[Consensus statement: recommendations for the management of metabolic bone disease in human immunodeficiency virus patients]. / Documento de consenso: Recomendaciones para el manejo de la enfermedad ósea metabólica en pacientes con virus de la inmunodeficiencia humana.

OBJECTIVE: To provide practical recommendations for the evaluation and treatment of metabolic bone disease in human immunodeficiency virus (HIV) patients. PARTICIPANTS: Members of scientific societies related to bone metabolism and HIV: Grupo de Estudio de Sida (GeSIDA), Sociedad Española de Endocrinología y Nutrición (SEEN), Sociedad Española de Investigación Ósea y del Metabolismo Mineral (SEIOMM), and Sociedad Española de Fractura Osteoporótica (SEFRAOS). METHODS: A systematic search was carried out in PubMed, and papers in English and Spanish with a publication date before 28 May 2013 were included. Recommendations were formulated according to GRADE system (Grading of Recommendations, Assessment, Development, and Evaluation) setting both their strength and the quality of supporting evidence. Working groups were established for each major part, and the final resulting document was later discussed in a face-to-face meeting. All the authors reviewed the final written document and agreed with its content. CONCLUSIONS: The document provides evidence-based practical recommendations on the detection and treatment of bone disease in HIV-infected patients.

[Consensus statement on monitoring of HIV: pregnancy, birth, and prevention of mother-to-child transmission]. / Documento de consenso para el seguimiento de la infección por el virus de la inmunodeficiencia humana en relación con la reproducción, el embarazo, el parto y la profilaxis de la transmisión vertical del niño expuesto.

OBJECTIVE: The main objective in the management of HIV-infected pregnant women is prevention of mother-to-child transmission; therefore, it is essential to provide universal antiretroviral treatment, regardless of CD4 count. All pregnant women must receive adequate information and undergo HIV serology testing at the first visit. METHODS: We assembled a panel of experts appointed by the Secretariat of the National AIDS Plan (SPNS) and the other participating Scientific Societies, which included internal medicine physicians with expertise in the field of HIV infection, gynecologists, pediatricians and psychologists. Four panel members acted as coordinators. Scientific information was reviewed in publications and conference reports up to November 2012. In keeping with the criteria of the Infectious Diseases Society of America, 2levels of evidence were applied to support the proposed recommendations: the strength of the recommendation according to expert opinion (A, B, C), and the level of empirical evidence (I, II, III). This approach has already been used in previous documents from SPNS. RESULTS AND CONCLUSIONS: The aim of this paper was to review current scientific knowledge, and, accordingly, develop a set of recommendations regarding antiretroviral therapy (ART), regarding the health of the mother, and from the perspective of minimizing mother-to-child transmission (MTCT), also taking into account the rest of the health care of pregnant women with HIV infection. We also discuss and evaluate other strategies to reduce the MTCT (elective Cesarean, child's treatment…), and different aspects of the topic (ARV regimens, their toxicity, monitoring during pregnancy and postpartum, etc.).

Executive summary of the Consensus Statement on monitoring HIV: pregnancy, birth, and prevention of mother-to-child transmission.

The main objective in the management of HIV-infected pregnant women is prevention of mother-to-child transmission; therefore, it is essential to provide universal antiretroviral treatment, regardless of CD4 count. All pregnant women must receive adequate information and undergo HIV serology testing at the first visit. If the serological status is unknown at the time of delivery, or in the immediate postpartum, HIV serology testing has to be performed as soon as possible. In this document, recommendations are made regarding the health of the mother and from the perspective of minimizing mother-to-child transmission.

[Comparative cost-effectiveness analysis between darunavir/ritonavir and other protease inhibitors in treatment-naive human immunodeficiency syndrome type 1-infected patients in Spain]. / Análisis comparativo de coste-eficacia entre darunavir/ritonavir y otros inhibidores de la proteasa en el tratamiento de la infección por el virus de la inmunodeficiencia humana de tipo 1 en pacientes naïve en España.

