Simultaneous Determination of Blood Concentrations of Five Antiretrovirals in Human Plasma by Ultra High Performance Liquid Chromatography-tandem Mass Spectormetry Method / 医药导报

Objective To develop an ultra-performance liquid chromatography-mass spectrometry(UPLC-MS/MS)method for the simultaneous quantification of dolutegravir,raltegravir,efavirenz,lamivudine and tenofovir in human plasma and to apply it to the therapeutic monitoring.Methods Dolutegravir-D5,raltegravir-D4,efavirenz-D5,lamivudine-13 C-15 N2 and tenofovir-D7 were used as internal standard,respectively.All samples were extracted using the protein precipitation method with acetonitrile and then diluted for analysis.Chromatographic separation was performed on Shim-pack XR-ODS Ⅲ(2.0 mmx50 mm,1.6 μm)column.Mobile phases A and B consisted of 0.1％formic acid in water and acetonitrile respectively.A programmed mobile phase gradient was used at a flow rate of 0.3 mL·min-1 and column temperature of 40 ℃.The tandem mass spectrometer was equipped with an electrospray ionization(ESI)source operating in multiple reaction monitoring(MRM)modes.After methodological validation,it can be used for therapeutic drug monitoring in HIV patients.Results There was good linearity in the validated concentration ranges of 62.5-3 000 ng·mL-1 for dolutegravir,10-500 ng·mL-1 for raltegravir,125-6 000 ng·mL-1for efavirenz,10-500 ng·mL-1 for lamivudine and 10-500 ng·mL-1 for tenofovir with the linear correlation coeffificients of determination(R2)of all higher than 0.998.The accuracy of both intra-day and inter-day studies ranged from 94.0％-109.3％,and the relative standard deviations were less than 7％.The IS-normalized matrix factor and extraction recoveries of all analytes were 95.7％-106.0％and 98.7％-104.5％at all concentrations.All analytes were stable in plasma at a certain storage environment.The trough blood concentrations of dolutegravir,efavirenz,lamivudine and tenofovir were 107.7-2 366.0,740.0-3 410.0,38.5-1 229.3,31.6-224.4ng·mL-1 in HIV patients,respectively.Conclusion The method is highly aceurate,easy to perform,low-cost,and suitable for therapeutic drug monitoring of dolutegravir,raltegravir,efavirenz,lamivudine and tenofovir in HIV patients.

Effect of Elvitegravir,Cobicistat,Emtricitabine and Tenofovir Alafenamide single tablet alone and TDF+3TC+EFV scheme in the treatment of AIDS based on single blind prospective randomized trials / 国际检验医学杂志

Objective To investigate the effect of Elvitegravir,Cobicistat,Emtricitabine and Tenofovir Alafenamide single tablet alone versus tenofovir(TDF)+lamivudine(3TC)+efavirenz(EFV)scheme in the treatment of patients with acquired immunodeficiency syndrome(AIDS).Methods A total of 100 patients with AIDS who visited the hospital from January 2022 to October 2022 were selected and divided into two groups by random number table method,50 cases in each group.Group A was treated with Elvitegravir,Cobi-cistat,Emtricitabine and Tenofovir Alafenamide single tablet monotherapy and Group B was treated with TDF+3TC+EFV scheme.The human immunodeficiency virus(HIV)load,body immunity(CD4+,CD8+,CD4+CD38+cell ratio,CD8+CD38+cell ratio),lipid metabolism indexes[total cholesterol(TC),triglycerides(TG),low-density lipoprotein cholesterol(LDL-C),high-density lipoprotein cholesterol(HDL-C)],glucose metabolism indexes[fasting blood glucose(FPG),glycated hemoglobin(HbA1c)],glycoprotein 130(gp130),interleukin-35(IL-35)and its receptor IL-12Rβ2 levels were observed before and after treatment in the two groups,and the drug safety in the two groups was counted.Results After 3 months of treatment,HIV load,CD8+count,CD4+CD38+cell ratio,and CD8+CD38+cell ratio in both groups were lower than those before treatment,and CD4+count was higher than that before treatment(P＜0.05),but the difference was not statistically significant when compared between A and B groups(P＞0.05).After 3 months of treat-ment,the levels of IL-12Rβ2,gp130,IL-35,TC,TG,and LDL-C in both groups were higher than those before treatment,and HDL-C level was lower than that before treatment,and the change in group B was greater than that in group A(P＜0.05).FPG and HbAlc levels were higher in group B after 1 month and 3 months of treatment,and were higher than those in group A(P＜0.05).Drug safety analysis showed that the incidence rates of adverse reactions were 12.00％(6/50)in group A and 26.00％(13/50)in group B,and there was no statistically significant difference between the two groups(P＞0.05).The incidence rates of liver and kidney injury in group A was 10.00％(5/50),and that in group B was 12.00％(6/50),and there was no statistically significant difference between two groups(P＞0.05).Conclusion Elvitegravir,Cobicistat,Emtricitabine and Tenofovir Alafenamide single tablet monotherapy and the TDF+3TC+EFV scheme could significantly re-duce the HIV load of AIDS patients and improve their immune level,but the former has less effect on pa-tients'glycolipid metabolism and inflammatory factors,and the monotherapy scheme is superior based on the comprehensive consideration of safety and efficacy.

