrosis stage, interleukin (IL)-28B genotype, Th1/Th2/Th17 cytokine levels, immune activation, inflammation, and microbial translocation., Results: HTLV-2-HIV-1-HCV co-infected patients had lower alanine aminotransferase levels (P = 0.023) and hepatic fibrosis (P = 0.012), compared to HIV-1-HCV co-infected patients. Moreover, Kaplan-Meier survival analysis showed a delay in hepatic fibrosis development for up to 5 years (P = 0.032). HTLV-2-HIV-1-HCV co-infected patients also had higher Th1/Th2 ratio (interferon γ/IL-4 ratio, P = 0.043; tumor necrosis factor α/IL-4 ratio, P = 0.010) and Th17 response (P = 0.015), whereas lower CD8 T-cell activation (P = 0.017) and lipopolysaccharide level (P = 0.001)., Conclusion: Findings strongly support that HTLV-2 co-infection might delay fibrosis development in HCV-HIV-1 co-infected patients.

Introduction: Although RTS as HIV Diagnosis was considered cost effectiveness [1], overall budget may be unaffordable for some countries. We explore Incremental cost per NDHI associated with different TS., Materials and Methods: From a health care perspective, using direct costs and Euros currency, we calculated budget and cost per NDHI of RTS (all patients were tested), TTS (Universal risk practices and clinical conditions-RP&CC - only positive were tested), and CPTS (Only patients physicians considered were tested). We considered DRIVE (Spanish acronym of HIV infection Rapid Diagnosis) study and clinical Practice outcomes. Population between 18-60 years, attending to a Hospital Emergency Room or to a Primary Care Center performed an HIV RP&CC questionnaire (Q) and an HIV rapid test (HIV RT). Unitary costs considered were: HIV RT, nurse, registry, transport and HIV confirmation when necessary, imputed to all population in RTS and CPTS and only in HIV RP&CC-Q positive in TTS analysis, while HIV RP&CC-Q costs were added to all population in TTS. Sensitivity analyses were performed with varying rates of NDHI and of positive HIV RP&CC-Q population, and different RP&CC Q sensitivity (SE) to predict HIV infection., Results: 5,329 HIV RP&CC-Q and HIV RT were performed to 49.64% women, median age 37 years old, 74.9% Spaniards. In DRIVE and CP, NDHI were 4.1‰, and 1.6‰, while HIV RP&CC-Q was positive in 51.2%. HIV RP&CC-Q SE was 100%. Overall budget employed in HIV testing was in RTS 43,503€, in TTS 24,472€ and in CPTS 5,032€. Cost per 1 NDHI was 1,977€, 1,112€ and 5,032€, respectively. A reduction in cost of 865€, favouring TTS vs. RTS, while an increased cost of 824€ in CPTS vs. RTS was obtained. Considering NDHI rate of 2.6‰ saving costs increased to 1379€ in TTS, while were reduced to 576€ if NDHI rate increases 6.2‰. Effect of RP&CC-Q positivity rate was similar, if 25% saving costs were 1368€, while if 75% were reduced to 399€. Varying SE of RP&CC-Q to 95%, 91% and 50% cost saving was 810€, 754€, and 208€, and number of MHI one, two and 11., Conclusions: In DRIVE study Targeted TS with universal screening of RP&CC before an HIV rapid test is cost saving, without missing NDHI, with respect to Routine TS. Lower rates of HIV infection and RP&CC in the population, increase costs savings.