INTRODUCTION: GESIDA (AIDS Study Group) has proposed preferred regimens of antiretroviral treatment as initial therapy in HIV infected patients. The objective of this analysis is to compare the costs and effectiveness of darunavir/r QD and other ritonavir-boosted (/r) protease inhibitors (PIs) currently recommended in GESIDA guidelines for treatment-naïve patients. METHODS: A cost-efficacy model compared the boosted PIs recommended as preferred or alternative treatment choices, each used with a nucleoside reverse transcriptase inhibitor backbone. Efficacy was measured by 48-week virological response (viral load < 50 copies/mL) adjusted by baseline viral load and CD4 cell count. To generate efficiency frontiers and cost-efficacy ratios, one-year antiretroviral therapy costs in Spain, and 48-week efficacy values were used. RESULTS: The model estimated that starting treatment with darunavir/r QD was the most cost-effective choice compared with the other preferred PI/r based therapies. The average cost per patient with a virological response was lower for darunavir/r QD (13,420€) than for atazanavir/r QD (14,000€), or lopinavir/r BID (13,815€). Among the preferred PI/r-based therapies, darunavir/r QD also was estimated to be the most efficient option for treatment-naïve patients. Atazanavir/r QD and lopinavir/r BID were found to be «dominated¼ by darunavir/r) and, consequently, were outside the efficiency frontier of PI/r-based first-line treatment. Given a fixed budget of 10 million euros for PI/r-based first-line therapy, the model estimated that darunavir/r QD would yield more responders (745) than atazanavir/r QD (714), or lopinavir/r BID (724). At the same time, darunavir/r QD would reduce the number of individuals failing treatment (150) compared with atazanavir/r QD (172) and lopinavir/r BID (286). CONCLUSIONS: In this model, darunavir/r QD was found to be the most cost-effective choice, among the preferred PI/r-based therapies recommended in the Spanish guidelines for treatment-naïve patients.

A diabetic milieu increases ACE2 expression and cellular susceptibility to SARS-CoV-2 infections in human kidney organoids and patient cells.

It is not well understood why diabetic individuals are more prone to develop severe COVID-19. To this, we here established a human kidney organoid model promoting early hallmarks of diabetic kidney disease development. Upon SARS-CoV-2 infection, diabetic-like kidney organoids exhibited higher viral loads compared with their control counterparts. Genetic deletion of the angiotensin-converting enzyme 2 (ACE2) in kidney organoids under control or diabetic-like conditions prevented viral detection. Moreover, cells isolated from kidney biopsies from diabetic patients exhibited altered mitochondrial respiration and enhanced glycolysis, resulting in higher SARS-CoV-2 infections compared with non-diabetic cells. Conversely, the exposure of patient cells to dichloroacetate (DCA), an inhibitor of aerobic glycolysis, resulted in reduced SARS-CoV-2 infections. Our results provide insights into the identification of diabetic-induced metabolic programming in the kidney as a critical event increasing SARS-CoV-2 infection susceptibility, opening the door to the identification of new interventions in COVID-19 pathogenesis targeting energy metabolism.

[Prevalence of arterial hypertension and lipid profile in HIV patients]. / Prevalencia de hipertensión arterial y perfil lipídico en pacientes con infección por el virus de la inmunodeficiencia humana.

BACKGROUND AND OBJECTIVE: It is not known whether human immunodeficiency virus (HIV)-infected patients present, compared to non-HIV controls, higher vascular risk factors. Our objective was to analyze whether there are differences in blood pressure in HIV patients compared to non-HIV controls. PATIENTS AND METHOD: We retrospectively analyzed all HIV patients controlled in our centre, who were compared with a control group of blood donors, matched for age and sex, blood pressure and lipid profile. We evaluated the following variables: demographic data, date of HIV diagnosis, presence of lipodystrophy, antiretroviral treatment, duration of this treatment, and vascular risk factors. RESULTS: We evaluated 740 patients (mean age: 41.8 years; 75% men). We detected a higher prevalence of hypertension in the HIV group (25% vs. 15%) with a significant difference in the mean systolic/diastolic blood pressure between both groups (p < 0.0001). In the HIV group, hypertensives were older than normotensives, and had higher prevalence of lipodystrophy and higher total cholesterol with a shorter disease duration (75 vs 85 months). In the total group of hypertensives, HIV patients were younger than non-HIV (44.2 vs 47.9 years; p < 0.009) and had higher total cholesterol values (5.44 vs 5.18 mmol/l; p < 0.052). CONCLUSIONS: We found a higher prevalence of hypertension in HIV patients compared with matched controls, as well as a higher prevalence of lipodystrophy and vascular risk factors in hypertensive HIV patients compared with non-hypertensive.

