Browsing by Author "Caixas, U"
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- Baseline Susceptibility of Primary HIV-2 to Entry InhibitorsPublication . Borrego, P; Calado, R; Marcelino, JM; Bártolo, I; Rocha, C; Cavaco-Silva, P; Doroana, M; Antunes, F; Maltez, F; Caixas, U; Barroso, H; Taveira, NBACKGROUND: The baseline susceptibility of primary HIV-2 to maraviroc (MVC) and other entry inhibitors is currently unknown. METHODS: The susceptibility of 19 HIV-2 isolates obtained from asymptomatic and AIDS patients and seven HIV-1 clinical isolates to the fusion inhibitors enfuvirtide (ENF) and T-1249, and to the coreceptor antagonists AMD3100, TAK-779 and MVC, was measured using a TZM-bl cell-based assay. The 50% inhibitory concentration (IC(50)), 90% inhibitory concentration (IC(90)) and dose-response curve slopes were determined for each drug. RESULTS: ENF and T-1249 were significantly less active on HIV-2 than on HIV-1 (211- and 2-fold, respectively). AMD3100 and TAK-779 inhibited HIV-2 and HIV-1 CXCR4 tropic (X4) and CCR5 tropic (R5) variants with similar IC(50) and IC(90) values. MVC, however, inhibited the replication of R5 HIV-2 variants with significantly higher IC(90) values (42.7 versus 9.7 nM; P<0.0001) and lower slope values (0.7 versus 1.3; P<0.0001) than HIV-1. HIV-2 R5 variants derived from AIDS patients were significantly less sensitive to MVC than variants from asymptomatic patients, this being inversely correlated with the absolute number of CD4(+) T-cells. CONCLUSIONS: T-1249 is a potent inhibitor of HIV-2 replication indicating that new fusion inhibitors might be useful to treat HIV-2 infection. Coreceptor antagonists TAK-779 and AMD3100 are also potent inhibitors of HIV-2 replication. The reduced sensitivity of R5 variants to MVC, especially in severely immunodeficient patients, indicates that the treatment of HIV-2-infected patients with MVC might require higher dosages than those used in HIV-1 patients, and should be adjusted to the disease stage.
- Comorbidities and Menopause Assessment in Women Living with HIV: a Survey of Healthcare Providers Across the WHO European RegionPublication . Caixas, U; Tariq, S; Morello, J; Dragovic, G; Lourida, G; Hachfeld, A; Nwokolo, NABSTRACTWomen living with HIV are reaching older age and experiencing menopause and age-related comorbidities. Data suggest that women living with HIV experience earlier menopause and more menopausal symptoms and age-related comorbidities compared to women without HIV. However, there are no guidelines on the screening for and management of age-related comorbidities and events in women living with HIV. Moreover, little is known about provision of care to this population across Europe. We surveyed 121 HIV healthcare providers in 25 World Health Organization European countries to ascertain screening practices for, and management of, menopause, psychosocial and sexual well-being and age-related comorbidities in women with HIV. Most respondents screened for diabetes, cardiovascular disease (CVD) risk factors and poor mental health at least annually. Low bone mineral density (BMD) was regularly checked but less than once a year. Fewer regularly screened for sexual well-being and intimate partner violence. Menstrual pattern and menopausal symptoms in women aged 45-54 were assessed by 67% and 59% of respondents. 44% stated that they were not confident assessing menopausal status and/or symptoms. CVD, diabetes, low BMD and poor mental health were managed mainly within HIV clinics, whereas menopause care was mainly provided by gynaecology or primary care. Most respondents stated a need for HIV and menopause guidelines. In conclusion, we found that whilst metabolic risk factors and poor mental health are regularly screened for, psychosocial and sexual well-being and menopausal symptoms could be improved. This highlights the need for international recommendations and clinician training to ensure the health of this population.