Renal injury caused by tenofovir disoproxil fumarate in a patient with liver cancer complicated with HBV infection：a case report and literature analysis / 中国药房

Tenofovir disoproxil fumarate （TDF） is a first-line treatment for chronic hepatitis B. With increasing use worldwide， the adverse events of renal injury caused by this drug have also attracted industry attention. This article reports a 61- year-old patient with liver cancer complicated with hepatitis B virus （HBV） infection. The patient started using TDF in mid-March 2022 and developed kidney injury after 2 months of treatment， during which he received 2 courses of donafenib combined with sintilimab chemotherapy and irregular administration of diclofenac for pain relief. In this paper， Naranjo’s assessment scale was used to evaluate the drugs that may be associated with renal injury， including TDF and sintilimab， and the drugs that are suspected to be associated with renal injury are donafenib and diclofenac. The renal injury caused by TDF can be judged according to the changes in the patient’s condition， the incidence of drug-induced renal injury， clinical manifestations， occurrence time， occurrence mechanism， drug combination， and high-risk factors. The changes of serum creatinine in patients with liver cancer complicated with HBV infection after TDF should be dynamically monitored in the clinic， and the dose of antiviral drugs should be adjusted if necessary and other antiviral drugs with less impact on renal function can be selected， to provide individualized medication recommendations for tumor patients， reduce the incidence of TDF-related renal injury.

Assessing bone mineral density in children and adolescents living with HIV and on treatment with tenofovir disoproxil fumarate: a systematic review / Avaliação da densidade mineral óssea em crianças e adolescentes que vivem com HIV e em tratamento com tenofovir disoproxil fumarato: uma revisão sistemática

ABSTRACT Objective: To investigate the impact of tenofovir disoproxil fumarate on bone mineral density and bone mineral content in children and adolescents infected with the human immunodeficiency virus. Data source: The search procedure was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Statement. The search was carried out until April 2022 in Medical Literature Analysis and Retrieval System Online (Medline), Embase, Cochrane Central, Latin American and Caribbean Health Sciences Literature, Web of Science, Scopus, and MedRxiv. The combination of terms used was: (Children OR Youth OR Teenagers) AND HIV AND (Tenofovir OR "Antiretroviral therapy") AND ("Bone density" OR Osteoporosis OR Osteopenia). The protocol was registered in the International Prospective Register of Systematic Reviews (PROSPERO, CRD42022312851) Data synthesis: The initial searches resulted in 1156 papers. After the exclusion of duplicate studies, three blinded reviewers analyzed the title and abstract of 563 papers, of which 57 remained to be read in full. Only nine papers met the eligibility criteria and were included in descriptive and risk-of-bias analyses. Regarding study design, four were cross-sectional, three were longitudinal before-after studies without a control group, and two were prospective cohorts. Among these nine papers, seven showed no significant association between tenofovir disoproxil fumarate use and reduced bone mass in young people. However, these papers did not have high methodological quality. Conclusions: Although most of the selected papers found no harmful effect of tenofovir disoproxil fumarate on bone mass, further primary research with higher methodological quality is needed so robust scientific evidences can be obtained.

RESUMO Objetivo: Investigar o impacto do tenofovir disoproxil fumarato sobre a densidade mineral óssea e o conteúdo mineral ósseo em crianças e adolescentes infectados pelo vírus da imunodeficiência humana. Fontes de dados: O procedimento de busca foi executado de acordo com o Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Statement. A busca foi realizada até abril de 2022 nas seguintes bases de dados: Medical Literature Analysis and Retrieval System Online (Medline), Embase, Cochrane Central, Literatura Latino-Americana e do Caribe em Ciências da Saúde (Lilacs), Web of Science, Scopus, and MedRxiv. A combinação de termos utilizada foi: (Children OR Youth OR Teenagers) AND HIV AND (Tenofovir OR "Antiretroviral therapy") AND ("Bone density" OR Osteoporosis OR Osteopenia). O protocolo foi registrado na base International Prospective Register of Systematic Reviews — PROSPERO (CRD42022312851). Síntese dos dados: As pesquisas iniciais resultaram em 1.156 artigos. Após a exclusão dos estudos duplicados, três revisores cegos analisaram título e resumo de 563 estudos, dos quais 57 permaneceram para leitura na íntegra. Somente nove artigos atenderam aos critérios de elegibilidade e foram incluídos para análises descritivas e de risco de viés. Com relação ao desenho dos estudos, quatro foram transversais, três foram estudos longitudinais antes-depois sem grupo controle e dois foram coortes prospectivas. Dos nove artigos, sete não mostraram associação significativa entre uso de TDF e redução de massa óssea em pessoas jovens. Entretanto, esses estudos não tiveram alta qualidade metodológica. Conclusões: Embora a maioria dos estudos selecionados não tenha encontrado efeito prejudicial do TDF sobre massa óssea, novas pesquisas primárias com maior qualidade metodológica são necessárias para que sejam obtidas evidências científicas robustas.

Research advances in tenofovir alafenamide fumarate in treatment of special chronic hepatitis B / 临床肝胆病杂志

There are a large number of individuals with HBV infection in China, which seriously endangers public health safety. As a first-line drug used in clinical practice, tenofovir alafenamide fumarate (TAF) has the characteristics of strong efficacy, low drug resistance, and bone and kidney safety. This article summarizes the role of TAF in patients with special types of chronic hepatitis B, such as low-level viremia, multidrug resistance, pregnancy, liver failure, and liver transplantation, and the analysis shows that TAF can reduce viral load in patients with low-level viremia to achieve virologic response, provide new regimens for patients with drug resistance, block mother-to-child transmission, reduce the mortality rate of patients with end-stage liver disease, and improve renal function in patients with chronic kidney disease.