Background: Immigrant women living with HIV generally have worse adherence to medical treatment and follow-up when compared to native women and immigrant or native men. The general aim of this study was to improve healthcare services for HIV-positive women and to better understand why some of them discontinue treatment. The specific objectives were: (1) to explore the barriers and facilitators to medical follow-up among women and (2) to use the findings to create a guide for healthcare professionals with strategies and tools to encourage the immigrant women to continue with their healthcare treatment., Methods: We conducted a qualitative, patient-centred research based on semi-structured interviews in order to understand the drivers and barriers for HIV positive immigrant women to adhere to medical follow-up. A total of 26 women in active or discontinued treatment (from sub-Saharan Africa (10), Latin America (8) and Spain (8)) were interviewed in 2012 using a purposive sampling methodology. The semi-structured interviews were transcribed and analysed based on the grounded theory approach and the framework method. Three researchers took part in the triangulation of results.The study was approved by the Ethical Committee of the Hospital Universitario Ramón y Cajal., Results: The study revealed eight categories that impacted adherence to treatment and medical follow-up: doctor-patient relationship, relationship between body and HIV, employment, gender roles, representations of AIDS, emotional support received, trust in biomedical system, and psychological condition. Specific barriers and facilitators related to these categories were identified. In immigrant women, the influence of these barriers was greater than in Spanish women.Recommendations for healthcare professionals based on this study have been compiled in an informative brochure., Conclusions: Social, cultural, and psychological aspects as well as self-perception of body changes, gender roles, and the relationship with the healthcare system, are key elements that may affect the adherence to medical treatment of immigrant women living with HIV.Qualitative research focused on the comprehensive experience of living with HIV can be useful for creating tools that pave the way to detect barriers and facilitators to medical follow-up in specific populations.

Background: A low CD4/CD8 ratio has been identified in the general population as a hallmark of inmmunosenescence and a surrogate of all-cause mortality. We aimed to investigate in treated HIV-infected individuals the relationship between the CD4/CD8 ratio and serious non-AIDS events., Methods: Case-control study within a prospective hospital-based cohort of HIV-infected subjects during at least one year of ART-mediated viral suppression. Cases were patients with serious non-AIDS events (non-AIDS malignancies, cardiovascular disease, and end-stage kidney disease), and controls individuals who did not developed non-AIDS events during follow-up. Data were analyzed using ROC analysis and multivariate logistic regression. Conditional logistic regression was performed in 200 cases/controls matched by age, sex, nadir CD4 and proximal CD4 counts., Results: We analyzed 407 subjects (109 cases, 298 controls). The CD4/CD8 ratio was lower in cases (0.44 vs. 0.70, P<0.0001), with higher discriminatory ability for the detection of non-AIDS events than the CD4 count, CD8 count and nadir CD4. Multivariate analyses (adjusted for age, sex, nadir CD4, proximal CD4 count, year of ART initiation and ART duration) confirmed the independent association of a low CD4/CD8 ratio with the risk of non-AIDS morbidity (per CD4/CD8 ratio quartile decrease, OR, 2.9; 95% CI, 1.3-6.2) and non-AIDS mortality (OR, 2.8; 95% CI, 1.5-5.3)., Conclusions: The CD4/CD8 ratio provides additional information to the CD4 counts and nadir CD4 in treated HIV-infected individuals, since it is independently associated with the risk of non-AIDS-related morbidity and mortality. This association is robust and maintained within different subgroups of patients.

Objective: Antiretroviral therapy (ART) intensification has been shown to reduce the reservoir of latently infected CD4 T cells. However, it is currently unknown whether this effect is maintained after discontinuation of the intensifying drug., Design: The effect of ART intensification during 48 weeks with maraviroc or raltegravir in chronically HIV-1-infected patients was assessed in two previous clinical trials. In this study, we analysed this effect at week 24 after discontinuation of the intensifying drugs, at baseline and 48 weeks of intensification., Methods: We measured the latently infected memory CD4 T cells carrying replication-competent virus, 2-long terminal repeat (2-LTR) circles and CD4/CD8 T cells activation., Results: Fifteen patients were evaluated. After 48 weeks of intensification, HIV-1 reservoir size significantly decreased from 1.1 to 0.0 infectious units per million (IUPM) (P=0.004). After 24 weeks of drug discontinuation, the median size of the reservoir was still significantly lower than at baseline (P=0.008). 2-LTRs were undetectable in all individuals at baseline and after 48 weeks of intensification, continuing undetectable in all patients except two at week 24 after discontinuation (P=0.1). CD4 and CD8 T-cell activation significantly decreased at 48 weeks after intensification, without further increase after discontinuation., Conclusion: The effects of ART intensification with maraviroc or raltegravir persist at least 24 weeks after discontinuation of the drug. In a global strategy, ART intensification should be considered as part of a combination approach to achieve a functional cure or HIV eradication.

