Remdesivir and corticosteroids in the treatment of hospitalized COVID-19 patients.

Coronavirus disease 2019 (COVID-19) is a pandemic infection caused by the newly discovered severe acute respiratory syndrome coronavirus 2. Remdesivir (RDV) and corticosteroids are used mainly in COVID-19 patients with acute respiratory failure. The main objective of the study was to assess the effectiveness of remdesivir with and without corticosteroids in the treatment of COVID-19 patients. We conducted a prospective observational study, including adult patients consecutively hospitalized with confirmed COVID-19 and acute respiratory failure. Patients were divided according to treatment strategy: RDV alone versus RDV with corticosteroids. The primary outcome was the time to recovery in both treatment groups. We included 374 COVID-19 adult patients, 184 were treated with RDV, and 190 were treated with RDV and corticosteroid. Patients in the RDV group had a shorter time to recovery in comparison with patients in the RDV plus corticosteroids group at 28 days after admission [11 vs. 16 days (95% confidence Interval 9.7-12.8; 14.9-17.1; p = .016)]. Patients treated with RDV alone had a shorter length of hospital stay. The use of corticosteroids as adjunctive therapy of RDV was not associated with improvement in mortality of COVID-19 patients.

A prospective, observational study to evaluate adverse drug reactions in patients with COVID-19 treated with remdesivir or hydroxychloroquine: a preliminary report.

OBJECTIVES: Since the outbreak of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the pressure to minimise its impact on public health has led to the implementation of different therapeutic strategies, the efficacy of which for the treatment of coronavirus disease 2019 (COVID-19) was unknown at the time. Remdesivir (REM) was granted its first conditional marketing authorisation in the EU in June 2020. The European Medicines Agency (EMA) and local health authorities all across the EU have since strongly recommended the implementation of pharmacovigilance activities aimed at further evaluating the safety of this new drug. The objective of this study was to evaluate adverse drug reactions (ADRs) attributed to either REM or hydroxychloroquine (HCQ) in patients hospitalised for COVID-19 in Centro Hospitalar de Lisboa Ocidental, a Portuguese hospital centre based in Lisbon. We present the preliminary results reporting plausible adverse effects of either HCQ or REM. METHODS: An observational cohort study was carried out between 16 March and 15 August 2020. Participants were divided into two cohorts: those prescribed an HCQ regimen, and those prescribed REM. Suspected ADRs were identified using an active monitoring model and reported to the Portuguese Pharmacovigilance System through its online notification tool. The ADR cumulative incidence was compared between the two cohorts. RESULTS: The study included 149 patients, of whom 101 were treated with HCQ and the remaining 48 with REM. The baseline characteristics were similar between the two cohorts. A total of 102 ADRs were identified during the study period, with a greater incidence in the HCQ cohort compared with the REM cohort (47.5% vs 12.5%; p<0.001). Causality was assessed in 81 ADRs, all of which were considered possible. CONCLUSIONS: Real-world data are crucial to further establish the safety profile for REM. HCQ is no longer recommended for the treatment of COVID-19.

Experience of a Portuguese Center: Effectiveness of Direct-Acting Antiviral Therapy for Hepatitis C.

INTRODUCTION: In late 2014, Portugal implemented a national program for the treatment of patients with chronic hepatitis C with directacting antiviral agents. This program has made Portugal one of the first European countries to implement a structured measure of treatment to eliminate this serious public health problem. The aim of this study was to assess the effectiveness of direct-acting antiviral therapy in the treatment of patients with chronic hepatitis C virus infection. MATERIAL AND METHODS: A retrospective observational study was conducted at Centro Hospitalar de Lisboa Ocidental on the national online platform from December 2014 until February 2017 and included patients with hepatitis C virus infection who underwent treatment. The primary endpoint was sustained virologic response at least 12 weeks post treatment. Data was analyzed with the SPSS 17.0 program. RESULTS: During the study period, 820 patients completed therapy and achieved sufficient follow-up time to assess sustained virologic response with an overall response rate of 97.2% (n = 797) and a response rate of 98.0%, 99.5%, 90.9%, 95.1% and 94.2% for genotypes 1a, 1b, 2, 3 and 4, respectively. Data suggested that advanced fibrosis (F3/F4), human immunodeficiency virus co-infection and treatment failure with interferon and ribavirin were not negatively related with sustained virologic response in our population. Most patients (80.1%) completed treatment with ledipasvir/sofosbuvir ± ribavirin. The most common adverse events were fatigue and insomnia followed by headache and weight loss. DISCUSSION: Patients predominantly had genotype 1 infection which correlates with HCV distribution in Europe, but we found a major proportion in genotype 4 which can be explained by immigration from African countries. Our patients' ages ranging from 22 to 90 years, reflected a new approach with no upper age limit. Direct-acting antivirals regimens resulted in remarkably high SVR rates compared to interferon-based regimens, which were consistent with clinical trials data. CONCLUSION: Our data showed that direct-acting antiviral-based regimens are safe and have a high success rate in the treatment of patients with hepatitis C virus infection in a real-world setting.

