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- A case of Birt-Hogg-Dubé syndromePublication . Martins, L; Caixeiro, M; Costa, C; Feijó, S; Bárbara, C
- Chronic hepatitis C treatment in HIV co-infection in Portugal: Results from a cohort OF 2133 patients presented by GEPCOI (Portuguese Coinfection Study Group)Publication . Miranda, AC; Mendez J, J; Serrão, R; Vale, F; Manata, MJ; Pinto, S; Gomes, A; Valente, C; Pacheco, P, et al.Direct-acting antiviral drugs (DAAs) have recently changed the paradigm of hepatitis C therapy, significantly improving treatment response rates, patient life expectancy and quality of life. In Portugal, sofosbuvir (SOF) and SOF/ledipasvir (SOF/LDV) were fully reimbursed by the National Health System since early 2015 and generalized use of interferon-free DAA based regimens became current practice. During 2016, the remaining DAAs were sequentially added and covered by the same health access policy. The Portuguese Study Group of Hepatitis and HIV Co-infection (GEPCOI) collected data from 15 clinical centres in Portugal, pertaining to the HCV treatment experience with DAA regimens. A cohort of 2133 patients was analysed, representing one of the largest DAA treated HCV/HIV co-infected individuals. The global sustained virologic response (SVR) achieved was 95% in this real-life cohort setting. Linear regression analysis showed significant differences in treatment response rates when using SOF plus ribavirin (RBV) combination in genotype 2 or 3 infected individuals (P < .002) and in those with liver cirrhosis (P < .002). These findings corroborate that early treatment is mandatory in HIV/HCV co-infected patients, as response rates may be negatively influenced by higher fibrosis stages and suboptimal DAA regimens. The current national Portuguese health policy should continue to promote wider treatment access and individualized therapy strategies, aiming at the elimination of HCV infection in this high-risk co-infected population
- Clinical experience in invasive fungal infectionsPublication . Pacheco, P; Ventura, A; Branco, T; Gonçalves, L; Carvalho, CLung infections caused by invasive filamentous fungi are very rare conditions in AIDS, but must be considered in patients with profound immune suppression especially in the presence of additional risk factors, such as hematologic malignancies, corticosteroid therapy, neutropenia, and chemotherapy. The authors report a case of dual lung infection caused by Aspergillus and Mucor, which occurred in a 34-year-old AIDS patient who was treated with chemotherapy for oral plasmablastic lymphoma. The case presented clinically with low grade fever and pulmonary cavitation, which suggested tuberculosis. After extensive investigation the diagnosis of mucormycosis was established and the patient was treated sequentially with liposomal amphotericin B and posaconazole. Despite a reduction in the size of the pulmonary cavitation, improvement of the lung interstitial infiltrates and clinical recovery, the patient was submitted to cardiothoracic surgery given the aggressive behavior of this invasive fungus. Histology of the surgical specimen showed numerous hyphae with a morphologic pattern compatible with Aspergillus as well as hyphae that were suggestive of Mucor.
- Clinical management of ageing people living with HIV in Europe: the view of the care providersPublication . Boffito, M; Ryom, L; Spinner, C; Martinez, E; Behrens, G; Rockstroh, J; Hohenauer, J; Lacombe, K; Psichogyiou, M; Voith, N; Mallon, P; Branco, T, et al.BACKGROUND: Although guidelines for the management of HIV infection include recommendations for aging people living with HIV (PLWH), clinical practice of European HIV care providers may vary. METHOD: We performed a study using a 3-phase Delphi methodology by involving a panel of clinicians with expertise in HIV infection clinical management. The main aim of the study was to assess the care provider prospective on how HIV clinical care should be delivered to ageing PLWH. The first phase involved ten clinicians to identify HIV comorbidities of interest. The second and third phases recruited clinicians virtually via a web-based questionnaire that included 137 questions focussed on 11 comorbidities (e.g. cardiovascular disease, pulmonary disease, etc.). RESULTS: Results were analysed thematically and consensus (or not) among European physicians reported. Ninety-seven and 85 responses were collected in phase 2 and 3, respectively. High levels of agreement were found among clinical care providers across Europe and with the European AIDS Conference Society guidelines regarding key items of clinical management of comorbidities in ageing PLWH. CONCLUSION: However, we identified some important gaps, such as the lack of standardisation or implementation of the assessment of frailty or menopause, which are emerging as important factors to optimise ageing PLWH clinical care. Further studies are warranted to confirm whether intensified screening translates into HIV morbidity advances.
