Síndrome de hiperémesis cannabinoide: a propósito de un caso / Cannabinoid hyperemesis syndrome: a case report

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Mitochondrial Toxicogenomics for Antiretroviral Management: HIV Post-exposure Prophylaxis in Uninfected Patients.

Background: Mitochondrial genome has been used across multiple fields in research, diagnosis, and toxicogenomics. Several compounds damage mitochondrial DNA (mtDNA), including biological and therapeutic agents like the human immunodeficiency virus (HIV) but also its antiretroviral treatment, leading to adverse clinical manifestations. HIV-infected and treated patients may show impaired mitochondrial and metabolic profile, but specific contribution of viral or treatment toxicity remains elusive. The evaluation of HIV consequences without treatment interference has been performed in naïve (non-treated) patients, but assessment of treatment toxicity without viral interference is usually restricted to in vitro assays. Objective: The objective of the present study is to determine whether antiretroviral treatment without HIV interference can lead to mtDNA disturbances. We studied clinical, mitochondrial, and metabolic toxicity in non-infected healthy patients who received HIV post-exposure prophylaxis (PEP) to prevent further infection. We assessed two different PEP regimens according to their composition to ascertain if they were the cause of tolerability issues and derived toxicity. Methods: We analyzed reasons for PEP discontinuation and main secondary effects of treatment withdrawal, mtDNA content from peripheral blood mononuclear cells and metabolic profile, before and after 28 days of PEP, in 23 patients classified depending on PEP composition: one protease inhibitor (PI) plus Zidovudine/Lamivudine (PI plus AZT + 3TC; n = 9) or PI plus Tenofovir/Emtricitabine (PI plus TDF + FTC; n = 14). Results: Zidovudine-containing-regimens showed an increased risk for drug discontinuation (RR = 9.33; 95% CI = 1.34-65.23) due to adverse effects of medication related to gastrointestinal complications. In the absence of metabolic disturbances, 4-week PEP containing PI plus AZT + 3TC led to higher mitochondrial toxicity (-17.9 ± 25.8 decrease in mtDNA/nDNA levels) than PI plus TDF + FTC (which increased by 43.2 ± 24.3 units mtDNA/nDNA; p < 0.05 between groups). MtDNA changes showed a significant and negative correlation with baseline alanine transaminase levels (p < 0.05), suggesting that a proper hepatic function may protect from antiretroviral toxicity. Conclusions: In absence of HIV infection, preventive short antiretroviral treatment can cause secondary effects responsible for treatment discontinuation and subclinical mitochondrial damage, especially pyrimidine analogs such as AZT, which still rank as the alternative option and first choice in certain cohorts for PEP. Forthcoming efforts should be focused on launching new strategies with safer clinical and mitotoxic profile.

Renal safety of coformulated tenofovir/emtricitabine vs other nucleoside analogues in combination therapy in antiretroviral-naive patients aged 50 years or older in Spain: The TRIP study.

OBJECTIVES: Our aim is to describe the impact of emtricitabine (FTC)/tenofovir (TDF) versus other nucleoside reverse transcriptase inhibitor (NRTIs)-based regimens on renal function of human immunodeficiency virus (HIV) naïve patients >50 years old who started combination antiretroviral therapy (cART). DESIGN: National, retrospective cohort analysis of patients >50 years old when they started cART (January 1, 2006-December 31, 2009). METHODS: We compared renal safety (changes in estimated glomerular filtration rate [eGFR] during the first year, and time to renal events during 4 years of follow-up) in FTC/TDF versus non-FTC/TDF users. Among FTC/TDF users, we compared protease inhibitors vs non-nucleoside reverse transcriptase inhibitors and Lopinavir/ritonavir vs Efavirenz. RESULTS: We included 103 patients: median age: 54.9 years, 84% males, median CD4 count 247 cells/µl, median viral load 4.7 log; median follow up 18 months (max: 48 months); 73 started with FTC/TDF and 30 with other NRTIs. Change in eGFR was significantly worse for ritonavir-boosted lopinavir (LPV/r) vs efavirenz (EFV) users in the FTC/TDF group (71.2 vs 98.9 ml/min/1.73 m(2) at month 12, P < 0.05). The risk of renal events (progression to an Chronic Kidney Disease Epidemiology Collaboration value < 60 ml/min/1.73 m(2) in subjects with baseline values >60) was comparable for FTC/TDF users and non users, but was higher and almost significant for LPV/r as compared to EFV users in the FTC/TDF group (adjusted hazard ratio 6.1, 95% CI 0.8-45.5). CONCLUSIONS: In our study with a population of HIV infected subjects ≥ 50 years old, renal safety was similar for FTC/TDF and other NRTI-based regimens, but worse for LPV/r as compared to other regimens.