Introdução: No final de 2014 foi implementado em Portugal um programa nacional para o tratamento de doentes com infecção crónica por vírus da hepatite C com recurso a antivíricos de acção directa. Este programa fez com que Portugal fosse um dos primeiros países europeus a implementar uma medida estruturante para a eliminação da hepatite C. Este estudo tem como objectivo a avaliação da efectividade dos antivíricos de acção directa no tratamento da hepatite C crónica. Material e Métodos: Estudo retrospectivo observacional dos doentes seguidos no Centro Hospitalar de Lisboa Ocidental, entre dezembro de 2014 e fevereiro de 2017. O objectivo primário do estudo é avaliar a resposta virológica sustentada a partir das 12 semanas pós tratamento. Analisámos os dados com o programa SPSS 17.0. Resultados: Durante o período do estudo 820 doentes completaram o tratamento e o tempo necessário para avaliação da resposta virológica sustentada. A resposta virológica sustentada global foi de 97.2% (n = 797), com taxas de resposta de 97,2%, 98,5%, 90,9%, 95,1% e 94,2% para os genótipos 1a, 1b, 2, 3 e 4, respectivamente. Os dados sugerem não haver relação entre a fibrose avançada (F3 / F4), a coinfecção pelo vírus da imunodeficiência humana e a falência do tratamento com interferão e ribavirina e uma menor resposta ao tratamento. A maioria dos doentes (80,1%) concluiu o tratamento com ledipasvir/sofosbuvir ± ribavirina. Os eventos adversos mais frequentes foram a fadiga e a insónia, seguida de dor de cabeça e perda de peso. Discussão: A população em estudo apresentou maior prevalência de infecção pelo genótipo 1, à semelhança dos restantes países Europeus, contudo a prevalência do genótipo 4 foi superior, reflectindo a imigração africana. A faixa etária (22 - 90 anos) dos doentes tratados reflecte uma nova abordagem sem limite superior de idade. A taxa de RVS obtida, muito superior à obtida com regimes baseados em interferão, foi consistente com os dados dos ensaios clínicos. Conclusão: Os dados encontrados demonstram que os regimes baseados em antivirais de acção directa, em contexto de vida real, são seguros e eficazes no tratamento de doentes com infecção por vírus da hepatite C.

Trends in human immunodeficiency virus diagnoses among men who have sex with men in North America, Western Europe, and Australia, 2000-2014.

PURPOSE: The aim of the article was to investigate recent trends in human immunodeficiency virus (HIV) diagnosis rates among men who have sex with men (MSM) in high-income countries in North America, Western Europe, and Australia. METHODS: Data on annual rates of HIV diagnoses among MSM aged 15 to 65 years from 2000 to 2014 were collected from 13 high-income countries. Joinpoint regression software was used to empirically determine country-specific trend periods. Trends in HIV diagnosis rates and in the proportion of diagnoses occurring in young MSM aged 15 to 24 years were analyzed using Poisson regression and log-binomial regression, respectively. RESULTS: Six countries experienced an increasing trend from 2000 to 2007-08 followed by either a stable or declining trend through 2014. Five countries had recently increasing trends, and two countries had one stable trend from 2000 to 2014. All 13 countries experienced increases in the proportion of diagnoses occurring in young MSM. CONCLUSIONS: Since 2008, half of the 13 high-income countries examined experienced stable or decreasing trends. Still, some countries continue to experience increasing HIV trends, and young MSM are increasingly represented among new diagnoses. Efforts to support early sexual health promotion, reduce barriers to pre-exposure prophylaxis, and improve care engagement for young MSM are critical to addressing current HIV trends.