Efficacy and safety of tenofovir alafenamide fumarate in treatment of chronic hepatitis B patients aged ≥60 years in Qingdao, China / 临床肝胆病杂志

Objective To investigate the application value of tenofovir alafenamide fumarate (TAF) in elderly patients with chronic hepatitis B (CHB) and its influence on bones and kidneys. Methods A total of 36 CHB patients, aged ≥60 years, who received TAF antiviral therapy in Qingdao Municipal Hospital, The Affiliated Hospital of Qingdao University, Qingdao Sixth People's Hospital, Chengyang People's Hospital, and Jimo People's Hospital from June 2021 to October 2022 were enrolled in this study, and all patients received TAF (25 mg/d) antiviral therapy. Related data were collected at baseline and weeks 24 and 48 of treatment, including virological indicators, biochemical parameters, urinary protein electrophoresis indices, transient elastography (FibroScan), and bone mineral density. Virological indicators included high-sensitivity HBV DNA quantification; biochemical parameters included total bilirubin, direct bilirubin (DBil), indirect bilirubin (IBil), alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, gamma-glutamyl transpeptidase, total bile acid (TBA), glucose, blood urea nitrogen, creatinine, estimated glomerular filtration rate, and cystatin C (Cys C); urinary protein electrophoresis indices included urinary β2 microglobulin (β2-MG), urinary retinol (URBP), and urinary α1 microspherin (α1-MG). The paired t -test was used for comparison of normally distributed continuous data before and after treatment, and the Wilcoxon signed-rank test was used for comparison of non-normally distributed continuous data before and after treatment; the chi-square test or the Fisher's exact test was used for comparison of categorical data. Results A total of 36 CHB patients completed 24 weeks of follow-up. The complete virological response rate after 24 weeks of treatment was higher than that at baseline [83.3% (30/36) vs 77.8% (28/36), χ 2 =0.36, P =0.55], and there were significant reductions in DBil ( t =-2.42, P =0.02) and Cys C ( t =-4.34, P 0.05). Conclusion TAF has a good antiviral effect in CHB patients aged ≥60 years and can help more CHB patients achieve complete virological response, without causing damage to the kidney, and it can also improve bone mineral density and liver fibrosis degree.

Adverse event analysis and renal safety comparison of tenofovir disoproxil and tenofovir alafenamide based on FAERS database / 药物流行病学杂志

Objective To explore the adverse events and renal safety of tenofovir disoproxil(TD)and tenofovir alafenamide(TA)by data mining from the U.S.Food and Drug Administration Adverse Event Reporting System(FAERS)database,so as to provide reference for clinical drug safety.Methods The adverse events of TD and TA reported in FAERS database between the first quarter of 2004 and the first quarter of 2023 were analyzed with the methods of the reporting odds ratio(ROR)method,proportional reporting ratio(PRR)method,the Medicines and Healthcare products Regulatory Agency(MHRA)method,and Bayesian Confidence Propagation Neural Network(BCPNN)method.The distribution and intensity of risk signals of the data were analyzed,and the SMQ search tool was employed to conduct in-depth analysis of"acute renal failure"and"chronic kidney disease".Results A total of 19 530 and 1 587 reports were extracted as primary suspect drugs for TD and TA.There were more males than females were found in reports,and the age was concentrated in 45-65 years old,and the number of signals satisfying the four excavation methods was 185 and 68,respectively.The high-frequency adverse event distribution showed significant differences between TD and TA.The main risk signals of TD were bone and renal diseases,manifested as decreased bone density,bone injury,osteoporosis,chronic kidney disease,and renal failure.The main risk signals of TA was systemic disease with few reports of bone and renal damage,most of which were negative signals.Further analysis of renal safety showed similar results.Conclusion There are certain differences in terms of high-frequency adverse events,systemic organ distribution,and overall safety between TD and TA,especially the safety of renal and bone.Patients with pre-existing renal and bone diseases prefer TA to TD,however,the short time to market and the deviation caused by the small number of reports for TA,the safety of the two drugs should be continuously paid attention to.

Effectiveness and safety of tenofovir alafenamide for chronic hepatitis B patients with decompensated cirrhosis / 实用医学杂志

Objective To investigate the efficacy and safety of tenofovir alafenamide fumarate(TAF)in the treatment of patients with decompensated hepatitis B cirrhosis.Methods We retrospective analyzed 41 patients with decompensated hepatitis B cirrhosis receiving TAF antiviral therapy for 24 weeks at Wuwei Tumor Hospital in Gansu province from June 2022 to June 2023.Primary endpoint was proportion of patients achieving virologic response(HBV DNA<20 IU/mL).Other endpoints included changes in ALT,AST,TBIL,Child-Pugh score(CTP),and MELD score from baseline to week 24.In terms of safety,changes in Scr,eGFR and adverse events from baseline to week 24 were observed.Results Of 41 patients,73.2%were male(n = 30),with mean age of 53.49 years.24 weeks after treatment with TAF,HBV DNA was undetectable in 90.2%of the patients.The median levels of ALT,AST and total bilirubin(TBIL)were 50.70 U/L,48.70 U/L and 26.40 μmol/L respectively at base-line,and reduced significantly to 31.50 U/L,37.8 U/L and 23.8 μmol/L(P<0.05)respectively after 24-week therapy with TAF.CTP score was improved in 58.6%of the patients(n = 24),and so was MELD score in 63.4%of the patients(n = 26)at week 24.The median serum creatinine and eGFR were 58.5 μmol/L and 106.15 mL/(min·1.73 m2)respectively at baseline,and creatinine and eGFR were stable during treatment.No drug-related adverse events or severe adverse events occurred during treatment,neither did creatinine and eGFR liver transplan-tation,HCC or death.Conclusions Our clinical studies demonstrated better effectiveness and safety of TAF for decompensated CHB patients.