[Consensus statement on metabolic disorders and cardiovascular risks in patients with human immunodeficiency virus]. / Documento de consenso sobre alteraciones metabólicas y riesgo cardiovascular en pacientes con infección por el virus de la inmunodeficiencia humana.

OBJECTIVE: This consensus document is an update of metabolic disorders and cardiovascular risk (CVR) guidelines for HIV-infected patients. METHODS: This document has been approved by an expert panel of GEAM, SPNS and GESIDA after reviewing the results of efficacy and safety of clinical trials, cohort and pharmacokinetic studies published in biomedical journals (PubMed and Embase) or presented in medical scientific meetings. Recommendation strength and the evidence in which they are supported are based on the GRADE system. RESULTS: A healthy lifestyle is recommended, no smoking and at least 30min of aerobic exercise daily. In diabetic patients the same treatment as non-HIV infected patients is recommended. HIV patients with dyslipidemia should be considered as high CVR, thus its therapeutic objective is an LDL less than 100mg/dL. The antihypertensive of ACE inhibitors and ARAII families are better tolerated and have a lower risk of interactions. In HIV-patients with diabetes or metabolic syndrome and elevated transaminases with no defined etiology, the recommended is to rule out a hepatic steatosis Recommendations for action in hormone alterations are also updated. CONCLUSIONS: These new guidelines update previous recommendations regarding all those metabolic disorders involved in CVR. Hormone changes and their management and the impact of metabolic disorders on the liver are also included.

Executive summary of the consensus document on metabolic disorders and cardiovascular risk in patients with HIV infection.

The importance of the metabolic disorders and their impact on patients with HIV infection requires an individualized study and continuous updating. HIV patients have the same cardiovascular risk factors as the general population. The HIV infection per se increases the cardiovascular risk, and metabolic disorders caused by some antiretroviral drugs are added risk factors. For this reason, the choice of drugs with a good metabolic profile is essential. The most common metabolic disorders of HIV infected-patients (insulin resistance, diabetes, hyperlipidemia or osteopenia), as well as other factors of cardiovascular risk, such as hypertension, should also be dealt with according to guidelines similar to the general population, as well as insisting on steps to healthier lifestyles. The aim of this document is to provide a query tool for all professionals who treat HIV-patients and who may present or display any metabolic disorders listed in this document.

[Reasons for antiretroviral treatment change in HIV+ patients in Spain in 2010-2011. SWITCH AUDIT Study]. / Causas que justifican el cambio del tratamiento antirretroviral en personas con infección por el VIH en España (años 2010-2011). Estudio SWITCH AUDIT.

Survey in 349 HIV infected subjects in 19 Spanish Hospitals in 2010-2011, to assess the reasons for antiretroviral treatment change. Simplification was the most frequent reason for change (37%), followed by toxicity (30%) and treatment failure (21%). There were statistically significant differences according to treatment line and transmission category. In conclusion, in many patients treatment is changed in order to obtain the benefits of a regimen easier to follow.