[Delayed diagnosis of HIV infection in the Spanish VACH cohort [1997-2002]]. / Diagnóstico tardío de la infección por el virus de la inmunodeficiencia humana en la Cohorte VACH (1997-2002).

OBJECTIVE: To study the prevalence of delayed diagnosis of HIV infection and associated factors. METHODS: A cross sectional study of patients included in the Spanish VACH cohort who had been diagnosed with HIV infection between 1997 and 2002 was performed. Delayed diagnosis was defined as patients diagnosed with HIV infection and AIDS simultaneously or within the first month after the first positive serologic test, or those with a first CD4+ cell count below 200/ml. The epidemiological characteristics of these patients were compared with those of the remaining patients RESULTS: Of 2,820 new cases of HIV infection, delayed diagnosis was found in 506 (18%). These patients differed from the remaining patients in their lower mean age and higher HIV viral load, as well as in their distribution by sex (higher proportion of males), occupational status, history of incarceration in prison, and HIV-risk transmission group. The median survival during follow-up was significantly lower among AIDS patients with a delayed diagnosis. CONCLUSIONS: Delayed diagnosis remains a cause for concern in our environment, due to its magnitude and its association with mortality. Some epidemiological characteristics provide clues to guide future programs directed at increasing information and improving prevention.

Nuke-sparing regimens as a main simplification strategy and high level of toxicity resolution after antiretroviral switch: the SWITCHART Study.

BACKGROUND: The advent of combined antiretroviral therapy (ART) in the past decade has led to HIV suppression in most cases. Virological failure was the main reason for ART switch a few years ago; however, toxicity and treatment simplification have now gained importance due to the availability of more effective and convenient drugs. This study assessed the reasons for ART switch in daily practice. MATERIAL AND METHODS: Observational retrospective study that included patients whose ART was switched between January 2011 and July 2012. Patients with any other switch during the follow-up period (until September 2013) were excluded. RESULTS: A total of 246 patients were included. Main reasons for ART switch were simplification (33%) and toxicity (31%), followed by clinical trial inclusion (13%), virological failure (6%), drug interaction (4%), patient decision (3%), lack of adherence (2%), pregnancy (1%) and other (8%). Eighty patients switched to a simpler regimen (median age 48 [40-53], mean CD4 count 608±265 cells/cl, 89% <50 copies/ml, mean number of previous regimens 6±5, mean time on previous ART 3±2 years). In this case, previous ART mostly included 2NRTI+1PI/r (54%) (Figure 1). The simplification strategy mainly contained nuke-sparing regimens (60%) based on PI (DRV/r 48%): monotherapy 46%, dual therapy 13% (PI/r+maraviroc 9%, PI/r+NNRTI 4%) and triple therapy 1% (PI/r+maraviroc+raltegravir). The second preferred simplification option was 2NRTI+1NNRTI (24%). Seventy-seven patients switched due to toxicities (median age 47 [43-53], mean CD4 count 606±350 cells/µl, <50 copies/ml 82%, mean number of previous regimens 4±3, mean time on previous ART 3±3 years). Renal (25%) and CNS (18%) toxicities were the main reasons for ART switch, followed by diarrhoea (16%), liver enzyme elevation (ALT 10%; AST 9%; bilirubin 7%), lipid elevation (cholesterol 5%; triglycerides 8%), nausea (7%) and other (=5%) (Figure 2). All patients with renal toxicity were under TDF and in most cases this drug was removed from the new regimen (with 3TC/ABC or nuke-sparing). Among patients with CNS toxicity, 79% were taking EFV; the main new treatment was a second-generation NNRTI (ETR)+2NRTI. Toxicities were completely resolved in 66% of patients, partially resolved in 22% and not resolved in only 12%; the median time from ART switch to toxicity resolution was 4 (2-8) months. CONCLUSIONS: The main reasons for ART switch in daily practice are simplification and toxicities, renal and CNS toxicities being the most prevalent. The preferred simplification strategies are nuke-sparing regimens, mainly DRV/r-based monotherapy and dual therapy. ART switch leads to a complete resolution of toxicities in most cases in the short term.