Regulatory effects of tenofovir disoproxil fumarate on oxidative stress and peripheral blood Th17/Treg balance in patients with hepatitis B cirrhosis / 中国基层医药

Objective:To investigate the regulatory effects of tenofovir disoproxil fumarate on oxidative stress and peripheral blood Th17/Treg balance in patients with hepatitis B cirrhosis.Methods:A total of 102 patients with hepatitis B cirrhosis who received treatment in the Marine Police Corps Hospital of Chinese People's Armed Police, China from March 2020 to June 2021 were included in this study. They were randomly assigned to undergo treatment with either tenofovir disoproxil fumarate ( n = 51, observation group) or entecavir ( n = 51, control group) for 42 weeks. The levels of malondialdehyde (MDA), superoxide dismutase (SOD), nitric oxide (NO), T helper 17 cells (Th17), regulatory T cells (Treg), Th17/Treg ratio, hyaluronic acid (HA), laminin (LN), type III procollagen (PC III), type IV collagen (IV-C), hepatitis B virus DNA negative rate, HBeAg negative rate, and alanine aminotransferase normalization rate pre- and post-treatment as well as the incidence of adverse reactions were compared between the two groups. Results:Before treatment, there were no significant differences in SOD, MDA, NO, Th17, Treg, Th17/Treg ratio, HA, LN, PC III, IV-C between the two groups (all P > 0.05). After treatment, SOD and Treg in the observation group were (121.52 ± 23.52) U/L and (3.51 ± 0.70)% in the observation group, respectively, which were significantly higher than (113.30 ± 20.05) U/L and (3.14 ± 0.49)%, respectively in the control group ( t = 1.90, -4.14, both P < 0.05). MDA, NO and Th17, Th17/Treg ratio, HA, LN, PC III, and IV-C in the observation group were (7.40 ± 1.35) mmol/L, (22.56 ± 4.25) μmol/L, (1.29 ± 0.46)%, (0.45 ± 0.11), (212.52 ± 16.62) μg/L, (135.52 ± 14.02) μg/L, (132.52 ± 15.62) μg/L,(96.52 ± 10.02) μg/L, respectively, which were significantly lower compared with the control group ( t = -6.81, 4.02, 3.10, -8.46, -13.27, -15.23, -13.67, -17.38, all P < 0.05). Hepatitis B virus DNA negative rate, HBeAg negative rate, and alanine aminotransferase normalization rate in the observation group were 76.47% (39/51), 68.63% (35/51) and 74.51% (38/51), respectively, which were higher than 56.86% (29/51), 41.18% (21/51), 54.90% (28/51) in the control group ( χ2 = 4.41, 7.76, 4.29, all P < 0.05). There was no significant difference in the incidence of adverse reactions between the two groups ( P > 0.05). Conclusion:Tenofovir disoproxil fumarate is highly effective on hepatitis B cirrhosis. It can reduce oxidative stress and regulate peripheral blood Th17/Treg balance.

Research progress of tenofovir alafenamide in blocking mother-to-child transmission of hepatitis B virus / 中国临床药理学与治疗学

Hepatitis B virus (HBV) infection is a global public health problem, and the prevention of mother-to-child transmission (MTCT) is an important intervention method. As a new nucleoside reverse transcriptase inhibitor, tenofovir alafenamide (TAF) has the characteristics of strong liver targeting and low peripheral blood exposure. Although it has been used in the treatment of chronic hepatitis B widely, its application in blocking mother-to-child transmission of HBV is still limited. This paper reviews the characteristics of TAF, the effects of TAF on infants and pregnant women, in order to provide new ideas for the prevention of mother-to-child transmission of HBV.

Adverse effects of daily oral pre-exposure prophylaxis in men who have sex with men and transgender women: a systematic review and meta-analysis / Efeitos adversos da profilaxia pré-exposição oral diária para homens que fazem sexo com homens e mulheres trans: revisão sistemática e metanálise / Efectos adversos de la profilaxis preexposición oral diaria para hombres que tienen relaciones sexuales con hombres y mujeres trans: revisión sistemática y metaanálisis

Abstract: The adverse effects of oral pre-exposure prophylaxis (PrEP) using tenofovir disoproxil fumarate are barriers to PrEP initiation and continuation. Although serious effects are rare and predictable, evidence for this assessment among men who have sex with men (MSM) and transgender women (TGW) is still limited. This study assesses the adverse effects of daily oral PrEP in MSM and TGW. This is a systematic review and meta-analysis of clinical trials and cohort studies on the use of daily oral PrEP selected from the PubMed/MEDLINE, Embase, LILACS, and Cochrane CENTRAL databases. Data extraction included adverse effects and changes in renal and hepatic markers. Random effects models were used to summarize the risk of adverse effects throughout the study. Heterogeneity was assessed using the Cochran's Q test and the inconsistency test (I2). The risk of bias and the certainty of the evidence were assessed using the Cochrane Collaboration recommendations. The search identified 653 references. Of these, 10 were selected. All studies assessed the eligibility of renal and hepatic markers. The use of daily oral PrEP was not associated with grade 3 or 4 adverse events (RR = 0.99; 95%CI: 0.83-1.18; I2 = 26.1%), any serious adverse event (RR = 1.04; 95%CI: 0.58-1.87; I2 = 88.4%), grade 3+4 creatinine level (RR = 0.66; 95%CI: 0.24-1.84; I2 = 79.9%), and grade 3 or 4 hypophosphatemia (RR = 0.56; 95%CI: 0.15-2.10). The certainty of the evidence ranged from high to moderate for the outcomes analyzed. Daily oral PrEP is safe and well tolerated by MSM and TGW. Adverse effects were minimal and evenly distributed between intervention and control.