Objectives: The stability of the reservoir of latently infected memory CD4 T-cells may be associated with continuous replenishment from residual HIV-1, not completely eliminated by otherwise successful antiretroviral therapy (ART). Treatment intensification could help to control residual virus and to modify the latent reservoir. The objective of this work is to assess the effect of intensifying therapy with raltegravir on the HIV-1 cell reservoir., Design: A pilot open-label phase-II clinical trial was performed to analyze ART intensification with raltegravir after 48 weeks in chronically HIV-1-infected patients on stable ART., Methods: We measured the number of latently infected memory CD4 T cells, residual viremia, 2-long terminal repeat circles, CD4/CD8 T-cell activation, lymphocyte subpopulations, gut homing receptor, and bacterial translocation., Results: A significant decay of HIV-1 latent reservoir was observed after intensification in the nine patients included (P = 0.021). No variation was found in either residual viremia or 2-long terminal repeat circles, whereas CD8 T-cell activation decreased at week 36 (P = 0.028). No differences were found in naive T-cell or effector memory cell counts, and the frequencies of gut homing receptor on activated or effector memory CD8 T cells. Bacterial translocation was stable, with the exception of a late decrease in lipopolysaccharide levels., Conclusions: In this pilot noncomparative trial, treatment intensification with raltegravir significantly decreased the latent cellular HIV-1 reservoir and CD8 T-cell activation. Despite the limitations inherent to trial design, our results suggest that ART intensification should be considered as an adjuvant strategy to eradicate HIV-1 infection.

Although atazanavir is widely used in hepatitis C virus (HCV)-HIV-1 patients, little is known about its safety in advanced liver disease. We studied 34 HCV-HIV-1 patients with cirrhosis receiving atazanavir. After 551.2 patient-months of follow-up, there were no cases of serious liver toxicity or cirrhosis decompensation, and only 18.5% discontinued the drug. Despite median bilirubin level at inclusion was 1.5 mg/ml, increases in bilirubin level were mild. Model for end-stage liver disease score (MELD) increased to 1.35 points (95% confidence interval 0.13-2.6), but no patient changed their pretreatment situation after atazanavir introduction. Atazanavir is a well tolerated option in cirrhosis, and significant alterations in bilirubin or MELD were not observed.

Objective: The primary objective was to assess the effect of MVC intensification on latently infected CD4(+) T cells in chronically HIV-1-infected patients receiving antiretroviral therapy., Methods: We performed an open-label pilot phase II clinical trial involving chronically HIV-1-infected patients receiving stable antiretroviral therapy whose regimen was intensified with 48 weeks of maraviroc therapy. We analyzed the latent reservoir, the residual viremia and episomal 2LTR DNA to examine the relationship between these measures and the HIV-1 latent reservoir, immune activation, lymphocyte subsets (including effector and central memory T cells), and markers associated with bacterial translocation., Results: Overall a non significant reduction in the size of the latent reservoir was found (p = 0.068). A mean reduction of 1.82 IUPM was observed in 4 patients with detectable latent reservoir at baseline after 48 weeks of intensification. No effect on plasma residual viremia was observed. Unexpectedly, all the patients had detectable 2LTR DNA circles at week 24, while none of them showed those circles at the end of the study. No changes were detected in CD4(+) or CD8(+) counts, although a significant decrease was found in the proportion of HLA-DR(+)/CD38(+) CD4(+) and CD8(+) T-cells. LPS and sCD14 levels increased., Conclusions: Intensification with MVC was associated with a trend to a decrease in the size of the latent HIV-1 reservoir in memory T cells. No impact on residual viremia was detected. Additional studies with larger samples are needed to confirm the results., Trial Registration: ClinicalTrials.gov NCT00795444.