[Toxicogenetics of antiretroviral treatment (1): lipodystrophy, metabolic perturbations and atherosclerosis]. / Toxicogenética del tratamiento antirretroviral (I): lipodistrofia, alteraciones metabólicas y arteriosclerosis.

Among the adverse effects attributed to antiretroviral therapy, one of the most striking is probably the appearance of the lipodystrophy syndrome and its associated metabolic derangements, given its potential long-term effect as a cardiovascular risk factor. Since not all patients who receive antiretroviral drugs experience these adverse effects, a host genetic predisposition has been postulated. However, currently available data on this issue is inconclusive and preliminary. It has been consistently demonstrated that polymorphisms in the genes that encode for apolipoproteins A5, C3 and E, for the cholesterol ester transporter proteins (CETP), and in the ATP binding cassette type A1 (ABCA1) influence the development of dyslipidemia in patients treated with antiretroviral drugs, particularly if the therapeutic regimen includes protease inhibitors. Data on the effect of polymorphisms in the sterol regulatory ester binding protein type 1 (SREBP1) are inconsistent. The effect of mitochondrial DNA mutations on the risk of lipodystrophy has been assessed, with inconclusive data. No polymorphisms in the lamin A gene have been detected. Investigations have assessed the effect of diverse polymorphisms in the genes that encode for several proinflammatory cytokines such as tumour necrosis factor alpha (TNF-alpha), interleukin-1-beta (IL-1beta) and interleukin-6 (IL-6). The results show inconsistent data in the case of TNF-alpha, no association in the case of IL-6, and preliminary positive associations in IL-1beta. In contrast, polymorphisms in the genes encoding for stromal derived factor 1 (SDF-1) and for monocyte chemoattractant protein 1 (MCP-1) have been shown to influence the development of subclinical atherosclerosis in HIV-1-infected patients treated with antiretroviral drugs.

[Cost of nucleoside analogue reverse transcriptase inhibitor-related toxicity in HIV-1-infected patients]. / Costes de la toxicidad asociada a los análogos de nucleósidos inhibidores de la transcriptasa inversa en pacientes con infección por el VIH-1.

OBJECTIVE: To estimate the impact of toxicity related to nucleoside analogue reverse transcriptase inhibitors (NRTI) on the total cost of medical care in HIV-1-infected patients. METHODS: . A pharmacoeconomic model was developed from the data obtained by a prospective, observational, multicenter study performed in Spain (Recover). The study patients had developed one NRTI-associated adverse event (AE) that justified discontinuation of treatment with the drug. All costs derived from NRTI-associated AEs in the HAART regimens of HIV-1-infected patients over a period of one year were assessed. The cost assessment (2005 values) included direct medical costs (drugs and AE management) and indirect costs (loss of productivity). The healthcare resources used in AE management were estimated by an expert panel of clinicians. RESULTS: The use and cost of resources rose with increasing severity of all the AE. The average total cost per patient was estimated to be 4012 euro, which included 1789 euro in drug costs (NRTI associated with therapy discontinuation due to AE), and 2223 euro in direct and indirect costs of AE management (45% and 55% of total cost, respectively). Seventy-three per cent of AE-associated costs per patient came from lipoatrophy (560 euro), lipodystropy (535 euro) and peripheral neuropathy (533 euro). CONCLUSION: Management of NRTI-related toxicities is more costly than NRTI acquisition and produces a significant increase in the overall healthcare expenditure for HIV-1-infected patients. This fact should be taken into account when designing the most efficient antiretroviral treatment strategies.