Resumo: Os efeitos adversos da profilaxia pré-exposição (PrEP) oral com fumarato de tenofovir desoproxila são barreiras para o início e a continuidade da PrEP. Embora os efeitos graves sejam raros e previsíveis, as evidências dessa avaliação entre homens que fazem sexo com homens (HSH) e mulheres transgênero (MTG) ainda são limitadas. Este estudo avalia os efeitos adversos da PrEP oral diária em HSH e MTG. Trata-se de uma revisão sistemática e metanálise de ensaios clínicos e coortes que demonstram o uso de PrEP oral diária selecionados nas bases de dados PubMed/MEDLINE, Embase, LILACS e Cochrane CENTRAL. A extração de dados incluiu os efeitos adversos e alterações nos marcadores renais e hepáticos. Modelos de efeitos aleatórios foram usados para resumir o risco de efeitos adversos ao longo do estudo. A heterogeneidade foi avaliada pelo teste Q de Cochran e inconsistência (I2). O risco de viés e a certeza da evidência foram avaliados por meio das recomendações da Colaboração Cochrane. Foram identificadas 653 referências. Destes, dez foram selecionadas. Todos os estudos avaliaram marcadores renais de elegibilidade e marcadores hepáticos. O uso diário de PrEP oral não foi associado a eventos de grau 3 ou 4 (RR = 0,99; IC95%: 0,83-1,18; I2 = 26,1%), a qualquer evento adverso grave (RR = 1,04; IC95%: 0,58-1,87; I2 =88,4%), à creatinina grau 3 ou 4 (RR = 0,66; IC95%: 0,24-1,84; I2 = 79,9%) e à hipofosfatemia grau 3 ou 4 (RR = 0,56; IC95%: 0,15-2,10). A certeza das evidências variou de alta a moderada para os desfechos analisados. A PrEP oral diária é segura e bem tolerada por HSH e MTG. Os efeitos adversos foram mínimos e distribuídos uniformemente entre a intervenção e o controle.

Resumen: Los efectos adversos de la profilaxis preexposición (PrEP) oral con fumarato de disoproxilo de tenofovir son barreras para el inicio y la continuación de la PrEP. Aunque los efectos graves son raros y predecibles, la evidencia de esta evaluación entre hombres que tienen sexo con hombres (HSH) y mujeres transgénero (MTG) sigue siendo limitada. Este estudio evalúa los efectos adversos de la PrEP oral diaria en HSH y MTG. Se trata de una revisión sistemática y un metaanálisis de ensayos clínicos y cohortes que demuestran el uso de la PrEP oral diaria seleccionada de las bases de datos PubMed/MEDLINE, Embase, LILACS y Cochrane CENTRAL. La recolección de datos incluyó efectos adversos y cambios en los marcadores renales y hepáticos. Se utilizaron modelos de efectos aleatorios para resumir el riesgo de efectos adversos a lo largo del estudio. La heterogeneidad se evaluó mediante la prueba Q de Cochran y la inconsistencia (I2). El riesgo de sesgo y la certeza de la evidencia se evaluaron utilizando las recomendaciones de la Colaboración Cochrane. Se identificaron 653 referencias. De estas, se seleccionaron diez. Todos los estudios evaluaron los marcadores renales de elegibilidad y los marcadores hepáticos. El uso diario de la PrEP oral no se asoció con eventos de grado 3 o 4 (RR = 0,99; IC95%: 0,83-1,18; I2 = 26,1%), con ningún evento adverso grave (RR = 1,04; IC95%: 0,58-1,87; I2 = 88,4%), con creatinina de grado 3 o 4 (RR = 0,66; IC95%: 0,24-1,84; I2 = 79,9%) y con hipofosfatemia de grado 3 o 4 (RR = 0,56, IC95%: 0,15-2,10). La certeza de la evidencia varió de alta a moderada para los resultados analizados. La PrEP oral diaria es segura y bien tolerada por HSH y MTG. Los efectos adversos fueron mínimos y se distribuyeron uniformemente entre la intervención y el control.

Liver transplantation for acute-on-chronic liver failure / 器官移植

Acute-on-chronic liver failure (ACLF) is a specific category of liver failure, which is mainly characterized by rapid progression and multiple organ failure. At present, patients with ACLF are mainly given with systematic and comprehensive medical therapy to promote liver regeneration. However, liver transplantation is the only potentially curative treatment for patients who failed to respond to medical treatment and rapidly progress into multiple organ failure. Considering the differences of disease progression and clinical prognosis, and the shortage of donor liver in China, it is necessary to actively prevent the triggering factors of ACLF in patients with chronic liver diseases, screen out the recipients who are most likely to benefit from liver transplantation and deliver precision management during perioperative period of liver transplantation. In this article, the application of liver transplantation in ACLF was illustrated from the perspectives of accurate evaluation of ACLF, proper control of liver transplantation indications and meticulous perioperative management, aiming to optimize the therapeutic strategy of liver transplantation in patients with ACLF.

Comparison of tenofovir alafenamide and entecavir for hepatitis B virus-related acute-on-chronic liver failure / 中南大学学报(医学版)