- Differences in Nevirapine Biotransformation as a Factor for its Sex-Dependent Dimorphic Profile of Adverse Drug ReactionsPublication . Marinho, AT; Rodrigues, PM; Caixas, U; Antunes, A; Branco, T; Harjivan, S; Marques, MM; Monteiro, EC; Pereira, SAOBJECTIVES: 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, SA; Caixas, U; Branco, T; Germano, I; Lampreia, F; Papoila, AL; 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, SA; Batuca, JR; Caixas, U; Branco, T; Delgado-Alves, J; Germano, I; Lampreia, F; Monteiro, ECWHAT 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 ToxicityPublication . Caixas, U; Antunes, A; Marinho, A; Godinho, A; Grilo, N; Marques, M; Oliveira, MC; Branco, T; Monteiro, E; Pereira, SDespite its efficacy, including in the prevention of vertical transmission, the antiretroviral nevirapine is associated with severe idiosyncratic hepatotoxicity and skin rash. The mechanisms underlying nevirapine toxicity are not fully understood, but drug bioactivation to reactive metabolites capable of forming stable protein adducts is thought to be involved. This hypothesis is based on the paradigm that drug reactive metabolites have the potential to bind to self-proteins, which results in drug-modified proteins being perceived as foreign by the immune system. The aim of the present work was to identify hemoglobin adducts in HIV patients as biomarkers of nevirapine haptenation upon bioactivation. The ultimate goal is to develop diagnostic methods for predicting the onset of nevirapine-induced toxic reactions. All included subjects were adults on nevirapine-containing antiretroviral therapy for at least 1month. The protocol received prior approval from the Hospital Ethics Committees and patients gave their written informed consent. Nevirapine-derived adducts with the N-terminal valine of hemoglobin were analyzed by an established liquid chromatography-electrospray ionization-tandem mass spectrometry method and characterized on the basis of retention time and mass spectrometric fragmentation pattern by comparison with adduct standards prepared synthetically. The nevirapine adducts were detected in 12/13 patient samples, and quantified in 11/12 samples (2.58±0.8 fmol/g of hemoglobin). This work represents the first evidence of nevirapine-protein adduct formation in man and confirms the ability of nevirapine to modify self-proteins, thus providing clues to the molecular mechanisms underlying nevirapine toxicity. Moreover, the possibility of assessing nevirapine-protein adduct levels has the potential to become useful for predicting the onset of nevirapine-induced adverse reactions.
- Generalized Lymphadenopathy as the First Manifestation of Systemic Lupus ErythematosusPublication . Soares, L; Matos, A; Mello Vieira, M; Cruz, R; Caixas, ULymphadenopathy (LAP) is a common but nonspecific feature of many diseases, representing a vast spectrum of etiologies such as infectious or inflammatory diseases, malignancies, and drugs. In systemic lupus erythematosus (SLE), it can be the first manifestation. We present the case of a 20-year-old female with a history of fever, night sweats, anorexia, and asthenia for five months. She also had diffuse generalized LAP. Although malignant etiologies were our major concern, an extensive workup for malignancy and infections was unrevealing. However, an autoimmune workup led to the diagnosis of SLE. This case shows that SLE can present as generalized LAP with constitutional symptoms, and hence it should be considered in the differential diagnosis.
- In Vitro Evaluation of Novel Reverse Transcriptase Inhibitors TAF (Tenofovir Alafenamide) and OBP-601 (2,3-didehydro-3-deoxy-4-ethynylthymidine) Against Multi-Drug Resistant Primary Isolates of HIV-2Publication . Bártolo, I; Borrego, P; Gomes, P; Gonçalves, F; Caixas, U; Pinto, IV; Taveira, NNew antiretroviral drugs are needed to treat HIV-2 infected patients failing therapy. Herein, we evaluate the activity of novel reverse transcriptase inhibitors tenofovir alafenamide (TAF) and OBP-601(2,3-didehydro-3-deoxy-4-ethynylthymidine) against primary isolates from HIV-2 infected patients experiencing virologic failure. TAF and OBP-601 were tested against twelve primary isolates obtained from nine drug-experienced patients failing therapy and three drug naïve patients using a single-round infectivity assay in TZM-bl cells. The RT-coding region of pol was sequenced and the GRADE algorithm was used to identify resistance profiles and mutations. TAF and OBP-601 inhibited the replication of almost all isolates at a median EC50 of 0.27 nM and 6.83 nM, respectively. Two isolates showed moderate-level resistance to OBP-601 or TAF and two other isolates showed high-level resistance to OBP-601 or to both drugs. With one exception, all resistant viruses had canonical nucleoside reverse transcriptase inhibitors (NRTIs)-associated resistance mutations (K65R, N69S, V111I, Y115F, Q151M and M184V). Our results show that TAF has potent activity against most multi-drug resistant HIV-2 isolates and should be considered for the treatment of HIV-2 infected patients failing therapy.