Evolution trends over three decades of HIV infection late diagnosis: the experience of a Portuguese cohort of 705 HIV-infected patients.

INTRODUCTION: Late HIV diagnosis is common and associated with an increased risk of clinical progression, blunted immune response on antiretroviral (ARV) therapy and higher risk of drug toxicity. Across Europe, more than a third of patients are diagnosed late and consequently delay medical care. European Consensus definition group identify as late presentation (LP) persons, presenting for care, with a CD4 count below 350 cell/mm(3) or presenting with AIDS-defining event, regardless of CD4 cell count. Additionally, advanced HIV disease (AD) is defined by a CD4 count below 200 cell/mm(3) or an AIDS defining condition in persons presenting to care. MATERIALS AND METHODS: Retrospective observational study of a cohort of 705 HIV-infected patients diagnosed between 1986 and 2014 and medically followed at an Infectious Diseases Service in Lisbon. OBJECTIVES: Evaluate LP rate evolution in the last three decades (10-year time intervals considered: 1986-1995; 1996-2005; 2006-2014); compare clinic, immunologic, virologic and therapeutic response over time. Identify main reasons responsible for late HIV diagnosis in order to promote optimized intervention strategies. SPSS version 20.0 was used for statistical analysis. RESULTS: Study included 705 patients HIV diagnosed during 3 time intervals: group A n=82 [1986-1995]; group B n=332 [1996-2005]; group C n=291 [2006-2014]. Demographic and epidemiological characterization revealed (A vs B vs C): male predominance of 79% vs 66% vs 66%; mean age at diagnosis 30 vs 36 vs 42 years; Portugal (82% vs 70% vs 58%) and Africa (13% vs 23% vs 29%) as the main places of birth; transmission by heterosexual contact in 21% vs 47% vs 62%, MSM in 21% vs 15% vs 23% and IVDU in 57% vs 35% vs 13%. Mean CD4 at diagnosis was 362 vs 344 vs 377 cell/mm(3). Considering the time intervals, LP was found in 52% vs 56% vs 52% of patients and AD in 31% vs 38% vs 35%, respectively. At first health care encounter, 46% vs 43% vs 39% of individuals presented with AIDS. Over follow up, the vast majority initiated ARV (95% vs 98% vs 84%) and mean CD4 at that time was 254 vs 282 vs 250 cell/mm(3). The last immunologic and virologic determination available registered mean CD4 of 657 vs 644 vs 584 cell/mm(3) and undetectable HIV plasma RNA in 92% vs 84% vs 82% of treated patients. CONCLUSIONS: This study evidenced a maintained LP rate, slightly above 50% in each of the three analyzed last decades, and one-third of patients presented AD at HIV diagnosis. At initial health care contact, nearly 40% of individuals met AIDS clinical or immunological criteria.

Durability of first antiretroviral treatment in HIV chronically infected patients: why change and what are the outcomes?