Purpose: To evaluate clinical, immunological, and virological outcomes after first-line highly active antiretroviral therapy (HAART) with a regimen including either efavirenz (EFV) or lopinavir/ritonavir (LPV/r) in treatment-naive adult patients in routine clinical care., Method: An ongoing prospective, observational follow-up study included all patients starting their first antiretroviral therapy (ART) with any of the studied regimens from July 1998 to July 2004. The follow-up period was finalized in September 2006, when all patients completed an observation of at least 96 weeks. Mortality rates, CD4 counts, viral suppression (HIV RNA below 50 copies/mL), and discontinuation of any component of the regimen were compared at 48 and 96 weeks., Results: Despite the worst immunological status of the LPV/r group patients at baseline, this regimen was at least as effective as the one based on EFV not only in terms of treatment durability but also in terms of virological responses, nevertheless with an apparently quicker immune recovery. In general terms, both regimens present similar tolerability and safety outcomes except for the higher risk of increasing triglyceride (TG) levels in the LPV/r group. Low durability was observed in both regimens., Conclusion: In a routine clinical care setting, initial HAART containing LPV/r seems to present an effectiveness, tolerability, and toxicity similar to the one containing EFV.

Background: Mood disorders and other neuropsychiatric disorders are common adverse events limiting tolerability of alpha-interferon (IFN) therapy for hepatitis C virus (HCV). Because efavirenz (EFV) frequently produces neuropsychiatric side effects, we studied the effect of EFV in the incidence of these side effects in HIV/HCV patients receiving IFN., Methods: Prospective cohort of HIV/HCV patients receiving IFN and ribavirin. Adverse events and concomitant medications were systematically recorded once monthly., Results: Among 266 HIV/HCV patients starting a course of IFN (91% pegylated IFN) plus ribavirin, 53 (20%) received concomitant EFV and 213 (80%) did not. Most EFV patients (92%) were already on EFV before starting IFN (mean 26 months). Neuropsychiatric side effects were frequent, without significant differences between both groups (79% vs 65%, P = 0.051), and only 10 patients discontinued IFN. Mood disorders were reported more frequently in EFV patients (36% vs 23%, P = 0.046), but antidepressant therapy use was similar in both groups. The incidence of anxiety, insomnia, irritability, headache or prescription of anxiolytics or hypnotics was similar., Conclusions: Neuropsychiatric adverse events are common in HIV/HCV patients receiving IFN, usually mild or moderate. EFV may favor symptoms of mood disorders, although it was not related to an increased risk of significant depression requiring specific treatment.

Background: The combination of didanosine (ddI) and stavudine (d4T) is no longer recommended as a first-line treatment because of toxicity, but it may be useful in experienced patients., Methods: Retrospective chart review of experienced patients on ddI plus d4T was conducted at a single institution, recording the development of adverse events as well as their severity and action taken. The risk of developing severe toxicities was estimated by Kaplan-Meier analysis., Results: A total of 616 patients were on ddI plus d4T for a median time of 12 months (interquartile range: 5.0-24.7 months). Among them, 213 (34.6%) had AIDS, 161 (27.4%) had CD4 counts <200 cells/mm, and 503 (81.2%) had >2 previous treatment failures. Adverse events related to ddI plus d4T were recorded in 136 patients (22.1%), which were mild to moderate in 118 (19.1%) patients and severe in 18 (2.9%) patients. The mean times to development of severe and nonsevere adverse events were 72 (95% confidence interval [CI]: 70 to 75) weeks and 52 (95% CI: 48 to 55) weeks, respectively. The probability of developing severe adverse events was related to the nadir CD4 count, with higher risk in patients with <200 cells/mm (log rank test, P = 0.045)., Conclusions: Multiexperienced patients treated with combinations, including ddI plus d4T, frequently develop drug-related toxicity, but these events are rarely severe. Thus, these drugs can still be considered a valid option for salvage regimens.

Tuberculosis associated with HIV infection continues to be an important problem throughout the world. Since the advent of HAART, the medication of HIV-infected patients who have to receive concomitant treatment for tuberculosis has become a difficult task. The two main problems faced by clinicians include the significant pharmacokinetic interactions between rifamycins, a cornerstone in antituberculosis therapy, and protease inhibitors and nonnucleoside reverse transcriptase inhibitors, which are essential components of antiretroviral combination regimens, as well as the best moment to initiate antiretroviral therapy in patients with tuberculosis. The therapy of choice for patients with no previous antiretroviral experience includes an antituberculous regimen with rifampin and an efavirenz-based antiretroviral regimen. No dose adjustments of these drugs seem to be necessary. Nevirapine can be an alternative to efavirenz in this situation. For patients who cannot take efavirenz, either due to resistance or intolerance, rifabutin and a boosted protease inhibitor can be coadministered, with the necessary dose adjustments. No definite recommendations can be given regarding the optimal timing of antiretroviral therapy, but a delay of two months after initiation of antituberculosis therapy would be advisable and seems to be safe in most patients.