- In Vitro Evaluation of Novel Reverse Transcriptase Inhibitors TAF (Tenofovir Alafenamide) and OBP-601 (2,3-Didehydro-3-Deoxy-4-Ethynylthymidine) Against Multi-Drug Resistant Primary Isolates of HIV-2Publication . Bártolo, I; Borrego, P; Gomes, P; Gonçalves, F; Caixas, U; Pinto, I; Taveira, NNew antiretroviral drugs are needed to treat HIV-2 infected patients failing therapy. Herein, we evaluate the activity of novel reverse transcriptase inhibitors tenofovir alafenamide (TAF) and OBP-601(2,3-didehydro-3-deoxy-4-ethynylthymidine) against primary isolates from HIV-2 infected patients experiencing virologic failure. TAF and OBP-601 were tested against twelve primary isolates obtained from nine drug-experienced patients failing therapy and three drug naïve patients using a single-round infectivity assay in TZM-bl cells. The RT-coding region of pol was sequenced and the GRADE algorithm was used to identify resistance profiles and mutations. TAF and OBP-601 inhibited the replication of almost all isolates at a median EC50 of 0.27 nM and 6.83 nM, respectively. Two isolates showed moderate-level resistance to OBP-601 or TAF and two other isolates showed high-level resistance to OBP-601 or to both drugs. With one exception, all resistant viruses had canonical nucleoside reverse transcriptase inhibitors (NRTIs)-associated resistance mutations (K65R, N69S, V111I, Y115F, Q151M and M184V). Our results show that TAF has potent activity against most multi-drug resistant HIV-2 isolates and should be considered for the treatment of HIV-2 infected patients failing therapy.
- In vitro evaluation of novel reverse transcriptase inhibitors TAF (tenofovir alafenamide) and OBP-601 (2,3-didehydro-3-deoxy-4-ethynylthymidine) against multi-drug resistant primary isolates of HIV-2Publication . Bártolo, I; Borrego, P; Gomes, P; Gonçalves, F; Caixas, U; Pinto, IV; Taveira, NNew antiretroviral drugs are needed to treat HIV-2 infected patients failing therapy. Herein, we evaluate the activity of novel reverse transcriptase inhibitors tenofovir alafenamide (TAF) and OBP-601(2,3-didehydro-3-deoxy-4-ethynylthymidine) against primary isolates from HIV-2 infected patients experiencing virologic failure. TAF and OBP-601 were tested against twelve primary isolates obtained from nine drug-experienced patients failing therapy and three drug naïve patients using a single-round infectivity assay in TZM-bl cells. The RT-coding region of pol was sequenced and the GRADE algorithm was used to identify resistance profiles and mutations. TAF and OBP-601 inhibited the replication of almost all isolates at a median EC50 of 0.27 nM and 6.83 nM, respectively. Two isolates showed moderate-level resistance to OBP-601 or TAF and two other isolates showed high-level resistance to OBP-601 or to both drugs. With one exception, all resistant viruses had canonical nucleoside reverse transcriptase inhibitors (NRTIs)-associated resistance mutations (K65R, N69S, V111I, Y115F, Q151M and M184V). Our results show that TAF has potent activity against most multi-drug resistant HIV-2 isolates and should be considered for the treatment of HIV-2 infected patients failing therapy.