INTRODUCTION: First antiretroviral therapy (ART) is often switched to simpler, more potent or better tolerated regimens (1, 2). Although discontinuation rates are frequently studied, the durability of regimens is rarely approached. MATERIALS AND METHODS: Retrospective study with the following objectives: analyze first ART schemes and their durability in naive patients with chronic HIV-1 and 2 infections, evaluate factors influencing ART change, second-line ART and consequent virologic and immunologic responses. Patients had follow-ups in a Central University Hospital, started ART between January 2007 and December 2012 and changed first regimens. Clinical data was obtained from medical records and analyzed using the Statistical Package for the Social Sciences (version 20). RESULTS: Of the 652 naive patients who started ART, 164 changed regimens. The majority had HIV-1 infection (n=158). The mean age was 43.9 years (standard deviation±14.3), with a male predominance of 57.9%. Regimens with efavirenz were the most common amongst HIV-1 patients (50%) followed by lopinavir/r (22%). In HIV-2 patients, lopinavir/r (n=3) regimens were most prevalent. First ART regimens had a mean duration of 12.1 months. There was no difference between NNRTI (59.8%) and protease inhibitor (40.2%) schemes regarding durability. Adverse reactions were the major cause of ART switching (55.5%) followed by therapy resistance (12.1%). Age was inversely related to durability (p=0.007 Mann-Whitney, Phi coefficient -0.161) and associated with the appearance of adverse reactions (p=0.04, Chi-square). Younger patients had a reduced risk of adverse reactions by 27%. Adverse reactions increased the risk of inferior durability by 40%. Psychiatric symptoms (28.4%) were the most prevalent, all attributed to efavirenz. The year of ART initiation was associated with different durability rates (p=0.005, Mann-Whitney). Patients started on ART before the year 2010 reduced the probability of inferior ART duration by 25.8%. After second-line ART regimens, TCD4+ counts>500 cell/µL were increased by 38% and favourable virologic outcome achieved in 84%. CONCLUSIONS: Adverse reactions were the main cause for ART switching, supporting a cautious approach when initiating regimens, particularly in older patients. All ART naive patients who changed initial therapy had favourable immunological and virologic responses.

Clinical and laboratorial impact of antiretroviral therapy in a cohort of Portuguese patients chronically infected with HIV-2.

INTRODUCTION: HIV-2 infection is endemic in West Africa and some European countries, namely Portugal. HIV-2 antiretroviral (ARV) treatment presents some restrains related to intrinsic resistance to non-nucleoside reverse transcriptase inhibitors (NNRTI) and fusion inhibitors, and poorer response to protease inhibitors (PI). MATERIAL AND METHODS: Retrospective observational study of a cohort of 135 infected HIV-2 patients, diagnosed between 1989 and 2008. OBJECTIVES: Evaluation of epidemiologic, clinical, immunologic and virologic progression, comparing to groups of patients (naïve vs ARV experienced); characterization of therapeutic, immunologic and virologic response. SPSS version 20.0 was used for statistical analysis. RESULTS: The study included 135 patients: 41% (n=55) naïve and 59% (n=80) with ARV experience. The comparison between groups (naïve vs ARV) revealed: male prevalence 76% vs 50%; mean age 54.5 years vs 54.8 (p=0.90); main geographic origin Guiné Bissau (47% vs 44%) and Portugal (22% vs 33%); and transmission mainly acquired by heterosexual contact (87% vs 80%). Mean time since diagnosis was 14 vs 13 years (p=0.31); 2% vs 50% presented AIDS criteria at diagnosis (p<0.001) and 93% vs 38% registered TCD4>350 cell/mm(3) at diagnosis (p<0.001). Immunological evolution showed no significant decline in naïve population (Δ=-67 cell/mm(3) - p=0.18) and a significant recovery in ARV experienced (Δ=+207 cell/mm(3) - p<0.001). Global mortality rate found was 18% (6% vs 13% - p=0.122). Eighty patients initiated ARV: 84% presented a time interval of ARV exposure between 0-5 years (42%) and 5-10 years (42%). Fifty percent experienced ≤2 ARV regimens and the remaining >2 regimes. Considering the first ARV therapy: 56% initiated PI, 30% NTRI and 5% integrase inhibitor (II)-based regimens. Currently, 54 patients maintain regular follow-up and ARV therapy: 60% NTRI+PI; 37% NRTI+PI+II and 3% NRTI+II. TDF/FTC is the backbone in 56%. Most frequent PIs are LPV/r (54%), DRV/r (19%) and ATV/r (12%). Mean time of exposure to NRTI=3 years, PI=7 years and II=2 years. Immunologic recovery was sustained for each of the ARV class considered (NRTI Δ=+144 cell/mm(3); PI=Δ+92 cell/mm(3); II=Δ=+116 cell/mm(3)). CONCLUSIONS: This is a cohort accompanied for a long period and the majority of patients present extensive ARV experience. The ARV-experienced patients registered a favourable response to treatment, with sustained immune recovery (Δ=+207 cell/mm(3)) and virologic control in 74%. Immunologic behaviour evidenced a sustained gain for each of the ARV class considered.