- Correction to: Clinical management of ageing people living with HIV in Europe: the view of the care providers.Publication . Boffito, M; Ryom, L; Spinner, C; Martinez, E; Behrens, G; Rockstroh, J; Hohenauer, J; Lacombe, K; Psichogyiou, M; Voith, N; Mallon, P; Branco, T, et al.
- Differences in nevirapine biotransformation as a factor for its sex-dependent dimorphic profile of adverse drug reactions.Publication . Marinho, A; Rodrigues, P; Caixas, U; Antunes, A; Branco, T; Hargivan, S; Marques, M; Monteiro, E; Pereira, SOBJECTIVES: Nevirapine is widely used for the treatment of HIV-1 infection; however, its chronic use has been associated with severe liver and skin toxicity. Women are at increased risk for these toxic events, but the reasons for the sex-related differences are unclear. Disparities in the biotransformation of nevirapine and the generation of toxic metabolites between men and women might be the underlying cause. The present work aimed to explore sex differences in nevirapine biotransformation as a potential factor in nevirapine-induced toxicity. METHODS: All included subjects were adults who had been receiving 400 mg of nevirapine once daily for at least 1 month. Blood samples were collected and the levels of nevirapine and its phase I metabolites were quantified by HPLC. Anthropometric and clinical data, and nevirapine metabolite profiles, were assessed for sex-related differences. RESULTS: A total of 52 patients were included (63% were men). Body weight was lower in women (P = 0.028) and female sex was associated with higher alkaline phosphatase (P = 0.036) and lactate dehydrogenase (P = 0.037) levels. The plasma concentrations of nevirapine (P = 0.030) and the metabolite 3-hydroxy-nevirapine (P = 0.035), as well as the proportions of the metabolites 12-hydroxy-nevirapine (P = 0.037) and 3-hydroxy-nevirapine (P = 0.001), were higher in women, when adjusted for body weight. CONCLUSIONS: There was a sex-dependent variation in nevirapine biotransformation, particularly in the generation of the 12-hydroxy-nevirapine and 3-hydroxy-nevirapine metabolites. These data are consistent with the sex-dependent formation of toxic reactive metabolites, which may contribute to the sex-dependent dimorphic profile of nevirapine toxicity.
- Efavirenz concentrations in HIV-infected patients with and without viral hepatitisPublication . Pereira, S; Caixas, U; Branco, T; Germano, I; Lampreia, F; Papoila, A; Monteiro, EAIMS: Data on efavirenz in HIV/viral hepatitis co-infected patients is non-consensual, probably due to liver function heterogeneity in the patients included. METHODS: A case control study was performed on 27 HIV-infected patients, with controlled and homogenous markers of hepatic function, either mono-infected or co-infected with HBV/HCV, to ascertain the influence of viral hepatitis on efavirenz concentrations over a 2-year follow-up period. RESULTS: No differences were found in efavirenz concentrations between groups both during and at the end of the follow-up period: control (2.43 +/- 1.91 mg l(-1)) vs. co-infected individuals (2.37 +/- 0.37 mg l(-1)). CONCLUSION: It was concluded that HBV/HCV infections in themselves do not predispose to an overexposure to efavirenz.
- Effect of efavirenz on high-density lipoprotein antioxidant properties in HIV-infected patientsPublication . Pereira, S; Batuca, J; Caixas, U; Branco, T; Delgado-Alves, J; Germano, I; Lampreia, F; Monteiro, EWHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: * In previous work, we showed a long-term and concentration-dependent beneficial effect of the non-nucleoside reverse transcriptase inhibitor efavirenz (EFV) on high-density lipoproteins (HDL) in human immunodeficiency virus (HIV)-infected patients. * Furthermore, it has been suggested that instead of the current practice of only measuring HDL-chelesterol values, the evaluation of HDL function, namely its antioxidant properties, might be an improved tool for identifying subjects at increased risk for cardiovascular events. * Paraoxonase-1 (PON-1) is an enzyme associated with HDL that is responsible for HDL antioxidant function. WHAT THIS STUDY ADDS: * In the present work, we studied the effect of EFV on the activity of PON-1 and showed, for the first time, that EFV-based antiretroviral therapy is associated with a better antioxidant function, i.e. with a higher PON-1 activity. AIMS: A long-term and concentration-dependent beneficial effect of efavirenz (EFV) on cholesterol associated with high-density lipoprotein (HDL-c) in human immunodeficiency virus (HIV)-infected patients has been documented. Furthermore, it has been suggested that, instead of the current practice of only measuring HDL-c values, the evaluation of HDL quality might be an improved tool for identifying subjects at increased risk of cardiovascular events. Paraoxonase-1 (PON-1) is an enzyme associated with HDL that is involved in the onset of cardiovascular disease and responsible for HDL antioxidant function. The aim of the present study was to investigate the effect of EFV on the circulating activity of PON-1 in HIV-infected patients. METHODS: The patients included were adults with a documented HIV-1 infection, nontreated or treated with antiretroviral regimens including EFV 600 mg once daily as first therapeutic regimen for at least 3 months. The influence of treatment with EFV, HDL-c and CD4 cell count on PON-1 activity was analysed. RESULTS: HIV-infected White patients treated with EFV had higher PON-1 activity [77.35 U l(-1) (65.66, 89.04)] (P < 0.05) and higher PON-1 activity : HDL-c ratio [1.88 (1.49, 2.28)] (P < 0.01) than untreated patients. PON-1 activity was higher in Black patients (P < 0.001) and in patients with a CD4 cell count >500 cells ml(-1) (P= 0.0120). CONCLUSIONS: EFV-based antiretroviral regimens are associated with HDL particles with a better antioxidant function, i.e. with a higher PON-1 activity. The PON-1 activity of Black patients is higher than that found in Whites regardless of treatment. Ethnicity should be taken into consideration when studying drug effects on PON-1 activity.