OBJECTIVES@#Hepatitis B virus related acute-on-chronic liver failure (HBV-ACLF) is the most common type of liver failure in China, with a high mortality. Early rapid reduction of HBV-DNA load can improve the survival rate of HBV-ACLF patients. At present, the commonly used drugs are nucleoside (acid) analogues, such as entecavir (ETV), tenofovir, and so on. The newly listed tenofovir alafenamide fumarate (TAF) has attracted great attention of clinicians because of its stronger antiviral effect, higher transaminase normalization rate, better bone and kidney safety, and zero drug resistance. However, there are few clinical research data on the efficacy and safety of TAF in the treatment of Chinese HBV-ACLF patients, and there is a lack of pharmacoeconomic evaluation. This study aims to compare the efficacy, safety, and cost-effectiveness between TAF and ETV in patients with HBV-ACLF.@*METHODS@#The data were collected from 196 HBV-ACLF patients (80 patients in the TAF group and 116 patients in the ETV group) who were hospitalized in Xiangya Hospital, Central South University from May 2020 to March 2021. Biochemistry and virology were detected before and after treatment (at baseline, Week 2, 4, and 12). Clinical features, disease prognosis, and cost-effectiveness were compared between the 2 groups. According to the baseline, HBV-ACLF patients were divided into 4 stages including pre-liver failure stage, early stage, medium stage, and end stage. And the liver transplantation rate and mortality was also compared. Pharmacoeconomic evaluation was taken using cost-effectiveness analysis and cost minimization analysis．.@*RESULTS@#After 4 weeks of treatment, there were no significant differences in the efficacy (liver function, viral load) between the 2 groups (all P>0.05). The TAF group showed lower creatinine [(80.35±18.77) μmol/L vs (105.59±82.32) μmol/L, P<0.05] and higher estimated glomerular filtration rate (eGFR) levels [(95.65±23.21) mL/(min·1.73 m2) vs (82.68±26.32) mL/(min·1.73 m2), P<0.05] than the ETV group. After 12 weeks of treatment, the analysis of overall the liver transplantation rate and mortality between the 2 groups showed similar conclusion. However, the TAF group had a lower the liver transplantation rate and mortality than the ETV group in patients with pre-liver failure (0vs13.89%, P<0.05). No evident distinction was found in the liver transplantation rate and mortality during the early, medium, or end stages of liver failure (13.04% vs 17.65%, 37.50% vs 37.04%, and 54.55% vs 68.42%, respectively). Ratio of cost to effectiveness in the ETV group was higher than that in the TAF group.@*CONCLUSIONS@#TAF is not more efficient than ETV group in improving liver function and reducing viral load for HBV-ACLF patients and they also show similar safety. However, TAF has a greater advantage over ETV not only in preserving renal function, but also in reducing the liver transplantation rate and mortality in patients with pre-liver failure. TAF can provide economic benefit to patients with HBV-ACLF.

Tenofovir-induced renal and bone toxicity: report of two cases and literature review

ABSTRACT Tenofovir Disoproxil Fumarate (TDF) is one of the drugs in the initial first-line antiretroviral regimen for the treatment of hepatitis B and HIV infections. Despite its effectiveness and few adverse effects, it is related to renal and bone toxicity. We described two cases of HIV-positive middle-aged women who had been using TDF for two and four years (cases 1 and 2, respectively) and were admitted to the emergency room. Case 1 presented with metabolic ileum and diffuse bone pain while case 2 presented with bilateral coxo-femoral pain after a fall from standing height. Both cases had similar laboratory tests: hyperchloremic metabolic acidosis, hypophosphatemia, hypokalemia, hypouricemia and elevated plasma creatinine. In urinary exams, there was evidence of renal loss of electrolytes, justifying the serum alterations, in addition to glucosuria and proteinuria. The bone pain investigation identified bone fractures and reduced bone mineral density, together with increased levels of parathyroid hormone, alkaline phosphatase and vitamin D deficiency. These two cases illustrate the spectrum of adverse renal and bone effects associated with TDF use. TDF was discontinued and treatment was focused on correcting the electrolyte disturbances and acidosis, in addition to controlling the bone disease through vitamin D and calcium supplementation. The renal changes found in both cases characterized the Fanconi's syndrome, and occurred due to TDF toxicity to proximal tubule cells mitochondria. Bone toxicity occurred due to direct interference of TDF in bone homeostasis, in addition to vitamin D deficiency and phosphaturia resulting from tubulopathy. During the follow-up, both cases evolved with chronic kidney disease and in one of them, the Fanconi's syndrome did not revert. We emphasize the need to monitor markers of bone metabolism and glomerular and tubular functions in patients using TDF.

Fractura de fémur proximal (31-A3. 2) asociada al uso de tenofovir en paciente VIH+: reporte de caso / Proximal femur fracture (31-A3. 2) associated with the use of tenofovir in an HIV-positive patient: case report

Presentamos el primer reporte de caso en paciente adulto con virus de la inmunodeficiencia humana (VIH + ) con fractura por fragilidad en fémur proximal asociada al uso de terapia antirretroviral (TARV) con fumarato de disoproxilo de tenofovir (FDT) en Chile. Actualmente, los pacientes diagnosticados con VIH inician tratamiento precoz con TARV, lo que implica mayor cantidad de años de exposición a los fármacos de la terapia. El tiempo de exposición acumulado al FDT se ha asociado a disminución de la densidad mineral ósea y falla renal progresiva, pudiendo el paciente desarrollar síndrome de Fanconi adquirido y osteomalacia, con riesgo aumentado de fractura. Presentamos el caso de un hombre de 44 años, VIH+ , evaluado en urgencia tras caída a nivel que resultó en fractura patológica del fémur proximal. Los exámenes de ingreso destacaron hipocalemia, hipocalcemia, hipofosfatemia e hipovitaminosis D. Se realizó manejo multidisciplinario, con suspensión del FDT, un cambio en la TARV, y suplementación con calcio y carga de vitamina D. Se realizó reducción cerrada y fijación con clavo cefalomedular largo, que evolucionó favorablemente con rehabilitación motora precoz; el paciente recuperó su funcionalidad previa, y se observó consolidación ósea a las 12 semanas. La aparición de dolor osteomuscular en pacientes VIH+ en TARV debe levantar alta sospecha clínica de efecto adverso a medicamento; el seguimiento de estos pacientes debe incluir el control seriado de la función renal y de los niveles séricos de calcio y fósforo. La búsqueda y sospecha de estas complicaciones permitiría una intervención precoz, mejorando la condición de los pacientes y previniendo fracturas patológicas.