Improve screening of HCV infection by targeting high prevalence aged groups: analysis of a cohort of HCV and HIV co-infected patients.

INTRODUCTION: Hepatitis C constitutes a major public health burden. In Portugal, the prevalence is estimated at 1-1.5% (1). Of these, only 30% are presumed to be diagnosed, which reveals that most infections go unknown. The objective of this study is to identify the age-range distribution at HCV diagnosis and to identify the high-prevalence birth groups that could be targeted for screening, as a strategy to increase diagnosis and identify patients who would benefit most from treatment. METHODS: Retrospective observational study of a cohort of chronic HCV-infected and HIV co-infected patients followed at an Infectious Diseases Center, diagnosed between 1979 and 2014 (Figure 1). Hepatic fibrosis evaluation was performed by real time elastography using METAVIR score. Epidemiological, demographic, clinical, virological and therapeutic data was retrieved from clinical registries. Statistical analysis was performed using Microsoft Excel 2010®. Chi2, Student T were used for a significant p value of <0.05. RESULTS: Our study assessed a cohort of 665 patients: 442 (66.5%) HCV/HIV co-infected and 223 (33.5%) HCV monoinfected. There was a male predominance in both groups (74.9% vs 70.9%). The mean age was 47 HCV/HIV vs 49 years; Portuguese origin in 80% vs 83% and African in 14% vs 12%. The most frequently assumed transmission route was by intravenous drug use (IVDU) (81% vs 72%), followed by sexual contact (18% vs 20%). Mean age at diagnosis was 32 vs 40 years. Mean time since HCV diagnosis was 14, 6 vs 9, 6 years. Fibrosis stage evaluation by real time elastography was available for 133 (30%) and 99 (44.4%) patients (HCV/HIV vs HCV): 16% vs 13% F1; 32% vs 33% F2; 31% vs 35% F3; 21% vs 18% F4. The peak prevalence occurred between the birth intervals of 1960-1969 and 1970-1979 for both groups, corresponding to 81% vs 66,8% (p=0.003) (Figure 1). About three quarters of all patients (76%) were born between the year of 1960 and 1979, with a prevalence of 70% of IVDU. CONCLUSIONS: In our cohort we identify a high risk population for chronically HCV infection, which comprises people born between 1960 and 1979, findings common to those with mono or HIV co-infection. This finding is concordant with the epidemic of IVDU in Portugal around 1980-1990. These patients should be screened for diagnosis in order to be treated and to prevent further disease progression.

Risk of liver decompensation assessed in HIV/HCV co-infected individuals with advanced liver fibrosis: a faster countdown experience.