Causas que justifican el cambio del tratamiento antirretroviral en personas con infección por el VIH en España (años 2010-2011). Estudio SWITCH AUDIT / Reasons for antiretroviral treatment change in HIV+ patients in Spain in 2010-2011. SWITCH AUDIT Study

Encuesta transversal en 349 pacientes con VIH en 19 hospitales españoles, para caracterizar los motivos de cambio del tratamiento antirretroviral en 2010-2011. La causa más frecuente del cambio fue la simplificación (37%), seguida de la toxicidad (30%) y el fracaso terapéutico (21%). Se encontraron diferencias significativas en los motivos de cambio según la línea de tratamiento y la categoría de transmisión. En conclusión, en muchos pacientes se busca la optimización del tratamiento antirretroviral mediante la simplificación a pautas más fáciles de seguir (AU)

Survey in 349 HIV infected subjects in 19 Spanish Hospitals in 2010-2011, to assess the reasons for antiretroviral treatment change. Simplification was the most frequent reason for change (37%), followed by toxicity (30%) and treatment failure (21%). There were statistically significant differences according to treatment line and transmission category. In conclusion, in many patients treatment is changed in order to obtain the benefits of a regimen easier to follow (AU)

Virus de la inmunodeficiencia humana y servicios de urgencias. Réplica / Human inmunodeficiency virus and emergency departments. Reply

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Safety, efficacy, and persistence of emtricitabine/tenofovir versus other nucleoside analogues in naive subjects aged 50 years or older in Spain: the TRIP study.

OBJECTIVES: Current antiretroviral guidelines state that being older than 50 to 55 years of age is an indication to start antiretroviral therapy (ART), regardless of CD4 status. However, no references to the preferred combination ART (cART) for these patients have been described. Our study compares emtricitabine and tenofovir disoproxil fumarate (FTC/TDF) versus other nucleoside reverse transcriptase inhibitor (NNRTI) regimens in HIV ART-naïve patients who are ≥50 years. DESIGN: National, retrospective cohort analysis of patients who were ≥50 years old when they began the first cART (January 1, 2006 to December 31, 2009). METHODS: We compared safety, effectiveness, and persistence of treatment in FTC/TDF versus non-FTC/TDF users. Among FTC/TDF users, we compared protease inhibitor (PI) versus NNRTI users and lopinavir/r versus efavirenz users. RESULTS: We included 161 patients: median age was 54.6 years, 83% were men, median CD4 count was 191 cells/µL, median viral load was 4.7 log, and median follow-up was 19 months (maximum, 48 months). Of these participants, 112 started with FTC/TDF and 49 with other nucleotide reverse transcriptase inhibitors (NRTIs). During follow-up, 21.9% of subjects developed at least one laboratory event ≥grade 3, 5.6% interrupted cART due to adverse events,19.3% had virologic failure, and 49.1% modified cART. There were no statistically significant differences between FTC/TDF and non-FTC/TDF users for any output except for persistence: The proportion of subjects who changed cART was 71.4% for non-FTC/TDF users and 38.6% for FTC/TDF users (log rank 0.001; adjusted hazard ratio, 2.10; 95% CI, 1.34-3.29). CONCLUSIONS: In a population of HIV-infected subjects who were ≥50 years old, our study suggests that the use of FTC/TDF is generally safe and effective, with a longer persistence as compared to other regimens.

[Reasons for the introduction of darunavir in the antirretroviral treatment in HIV-infected patients]. / Motivos de introducción de darunavir en un régimen antirretroviral en pacientes infectados por el virus de la inmunodeficiencia adquirida.

INTRODUCTION: In 2009 a deep change in ARV treatment took place in Spain with the introduction of new ARV drugs. The principal objective of the study was to determine the clinical situation of the patients in which DRV/r was introduced in the ARV therapy. METHODS: Observational, cross sectional and multicentre study in which 91 reference hospitals participated. Patient's enrollment was carried out between 2008 and 2009. Data were collected retrospectively considering standard clinical practice. RESULTS: 719 medical records were reviewed. Patients had a different clinical situation compared to nowadays with predominance of multiresistant virus which leaded to virologic failure. The principal reason for introducing DRV/r in the ARV regimen was the virologic failure (54.2%). CONCLUSIONS: Considering this situation, DRV/r became a therapeutic option which represented a change in the ARV paradigm in that period.