We present the first case report of a human immunodeficiency virus (HIV)-positive adult patient with a fragility fracture of the proximal femur associated with antiretroviral therapy (ART) with tenofovir disoproxil fumarate (TDF) in Chile. Currently, patients diagnosed with HIV start ART early, resulting in more years of exposure to these drugs. The accumulated exposure time to TDF has been associated with a decreased bone mineral density and progressive renal failure, potentially leading to acquired Fanconi syndrome, osteomalacia, and an increased risk of fracture. We present a case of a 44-year-old, HIV-positive man assessed at the emergency room after a fall from standing height which resulted in a proximal femoral pathological fracture. Laboratory findings at admission revealed hypokalemia, hypocalcemia, hypophosphatemia, and hypovitaminosis D. Multidisciplinary management was performed, with TDF discontinuation, ART change, and supplementation with calcium and vitamin D. Closed reduction and fixation with a long cephalomedullary nail was successful, with early motor rehabilitation, functional recovery, and bone consolidation at 12 weeks. Musculoskeletal pain in HIV-positive patients on ART must raise the clinical suspicion of an adverse drug effect; the follow-up of these subjects must include serial monitoring of renal function and serum calcium and phosphorus levels. Screening and suspicion of such complications would enable an early intervention, improving the patients' condition and preventing pathological fractures.

Effects of different postpartum withdrawal time of tenofovir on hepatitis B virus markers, virology and biochemical indexes / 中国临床药理学与治疗学

AIM: To evaluate the effect of TDF withdrawal time on changes of serum HBV-M, HBV DNA and ALT level in the mother-to-child blocking of the maternal population. METHODS: A prospective, randomized and controlled study was conducted. The 120 pregnant women with HBV who took TDF during 24 to 28 weeks of gestation were randomly divided into group A (withdrawal at delivery) and group B (withdrawal at 4 weeks postpartum), levels of HBV-M, HBV DNA, and ALT at different times were detected. The results were statistically analyzed by Wilcoxon Rank-sum test and χ

VIH y salud ósea / HIV and bone health

Con el advenimiento de la terapia antirretroviral, el pronóstico y la sobrevida de los pacientes infectados con el virus de la inmunodeficiencia humana (VIH) han cambiado de manera radical, por lo cual en la actualidad se evidencia un aumento en el riesgo de padecer enfermedades no relacionadas con el VIH como, por ejemplo, la osteoporosis. La disminución de la densidad mineral ósea (DMO) se observa en el 40-90% de las personas infectadas por el VIH, con una prevalencia de osteopenia y osteoporosis del 52 y 15%, respectivamente. Esta población de pacientes tiene un mayor riesgo de fracturas (60%) en comparación con personas no infectadas y un riesgo de fracturas vertebrales 2,3 veces mayor que en la población general. El tenofovir fumarato se asoció con un aumento de pérdida renal de fósforo e hiperparatiroidismo secundario. El efavirenz y los inhibidores de proteasas (IP) afectan el metabolismo de la vitamina D; actúan a nivel enzimático aumentando la expresión de la enzima CYP24 que lleva a producción de vitamina D inactiva. El FRAX es una herramienta sencilla y accesible, por lo que su uso está recomendado en pacientes con VIH. Además de las medidas higiénico-dietéticas, actividad física, calcio y vitamina D, el uso de bifosfonatos está indicado en el tratamiento de la osteoporosis en estos pacientes. (AU)

With the advent of antiretroviral therapy, the prognosis and survival of patients infected with the human immunodeficiency virus (HIV) have radically changed, which is why there is now evidence of an increased risk of suffering from diseases not related to HIV such as osteoporosis. The decrease in bone mineral density (BMD) is observed in 40-90% of people infected with HIV, with a prevalence of osteopenia and osteoporosis of 52 and 15%, respectively. This patient population has a 60% higher risk of fractures compared to uninfected people and a risk of vertebral fractures 2.3 times higher than in the general population. Tenofovir fumarate administration is associated with increased renal phosphorus loss and secondary hyperparathyroidism. Efavirenz and protease inhibitors (IP) affect the metabolism of vitamin D, they act at the enzymatic level by increasing the expression of the CYP24 enzyme that leads to the production of inactive vitamin D. The FRAX is a simple and accessible tool, so its use is recommended in patients with HIV and in addition to dietary hygiene measures, physical activity, calcium, and vitamin D, the use of bisphosphonates is indicated in the treatment of osteoporosis in these patients. (AU)

Hepatitis B y C en personas con VIH del Instituto para el Desarrollo Humano / Hepatitis B and C in People

INTRODUCCIÓN: la coinfección del VIH con la hepatitis B o C es causa de patología hepática crónica, con diversas seroprevalencias en diferentes regiones del mundo. OBJETIVO: conocer la seroprevalencia de hepatitis B y C en personas con VIH que acuden a consulta en el Instituto para el Desarrollo Humano, Cochabamba-Bolivia, gestión 2017-2018. MATERIALES Y MÉTODOS: estudio descriptivo, prospectivo-transversal, cuantitativo, no experimental. Se analizaron los resultados serológicos de los marcadores: antígeno de superficie del virus hepatitis B, anticuerpo anti-core del virus de hepatitis B, anticuerpo contra el virus hepatitis C; historial de vacuna para hepatitis B y esquema de tratamiento antirretroviral, de 195 personas con VIH en el Instituto para el Desarrollo Humano, se realizó análisis bivariado para la obtención de datos. RESULTADOS: la seroprevalencia obtenida para hepatitis B es de 7,7% y hepatitis C de 0,5%; la coinfección entre VIH y hepatitis B es de 80% con esquema antirretroviral tenofovir/lamivudina. El grupo poblacional homosexual tiene un riesgo de 5,5 veces más de tener la co-infección de VIH y hepatitis B con un valor de p de 0,006; con relación a la inmunización para hepatitis B solo el 9,2% de los pacientes cuentan con el esquema completo. CONCLUSIÓN: es imperativo ofertar las pruebas para hepatitis B y C a todas las personas con VIH; haciendo énfasis en los grupos más vulnerables homosexuales; es importante el abastecimiento de dosis para la inmunización completa contra la hepatitis B en todos los servicios de salud públicos del país.