Objective: To validate a questionnaire to identify psychosocial repercussions of the lipodystrophy syndrome (LD) in HIV-infected patients., Methods: A questionnaire containing 35 items in 6 subscales [body image, anxiety, depression, social support, social distress, quality of life (QoL)] was consecutively administered to 128 patients with LD, 25 naive patients or on therapy without LD, and to 15 HIV negative patients from January to July '04. Reliability was assessed using Cronbach's alpha and the intraclass correlation coefficient (ICC). The area under the curve (AUC) was used for discrimination between patients and control groups, and the scores were compared according to the severity of the LD., Results: In all the subscales, the relationship between higher scores and LD severity was statistically significant (0.37-0.64, p<0.01), whereas the control groups had significantly lower scores. The internal consistency showed Cronbach's alpha coefficients ranging from 0.64 to 0.93. Test-retest reliability after 15 days in 30 patients showed ICC values of 0.8-0.94. AUC values for the different subscales were higher than 0.7 with the exception of QoL score, and construct validity showed a significant correlation with the Beck Depression Inventory and the MOS-HIV scores (0.49 and 0.51, respectively, p<0.01)., Conclusions: Our questionnaire shows satisfactory psychometric properties for identifying psychosocial repercussions of the LD in HIV-infected patients.

Background: Regimens with two nucleoside analogue reverse transcriptase inhibitors (NRTI) plus tenofovir DF have been associated with a high failure rate when administered as first line therapy. Little is known about patients with undetectable viral loads who are switched to these regimens., Methods: A post-hoc review of the virological outcomes at 24 weeks of patients who switched from a successful (< 50 copies/ml) highly active antiretroviral therapy regimen to a tenofovir plus two NRTI combination., Results: Fifty-five patients started a two NRTI plus tenofovir regimen mostly because of previous toxicity/intolerance of the original drugs (74%). After 24 weeks, only 17 patients (31%) remained virologically suppressed. Patients with a regimen including a didanosine plus tenofovir-based regimen had significantly poorer outcomes than those on other combinations (success rate 5 versus 47.1%, P = 0.001). In contrast, patients on a regimen including zidovudine plus tenofovir showed a trend towards a better outcome (75 versus 27%, P = 0.083). Multivariate analysis confirmed the combination of didanosine plus tenofovir as the only variable associated with a higher rate of failure (odds ratio 17.7; 95% confidence interval 2.1-147; P = 0.007). Patients with previous reverse transcriptase mutations presented virological failure in all cases. At failure a new pattern, including the K65R mutation with M184V or thymidine analogue mutations, was observed., Conclusions: Even in patients with suppressed viraemia, a two NRTI plus tenofovir regimen is associated with a high virological failure rate, but significant variations are found depending on the nucleosides included.