Motivos de introducción de darunavir en un régimen antirretroviral en pacientes infectados por el virus de la inmunodeficiencia adquirida / Reasons for the introduction of darunavir in the antirretroviral treatment in HIV-infected patients

Introducción. En el año 2009 se produjo un cambio muy sustancial en el tratamiento antirretroviral (ARV) de nuestro país con la introducción de nuevos fármacos antiretrovirales. El objetivo fue conocer la situación clínica de los pacientes en los que se introducía darunavir (DRV/r) en el tratamiento antirretroviral. Métodos. Estudio observacional, transversal y retrospectivo, en el que participaron 91 centros españoles de referencia. El periodo de reclutamiento del estudio se llevó a cabo entre 2008 y 2009. Se recogieron datos relacionados con la práctica clínica habitual. Resultados. Se revisaron 719 historias clínicas. La situación clínica prevalente entre los pacientes que necesitaban un ajuste al tratamiento antirretroviral era diferente a la actual con predominio de multirresistencias que llevaban a fracaso. El motivo principal por el que se había incluido DRV/r en la pauta fue el fracaso virológico (54,2%). Conclusiones. En esa situación, DRV/r constituyó una opción terapéutica que supuso un cambio en el paradigma del tratamiento antirretroviral de la época(AU)

Introduction. In 2009 a deep change in ARV treatment took place in Spain with the introduction of new ARV drugs. The principal objective of the study was to determine the clinical situation of the patients in which DRV/r was introduced in the ARV therapy. Methods. Observational, cross sectional and multicentre study in which 91 reference hospitals participated. Patient’s enrolment was carried out between 2008 and 2009. Data were collected retrospectively considering standard clinical practice. Results. 719 medical records were reviewed. Patients had a different clinical situation compared to nowadays with predominance of multiresistant virus which leaded to virologic failure. The principal reason for introducing DRV/r in the ARV regimen was the virologic failure (54.2%). Conclusions. Considering this situation, DRV/r became a therapeutic option which represented a change in the ARV paradigm in that period(AU)

Evaluation of the safety and effectiveness of nevirapine plus coformulated tenofovir/emtricitabine as first-line therapy in routine clinical practice.

Despite having demonstrated noninferior efficacy against atazanavir/ritonavir plus coformulated tenofovir/emtricitabine (cTDF/FTC), the combination of nevirapine plus cTDF/FTC is not included among preferred regimens in some international guidelines. This combination is frequently used in Spain. We analyzed its effectiveness and safety as first-line therapy in a routine clinical practice. A retrospective, multicenter study was performed in treatment-naive HIV-1-infected subjects who started nevirapine plus cTDF/FTC as first-line therapy according to the nevirapine CD4(+) cell count threshold. The primary endpoint was the proportion of subjects with plasma HIV-1 RNA <50 copies/ml at week 48. We included 123 subjects starting the regimen from 2005 to 2008. The median age was 41.0 years, the median baseline CD4(+) cell count was 215 cells/µl, the median plasma viral load (VL) was 4.83 log(10) copies/ml, and 22% had hepatitis C coinfection. At week 48, 96 subjects (78%; 95% CI: 69.9-84.4) had a VL <50 copies/ml in an ITT analysis, and the median rise in the CD4(+) cell count was 118 cells/µl. Virological failure was observed in 6.5% (8/123) of subjects, all them before week 24 and related to poor adherence. There was no relationship between virological failure and baseline CD4(+) cell count or VL. Ten percent (13/123) of the subjects discontinued the treatment due to adverse events. There was a significant decrease in total/HDL-cholesterol ratio (p=0.03) with an increase in HDL-cholesterol (p=0.01) over 48 weeks. The combination of nevirapine plus cTDF/FTC showed a high virological efficacy without unexpected toxicities as a first-line treatment in a routine clinical practice.

Dyslipidaemia in HIV-infected women on antiretroviral therapy. Analysis of 922 patients from the Spanish VACH cohort.