INTRODUCTION: HIV co-infection with hepatitis B or C is the cause of chronic liver disease, with various seroprevalences in different regions of the world. OBJECTIVE: To know the seroprevalence of hepatitis B and C in people with HIV who come for consultation at the Institute for Human Development, Cochabamba-Bolivia, management 2017-2018. MATERIALS AND METHODS: descriptive, prospective-cross-sectional, quantitative, non-experimental study. The serological results of the markers were analyzed: Hepatitis B virus surface antigen, Hepatitis B virus anti-core antibody, Hepatitis C virus antibody; Hepatitis B vaccine history and antiretroviral treatment scheme of 195 people with HIV at the Institute for Human Development, bivariate analysis was performed to obtain data. RESULTS: the seroprevalence obtained for hepatitis B is 7.7% and hepatitis C 0.5%; coinfection between HIV and hepatitis B is 80% with the antiretroviral regimen tenofovir / lamivudine. The homosexual population group hasa 5.5 times risk of having HIV and hepatitis B co-infection with a p value of 0.006; Regarding immunization for hepatitis B, only 9.2% of patients have the complete scheme. CONCLUSION: it is imperative to offer hepatitis B and C testing to all people with HIV; emphasizing the most vulnerable groups (homosexuals); The provision of doses for complete immunization against hepatitis B in all public health services in the country is important.

Grado de satisfacción y conocimiento de pacientes positivos para HIV ante el cambio de tenofovir a tenofovir-alafenamida en tratamientos con emtricitabina y rilpivirina / Satisfaction and knowledge among patients with HIV after switching from tenofovir to tenofovir alafenamide in regimens containing emtricitabine and rilpivirine

Introducción. La satisfacción y el conocimiento del cambio de tenofovir por tenofovir- alafenamida en pacientes con HIV no se han estudiado aún. Estos dos parámetros se relacionan con mejores resultados en salud y, por lo tanto, es importante medirlos durante la práctica clínica habitual. Objetivo. Evaluar el grado de conocimiento y satisfacción de los pacientes positivos para HIV ante el cambio de tratamiento antirretroviral con rilpivirina, emtricitabina y tenofovir (RPV-FTC-TDF) por rilpivirina, emtricitabina y tenofovir-alafenamida (RPV-FTC-TAF). Materiales y métodos. Se llevó a cabo un estudio prospectivo en un hospital de tercer nivel entre los meses de septiembre y noviembre de 2018. Se incluyeron pacientes previamente tratados con RPV-FTC-TDF que acudían por segunda vez a consulta para recibir el tratamiento con RPV-FTC-TAF. La satisfacción y el grado de conocimiento se analizaron mediante nueve preguntas, usando una escala de tipo Likert de 5 puntos para evaluar el grado de acuerdo. Resultados. Se incluyeron 116 pacientes en el estudio. El 75 % de ellos se mostró satisfecho con el cambio y se consideró que el 64 % conocía lo que implicaba. Los pacientes jóvenes se mostraron menos satisfechos con el modo en que se les explicó el cambio (p=0,0487). Los pacientes estaban mejor informados sobre las ventajas renales (85 % de conocimiento) y óseas (82 %) de la nueva medicación, que sobre sus inconvenientes para el perfil lipídico (40 %). Conclusiones. En general, los pacientes se mostraron satisfechos con el cambio de medicación y conocían la posología del medicamento y las ventajas de la tenofovir- alafenamida frente al tenofovir, pero no sus posibles efectos adversos.

Introduction: Satisfaction and knowledge among patients with HIV after switching from tenofovir to tenofovir/alafenamide remain unexplored. Given that both parameters are associated with better health outcomes it is relevant to measure them in patients during routine clinical practice. Objective: To evaluate the degree of knowledge and satisfaction in patients who had their antiretroviral regimen switched from rilpivirine (RPV)/emtricitabine (FTC)/TDF to RPV/FTC/TAF. Materials and methods: We conducted a prospective study in a third-level hospital between September, 2018, and November, 2018. We included patients who had previously been treated with RPV/FTC/TDF and collected their RPV/FTC/TAF treatment in the second visit. A 5-point Likert-type agreement/disagreement scale was used to assess satisfaction and knowledge regarding the medication switch. Results: We included 116 patients in the study of whom 75% were satisfied and 64% had a high-level of knowledge. Young patients were less satisfied with the way in which the change was explained (p=0.0487). Concerning the new medication, the patients were better informed about its renal (85% of them) and bone benefits (82%) than about its adverse effects on the lipid profile (40%). Conclusions: The patients were generally satisfied with the change in medication and well informed about the dosage and advantages of TAF over TDF, but less well informed about the possible adverse effects of TAF.

Factors associated to modification of first-line antiretroviral therapy due to adverse events in people living with HIV/AIDS

ABSTRACT Antiretroviral therapy (ART) has modified the outcome of patients with HIV infection, providing virological control and reducing mortality. However, there are several reasons as to why patients may discontinue their antiretroviral therapy, with adverse events being one of the main reasons reported in the literature. This is a case-control nested in a cohort of people living with HIV/AIDS, conducted to identify the incidence of ART modification due to adverse events and the associated factors, in two referral services in Recife, Brazil, between 2011 and 2014. Of the modifications occurred in the first year of ART, 25.7% were driven by adverse events. The median time elapsed between initiating ART and the first modification due to adverse events was 70.5 days (95% CI: 26-161 days). The main adverse events were dermatological, neuropsychiatric and gastrointestinal. Dermatological events were the earliest to appear after initiating ART. Efavirenz was the most prescribed and most modified drug during the study period. The group of participants who used zidovudine, lamivudine, and efavirenz had a 2-fold greater chance (adjusted OR: 2.16 95% CI: 1.28-3.65) of switching ART due to adverse events when compared to the group that used tenofovir with lamivudine and efavirenz.