INTRODUCTION: Cirrhosis secondary to HCV infection is expected to peak in the next decade, particularly in the HIV co-infected subgroup and has become a leading cause of morbidity among these individuals. Efforts must be done to estimate the risk of liver decompensation (LD) in the short term, in order to define the appropriate time for HCV treatment. MATERIALS AND METHODS: Retrospective observational cohort study aimed to assess the risk of LD among a group of HIV/HCV co-infected patients diagnosed in the past 23 years in a central hospital of Lisbon. INCLUSION CRITERIA: (1) advanced liver fibrosis ≥F3; (2) HCV treatment naïve or without sustained virologic response (SVR). Patients had a one to five years period of follow-up. Multiple linear regression, Mann-Whitney and Kendall were the statistical tests performed. RESULTS: From 444 HIV/HCV co-infections, 66 met the inclusion criteria, with preponderance of male gender (82%), 35-45 years of age (55%), genotype 1a (52%), a mean of 13 years of co-infection and an AIDS stage documented in 65%, though the majority is under antiretroviral therapy (86%) and have TCD4+>500 µ/L (59%). Half (52%) showed evidence of steatosis, many of these (41%) presenting a history of alcoholism or overweight (BMI ≥25 Kg/m(2)). Pre-cirrhotic (F3 or F3/4) or cirrhotic (F4) stage was documented in 36 and 30 patients respectively. After staging, 28 (42%) initiated HCV treatment and SVR was achieved in 8 (29%) of those. Five (14%) pre-cirrhotic and twelve (40%) cirrhotic patients experienced at least one LD episode: 8 vs 28 cumulative events at five years and 2.8 vs 1.8 average years up to the first LD episode for pre-cirrhotic vs cirrhotic. The probability of remaining free of LD for pre-cirrhotic vs cirrhotic patients was 97% vs 78% (p≤0.01) at one year; 88% vs 65% (p≤0.001) at three years and 71% vs 44% (p≤0.001) at five years. Positive correlation was found between LD and the cirrhotic stage (vs pre-cirrhosis, p≤0.001), baseline AST ≥100 µ/L (vs <100 µ/L, p≤0.01) and platelet count <120 x 109/L (vs >120 x 109/L, p≤0.05). CONCLUSIONS: Cirrhosis accounts for a significant superior risk of LD. The time up to the first LD event differed in only one year between pre-cirrhotic and cirrhotic, standing for the importance of a rapid treatment referral in both subgroups. Modifiable risk factors that accelerate fibrosis are prevalent in HIV/HCV co-infected patients. Low platelet count, elevated AST and F4 stage predict the rapid progression to LD and the need for early HCV treatment. Large studies are required for further support of these results.

Single-tablet regimens in HIV: does it really make a difference?

OBJECTIVES: Review of the available data on the currently available single-tablet regimens (STRs), from the analysis of efficacy and safety to the key points of value in terms of adherence, quality of life and pharmacoeconomic evaluation. METHODS: For this narrative review, literature searches have been performed in PubMed, IndexRevMed and Cochrane, using the search terms HIV, single-tablet, one-pill, single dose, fixed-dose, and STR. These have been reviewed and complemented with the most recent publications of interest. RESULTS: Fixed-dose combinations are a significant advance in antiretroviral treatment simplification, contributing to an increase in compliance with complex chronic therapies, thus improving patients' quality of life. Reducing the number of pills and daily doses is associated with higher adherence and better quality of life. As a fixed-dose combination tablet given once daily, EFV/FTC/TDF was the first available STR combining efficacy, tolerability and convenience, with the simplest dosing schedule and smallest numbers of pills of any ART combination therapy. The RPV/FTC/TDF is a next-generation NNRTI-based STR, a once daily complete ART regimen for the treatment of HIV-1 infection. Recently the combination of EVG/COBI/FTC/TDF was also approved by the European Commission, and is the first integrase inhibitor-based STR. Receiving antiretroviral therapy as once daily STR is associated with both clinical and economic benefits, which confirms previous research. CONCLUSIONS: The associated benefits of STRs provide a valid strategy for the treatment of HIV-infected patients.

Evaluation of the Treponema pallidum particle agglutination technique (TP.PA) in the diagnosis of neurosyphilis.

The Treponema pallidum particle agglutination technique (TP.PA) was evaluated, in comparison with the Venereal Disease Research Laboratory (VDRL) test, microhemagglutination assay for Treponema pallidum antibodies (MHA-TP), and fluorescent treponemal antibody-ABS (FTA-Abs) test for the diagnosis of neurosyphilis. We have studied 198 cerebrospinal fluid (CSF) samples from patients with syphilis, including neurosyphilis, treated syphilis, and with other neurological manifestations than neurosyphilis. All tests were nonreactive in these last group of patients. In the neurosyphilis patients, sensitivity of the TP.PA was 100%. The performance of this test in CSF from patients with primary syphilis was as good as that of the other tests. In secondary and latent syphilis, the TP.PA results (27 reactive samples/73) were similar to those of the MHA-TP (25 reactive samples/73). In the individuals treated for syphilis, the TP.PA, FTA-Abs, and MHA-TP tests were found to be reactive in eight, six, and eight samples, respectively. In conclusion, it seems that the TP.PA can be used in CSF to diagnose neurosyphilis, although as for other serological tests, interpretation of results should be done in conjunction with other neurosyphilis parameters.