BACKGROUND: Information concerning lipid disturbances in HIV-infected women on antiretroviral therapy (ART) is scarce. The objective of the study is to describe the lipid profile in a large cohort of HIV-infected women on contemporary ART and analyse differences between regimes and patient's characteristics. METHODS: Observational, multicentre, cross-sectional study from the Spanish VACH Cohort. 922 women on stable ART without lipid-lowering treatment were included. RESULTS: Median age was 42 years, median CD4 lymphocyte count was 544 cells/mm3, and 85.6% presented undetectable HIV-1 viral load. Median total cholesterol (TC) was 189 mg/dL (interquartile range, IQR, 165-221), HDL cholesterol 53 mg/dL (IQR, 44-64), LDL cholesterol 108 mg/dL (IQR, 86-134), and triglycerides 116 mg/dL (IQR, 85-163). Mean accumulated time on ART was 116 months; 47.4% were on NNRTI-based regimes, 44.7% on PI, and 6.7% on only-NRTI therapy. 43.8% were also hepatitis C (HCV) coinfected. Patients on PI treatment presented higher TC/HDL ratio than those on NNRTI (p < 0.001). Significantly higher HDL values were observed in NNRTI-treated patients. HCV-coinfected patients presented lower TC/HDL ratio than the non HCV-coinfected. In multivariate analysis, factors independently associated with TC/HDL ratio were age, triglyceride levels and HCV co-infection. PI treatment presented a non-significant association with higher TC/HDL ratio. CONCLUSIONS: In HIV-infected women, the NNRTI-based ART is associated with a better lipid profile than the PI-based. Factors unrelated to ART selection may also exert an independent, significant influence on lipids; in particular, age, and triglyceride levels are associated with an increased TC/HDL ratio while HCV co-infection is associated with a reduced TC/HDL ratio.

Characteristics and outcome of HIV infection in gypsies in the Spanish VACH Cohort

Objective To study the characteristics of HIV infection in the gypsy (Roma) population in Spain, as compared with those of the Caucasian, non-gypsy majority. Design Cross-sectional, historical cohort study from the Spanish VACH Cohort. Methods Patients attending VACH clinics between 1 June 2004 and 30 November 2004 were classified according to their racial and ethnic origin as “gypsies”, Caucasian non-gypsy Spanish natives (CNGN), and “other” (the last being excluded from this study). Their sociodemographic and clinico-epidemiological characteristics were compared, as well as the Kaplan–Meier curves of time to AIDS, or death, or disease progression (either of the 2 outcomes).Results4819 (48%) of 10,032 cases included in the VACH database were eligible: 210 (4.2%) were gypsies and 4252 (84.8%) were CNGN. Differences were observed in age, household, academic, inmate, marital, and employment history. Injecting drug use had been the most frequent mechanism of transmission in both groups, but to a greater extent among gypsies (72% versus 50%; P<0.000). Sex distribution, CD4 cell counts, and viral loads at the first visit were similar in the 2 groups, as was the percentage of patients with previous AIDS, percentage receiving antiretrovirals, and percentage subsequently starting antiretroviral therapy. Up to 1 April 2005, 416 new AIDS cases and 85 deaths were recorded. The percentage of these outcomes did not differ between groups, but log-rank test showed a shorter time to AIDS and disease progression among gypsies. Conclusions The sociodemographic characteristics of gypsies, the largest minority in the VACH Cohort, show differences relative to those of CNGN. HIV-related outcomes suggest that gypsies have a poorer prognosis (AU)

