svr 24 achievement two weeks after a tripled dose of daclatasvir in an hcv genotype 3 patient

Abstract Directly-acting antivirals (DAA) have changed the chronic hepatitis C virus (HCV) infection therapeutic scenario allowing virus eradication in more than 95% of patients, independently from the genotype, with 12 to 24-week treatment regimens. We describe a 51-year-old Pakistani man with a chronic HCV-genotype 3 (GT3a) infection with moderate liver fibrosis, who achieved sustained virological response (SVR) 24 after a tripled dose of Daclatasvir (DCV) taken erroneously associated to Sofosbuvir (SOF). The patient had a concomitant intestinal TB infection whose treatment had been delayed in order to firstly eradicate HCV to reduce the liver toxicity of anti-mycobacterial drugs. Thanks to the cultural mediator support, we explained to the patient the correct posology of each drug to take during the day consisting of 12 week SOF (400 mg daily) plus DCV (60 mg daily) regimen. He returned 13 days after for a programmed visit and we were surprised to learn that he had taken 3 pills of DCV (180 mg/daily) instead of one, thus ending DCV assumption after only 9 days while SOF was taken correctly. He complained no symptoms. We immediately performed blood test that showed alteration of lactate dehydrogenase, creatine phosphokinase, and creatin kinase MB activity. At day 15 we stopped SOF closely monitoring the patient. Blood test alterations returned normal after one week of treatment suspension, HCV viremia remained suppressed after 4, 12 and 24 weeks proving HCV eradication. If confirmed, these data could suggest that higher doses of DCV, if tolerated, might be employed in short-time HCV-GT3 treatment

Natalizumab affects T-cell phenotype in multiple sclerosis: implications for JCV reactivation

The anti-CD49d monoclonal antibody natalizumab is currently an effective therapy against the relapsing-remitting form of multiple sclerosis (RRMS). Natalizumab therapeutic efficacy is limited by the reactivation of the John Cunningham polyomavirus (JCV) and development of progressive multifocal leukoencephalopathy (PML). To correlate natalizumab-induced phenotypic modifications of peripheral blood T-lymphocytes with JCV reactivation, JCV-specific antibodies (serum), JCV-DNA (blood and urine), CD49d expression and relative abundance of peripheral blood T-lymphocyte subsets were longitudinally assessed in 26 natalizumab-treated RRMS patients. Statistical analyses were performed using GraphPad Prism and R. Natalizumab treatment reduced CD49d expression on memory and effector subsets of peripheral blood T-lymphocytes. Moreover, accumulation of peripheral blood CD8+ memory and effector cells was observed after 12 and 24 months of treatment. CD4+ and CD8+ T-lymphocyte immune-activation was increased after 24 months of treatment. Higher percentages of CD8+ effectors were observed in subjects with detectable JCV-DNA. Natalizumab reduces CD49d expression on CD8+ T-lymphocyte memory and effector subsets, limiting their migration to the central nervous system and determining their accumulation in peripheral blood. Impairment of central nervous system immune surveillance and reactivation of latent JCV, can explain the increased risk of PML development in natalizumab-treated RRMS subjects

NEW INSIGHT ON EPIDEMIOLOGY AND MANAGEMENT OF BACTERIAL BLOODSTREAM INFECTION IN PATIENTS WITH HEMATOLOGICAL MALIGNACIES

Bloodstream infections (BSI) are an important cause of morbidity and mortality in onco-hematologic patients. The Gram-negative etiology was the main responsible of the febrile neutropenia in the sixties and its impact declined due to the use of fluoroquinolone prophylaxis; this situation was followed by the gradual emergence of Gram-positive bacteria also following of the increased use of intravascular devices and the introduction of new chemotherapeutic strategies. In the last decade the Gram-negative etiology is raising again because of the emergence of resistant strains that make questionable the usefulness of currentstrategies for prophylaxis and empirical treatment. Gram-negative BSI attributable mortality is relevant and the appropriate empirical treatment significantly improves the prognosis; on the other hand the delayed adequate treatment of Gram-positive BSI does not seem to have an high impact on survival. The clinician has to be aware of the epidemiology of his institution and of colonizations of his patients in order to choose the most appropriate empiric therapy. Ina setting of high endemicity of multidrug-resistant infections, even the choice of a targeted therapy can be a challenge, often requiring strategies based on off-label prescriptions and low grade evidences. In this review we summarize the current evidences for the best targeted therapies for difficult to treat bacteria BSIs and future perspectives in this topic. We also provide a flow chart for a rational approach to the empirical treatment of febrile neutropenia in a multidrug resistant high prevalence setting