Background: Coinfection with hepatitis C virus (HCV) and human immunodeficiency virus (HIV) is a known risk factor for hepatotoxicity in patients receiving highly active antiretroviral therapy (HAART). The aim of this study was to evaluate the role of HCV-related liver fibrosis in HAART-associated hepatotoxicity., Methods: In a prospective study involving 107 patients who underwent liver biopsy, fibrosis was graded according 5 stages, from F0 (no fibrosis) to F4 (cirrhosis). Hepatotoxicity was defined as an increase in levels of aspartate aminotransferase and alanine aminotransferase to >5 times the upper limit of normal, or a >3.5-fold increase if baseline levels were abnormal. The incidence of hepatotoxicity was compared with liver fibrosis stage and with time and composition of HAART., Results: Overall, 27 patients (25%) had hepatotoxic events (5.1 events/100 person-years of therapy). The incidence was greater for patients with stage F3 or F4 fibrosis (38%) than for those with stage F1 or F2 fibrosis (15%; 7.6 vs. 3 events/100 person-years; relative risk, 2.75; 95% confidence interval, 1.08-6.97; P=.013). Duration of HCV infection, duration of HAART, diagnosis of acquired immunodeficiency syndrome, HCV load, HCV genotype, and nadir CD4(+) cell count did not affect the risk of hepatotoxicity. Of the 86 patients who received nonnucleoside reverse-transcriptase inhibitors (NNRTIs), 11 (13%) developed liver toxicity. In these patients, fibrosis stages F1 and F2 were associated with similar rates of toxicity (3 events/100 person-years for patients who received nevirapine, 3.3 events/100 person-years for those who received efavirenz, and 3.4 events/100 person-years for those who received non-NNRTIs). There was a greater incidence among patients with F3 or F4 fibrosis who received NNRTIs (11.7 events/100 person-years for patients who received nevirapine, and 8.6 events/100 person-years for those who received efavirenz), compared with those who received non-NNRTIs (4 events/100 person-years)., Conclusions: HAART-associated hepatotoxicity correlates with liver histological stage in patients coinfected with HIV and HCV. There was no difference in hepatotoxicity risk for different antiretroviral therapies in patients with mild-to-moderate fibrosis.

We evaluated the impact of HIV risk practice on immune reconstitution in a prospective cohort of 288 patients (176 former injecting drug users) who maintained complete virus suppression for more than 24 months. Significant differences in CD4 cell counts at 6 and 24 months were detected. Multivariate analysis showed that drug use was an independent predictor of poor immunological recovery. Injection drug abuse impairs short and long-term CD4 cell recovery in HIV-positive patients initiating successful highly active antiretroviral therapy.

Background: Hepatitis C virus (HCV) and HIV coinfection constitutes an important epidemiological and clinical problem. We evaluated the safety and efficacy of Pegylated interferon alpha2b (Peg-IFN) and a fixed dose of ribavirin in the treatment of chronic hepatitis C in HIV coinfection., Methods: Open, prospective study in HCV-HIV coinfected patients with persistently elevated alanine aminotransferase (ALT) levels and a liver biopsy showing either portal or bridging fibrosis. Therapy included Peg-IFN (50 micro g weekly) with ribavirin 800 mg for 48 weeks. The primary end point was sustained virological response (SVR). Univariate and multivariate analyses were performed to determine factors associated with response., Results: By intent-to-treat analysis, 11 of 35 patients (31%) reached SVR. SVR was significantly better for genotypes 2/3 than for genotype 1 (54% versus 21%; P < 0.05). By multivariate logistic regression analysis, only a non-1 genotype was an independent factor for SVR [odds ratio (OR), 6; 95% confidence interval (CI), 1.1-31.7; P < 0.005]. A decrease of at least 1.5 log10 HCV RNA at week 12 of therapy was highly predictive of SVR (OR, 49.9; 95% CI, 4.9-508.2; P < 0.001). Most patients developed adverse events, although only six patients (17%) discontinued treatment due to toxicity., Conclusions: The combination of low doses of Peg-IFN plus a fixed dose of ribavirin resulted in a rate of SVR similar to that obtained with higher doses of the drugs in HIV-infected patients and lower than those obtained in non-HIV patients. Response at week 12 may be useful to help guide therapy in HCV-HIV co-infected patients.

We analyzed survival rates, neurologic function, and prognostic factors for 118 consecutive patients with acquired immunodeficiency syndrome-associated progressive multifocal leukoencephalopathy (PML) treated with highly active antiretroviral therapy (HAART) in 11 hospitals throughout Spain. Seventy-five patients (63.6%) remained alive for a median of 114 weeks (2.2 years) after diagnosis of PML. Neurologic function of the survivors was categorized as cure or improvement in 33, stabilization or worsening in 40, and unknown in 2. The baseline CD4+ cell count was the only variable found with prognostic significance. The odds ratio of death was 2.71 (95% confidence interval, 1.19-6.15) for patients with CD4+ cell counts of <100 cells/microL, compared with patients who had CD4+ cell counts of > or =100 cells/microL. One-third of patients with PML died despite receipt of HAART; neurologic function improved in approximately one-half of the survivors. A CD4+ cell count of <100 cells/microL was associated with higher mortality.