Objetivo estudiar las características de la infección por el VIH en gitanos en España, en comparación con las de la mayoría caucásica no gitana (CNG).Métodos estudio transversal y de cohortes históricas en la Cohorte VACH. Clasificamos a los pacientes que acudieron a las clínicas participantes en VACH entre el 1 de junio de 2004 y el 30 de noviembre de 2004 de acuerdo a su raza y etnia, como «gitanos», «nativos españoles CNG» u «otros» (estos, excluidos de este estudio). Comparamos sus características sociodemográficas y clinicoepidemiológicas, así como sus curvas de Kaplan–Meier del tiempo hasta sida, muerte o progresión de la enfermedad (cualquiera de ambos).Resultados4819 (48%) de 10.032 casos recogidos en la base de datos de VACH fueron incluidos en el estudio: 210 (4,2%) eran gitanos y 4.252 (84,8%) eran nativos CNG. Observamos diferencias en sus distribuciones por edad, domicilio, estudios, antecedentes penales, situación laboral y marital. La inyección de drogas había sido el mecanismo de transmisión del VIH más frecuente en los dos grupos, pero más marcadamente en los gitanos (72% frente a 50%; p<0,000). La distribución por sexos, los recuentos de linfocitos CD4 y las cargas virales en la primera visita fueron similares en ambos grupos, así como las proporciones de pacientes con sida previo y las de quienes estaban ya en, o iniciaron entonces, tratamiento antirretroviral. Hasta el 1 de abril de 2005 se registraron 416 nuevos casos de sida y 85 muertes. La proporción de ambos resultados fue similar en ambos grupos, pero la prueba del rango logarítmico demostró una evolución más rápida a sida y a progresión de la (..) (AU)

Effect of TNF-alpha genetic variants and CCR5 Delta 32 on the vulnerability to HIV-1 infection and disease progression in Caucasian Spaniards.

BACKGROUND: Tumor necrosis factor alpha (TNF-alpha) is thought to be involved in the various immunogenetic events that influence HIV-1 infection. METHODS: We aimed to determine whether carriage of the TNF-alpha-238G>A, -308G>A and -863 C>A gene promoter single nucleotide polymorphisms (SNP) and the CCR5 Delta 32 variant allele influence the risk of HIV-1 infection and disease progression in Caucasian Spaniards. The study group consisted of 423 individuals. Of these, 239 were uninfected (36 heavily exposed but uninfected [EU] and 203 healthy controls [HC]) and 184 were HIV-1-infected (109 typical progressors [TP] and 75 long-term nonprogressors [LTNP] of over 16 years' duration). TNF-alpha SNP and the CCR5 Delta 32 allele were assessed using PCR-RFLP and automatic sequencing analysis methods on white blood cell DNA. Genotype and allele frequencies were compared using the chi 2 test and the Fisher exact test. Haplotypes were compared by logistic regression analysis. RESULTS: The distribution of TNF-alpha-238G>A, -308G>A and -863 C>A genetic variants was non-significantly different in HIV-1-infected patients compared with uninfected individuals: -238G>A, p = 0.7 and p = 0.3; -308G>A, p = 0.05 and p = 0.07; -863 C>A, p = 0.7 and p = 0.4, for genotype and allele comparisons, respectively. Haplotype analyses, however, indicated that carriers of the haplotype H3 were significantly more common among uninfected subjects (p = 0.04). Among the infected patients, the distribution of the three TNF-alpha genetic variants assessed was non-significantly different between TP and LTNP: -238G>A, p = 0.35 and p = 0.7; -308G>A, p = 0.7 and p = 0.6: -863 C>A, p = 0.2 and p = 0.2, for genotype and allele comparisons, respectively. Haplotype analyses also indicated non-significant associations. Subanalyses in the LTNP subset indicated that the TNF-alpha-238A variant allele was significantly overrepresented in patients who spontaneously controlled plasma viremia compared with those who had a detectable plasma viral load (genotype comparisons, p = 0.02; allele comparisons, p = 0.03). The CCR5 Delta 32 distribution was non-significantly different in HIV-1-infected patients with respect to the uninfected population (p = 0.15 and p = 0.2 for genotype and allele comparisons, respectively) and in LTNP vs TP (p = 0.4 and p = 0.5 for genotype and allele comparisons, respectively). CONCLUSIONS: In our cohort of Caucasian Spaniards, TNF-alpha genetic variants could be involved in the vulnerability to HIV-1 infection. TNF-alpha genetic variants were unrelated to disease progression in infected subjects. The -238G>A SNP may modulate the control of viremia in LTNP. Carriage of the CCR5 Delta 32 variant allele had no effect on the risk of infection and disease progression.