- Evidence for nevirapine bioactivation in man: Searching for the first step in the mechanism of nevirapine toxicity.Publication . Caixas, U; Antunes, A; Marinho, A; Godinho, A; Grilo, N; Marques, M; Oliveira, M; Branco, T; Monteiro, E; Pereira, SNevirapine (NVP) is a non-nucleoside reverse transcriptase inhibitor used against human immunodeficiency virus type-1 (HIV-1), mostly to prevent mother-to-child HIV-1 transmission in developing countries. Despite its clinical efficacy, NVP administration is associated with a variety of toxic responses that include hepatotoxicity and skin rash. Although the reasons for the adverse effects of NVP administration are still unclear, increasing evidence supports the involvement of metabolic activation to reactive electrophiles. In particular, Phase II activation of the NVP metabolite 12-hydroxy-NVP is thought to mediate NVP binding to bionucleophiles, which may be at the onset of toxicity. In the present study, we investigated the nature and specific locations of the covalent adducts produced in human serum albumin and human hemoglobin by reaction in vitro with the synthetic model electrophile 12-mesyloxy-NVP, used as a surrogate for the Phase II metabolite 12-sulfoxy-NVP. Multiple sites of modification were identified by two different mass spectrometry-based methodologies, liquid chromatography-electrospray ionization tandem mass spectrometry (LC-ESI-MS/MS) and matrix-assisted laser desorption ionization tandem mass spectrometry (MALDI-TOF-TOF-MS). These two distinct methodologies, which in some instances afforded complementary information, allowed the identification of multiple adducts involving cysteine, lysine, tryptophan, histidine, serine, and the N-terminal valine of hemoglobin. Tryptophan, which is not a common site of covalent protein modification, was the NVP-modified amino acid residue detected in the two proteins and consistently identified by both LC-ESI-MS/MS and MALDI-TOF-TOF-MS. The propensity of tryptophan to react with the NVP-derived electrophile is further emphasized by the fact that human serum albumin possesses a single tryptophan residue, which suggests a remarkable selectivity that may be useful for biomonitoring purposes. Likewise, the NVP adduct with the terminal valine of hemoglobin, detected by LC-ESI-MS/MS after N-alkyl Edman degradation, appears as an easily assessed marker of NVP binding to proteins. Our results demonstrate the merits and complementarity of the two MS-based methodologies for the characterization of protein binding by NVP and suggest a series of plausible biomarkers of NVP toxicity that should be useful in the monitoring of toxicity effects in patients administered NVP.
- Hepatite C em toxicodependentes: acompanhamento e acesso à terapêuticaPublication . Castro, R; Valente, C; Ramos, J; Almeida, J; Marinho, R; Branco, T; Andrade, S; Macedo, AA hepatite C constitui, actualmente, um grave problema de saúde pública. Estima-se que existam, em todo o mundo, 180 milhões de pessoas com infecção crónica por vírus da hepatite C (VHC) e que a sua prevalência na população portuguesa varie entre 1 e 1,5%. Em Portugal, não existem normas de orientação actualizadas de tratamento, nem recomendações para o diagnóstico e acompanhamento dos doentes com VHC e, em particular, para os UDEVs. O presente artigo reúne informação de consenso relativa à de prática clínica e propõe algumas orientações para o acompanhamento e acessibilidade ao tratamento dos doentes toxicodependentes com infecção crónica por VHC, em Portugal.