RIATTIVAZIONE DI EPATITE B OCCULTA IN CORSO DI TERAPIA CON CLORAMBUCILE

Introduzione: La riattivazione di un’epatite B occulta (Occult B Infection, OBI) in soggetti con pregressa infezione è nota in pazienti con patologie neoplastiche, ematologiche e terapie immunosoppressive, specialmente se includono steroidi, antracicline o farmaci anti CD-20 in combinazione. Il rischio di riattivazione (circa il 4.5%), varia a seconda della patologia e dei farmaci impiegati. Essa si può verificare durante o, più frequentemente, dopo l’interruzione del trattamento. Il clorambucile (CBC), agente alchilante che induce anche deplezione linfocitaria, raramente è associato a riattivazione di OBI soprattutto in monoterapia. L’OBI è diffusa nella popolazione italiana di età adulta-avanzata. La sua riattivazione può essere asintomatica, come anche richiedere l’interruzione delle terapie o condurre all’exitus. Tutti i soggetti con OBI dovrebbero essere individuati, monitorati ed eventualmente sottoposti a profilassi. Obiettivo: paziente con riattivazione di OBI in corso di CBC. Caso clinico: donna di 81 anni con ipertensione, diverticolosi colon, glaucoma bilaterale, osteoporosi e pregressa TB polmonare. Nel 2016 veniva sottoposta a chemioterapia (CHT) con CBC per linfoma linfoplasmocitico B linfocitario. Lo status sierologico antecedente la CHT mostrava un quadro di OBI (HBcAb +, HBsAg-, HBsAb-, HBeAg-, HBeAb+); mentre la sierologia per HCV e HIV risultava negativa. Durante la CHT non veniva profilassato con lamivudina, ma si monitorava la funzione epatica che durante il trattamento era nella norma; dopo 4 mesi dal termine della CHT, la paziente presentava astenia marcata, edemi declivi e versamento pleurico bilaterale. Visti i valori delle transaminasi (AST/ALT 83/78 UI/L), si ricercava l’HBV DNA che mostrava 5.210.000 UI/mL mentre una nuova sierologia per HBV evidenziava epatite acuta (HBsAg e HBeAg positivi; HBeAb ed HBsAb negativi). L’ecografia dell’addome rilevava epatomegalia a struttura omogenea, linfonodi ilari epatici (2 cm), milza (21 cm) immodificata rispetto ai precedenti controlli, non ascite. Si diagnosticava quindi riattivazione di OBI e si iniziava terapia con ETV, 1 mg/die. A causa di intolleranza all’antivirale (nausea e vomito), si sostituiva ETV con TELBIVIDINA (TBV) 100 mg/die che dopo15 giorni determinava calo della viremia (HBV DNA 1700 UI/mL) e normalizzazione del profilo epatico. Comparivano però proteinuria nefrosica, colite da C. difficile e successiva sepsi da S. aureus catetere-relata con conseguente decesso. Conclusioni: l’epatite anitterica da HBV insorta dopo riattivazione indotta da CBC (a basso rischio per riattivazione di OBI) dovrebbe rendere mandatoria la profilassi nei pazienti oncoematologuci. Assai scarsi sono i casi di riattivazione riportati in corso di CBC specialmente se somministrato in associazione con lo steroide, che ne amplifica il rischio. Da qui la necessità di uno screening accurato e capillare dei soggetti con OBI ed il monitoraggio durante e dopo il trattamento chemioterapico

EVALUATION OF THE SWITCH TO A DUAL ART REGIMEN WITH LAMIVUDINE PLUS DOLUTEGRAVIR OR PROTEASE INHIBITORS IN HIV-INFECTED VIROLOGICALLY SUPPRESSED PATIENTS. A REAL LIFE EXPERIENCE

Evaluation of the switch to a dual ART regimen with lamivudine plus dolutegravir or protease inhibitors in HIV-infected virologically suppressed patients. A real life experience BACKGROUND: Little is known about the durability of dual treatments in HIV-infected virologically suppressed patients. We explored the combination of lamivudine (3TC) + dolutegravir (DTG) and lamivudine + protease inhibitors (PI) as treatment options when switching from standard ART regimens. MATERIAL AND METHODS: We prospectively enrolled 36 HIV-infected patients under a standard ART regimen. Inclusion criteria were: HIV-RNAq < 40 cp/ml for at least 6 months and absence of mutations in the resistance assay. A simplification regimen with 3TC+DTG (13 pts; group A) or 3TC+PI (23; group B) has been adopted. HIV-RNAq, CD4, CD4/CD8 ratio, total cholesterol, triglycerides, creatinine and renal filtrate were compared at baseline and after 6 months from simplification. The same parameters were then evaluated among the groups A and B. A comparison between regimen costs was also investigated. RESULTS: All enrolled patients (36/36) maintained the same viro-immunological pattern after 6 months from the ART regimen simplification (no statistically significant difference was found in the HIV-RNAq and CD4 count), with the exception of an increase in the CD4/CD8 ratio (p<0.05). Total cholesterol was found to be statistically increased after 6 months of dual ART therapy compared with baseline (p<0.05). All the other parameters (triglycerides, creatinine and renal filtrate) were unchanged. The statistical comparison of the group A and B showed no significant difference in CD4 count, CD4/CD8 ratio, total cholesterol and triglycerides. Creatinine levels were statistically increased and decreased in group A and B, respectively (F (1) = 8.144, p = 0.007, repeated measures ANOVA for the interaction between simplification and creatinine). A marked decrease of renal filtrate (vegf) was observed in group A while an increase in group B. The comparison between the two groups at 6 months showed a statistically significance difference (p <0.05), while only group B showed a significantly higher value of VEGF at 6 months compared to baseline (Wilcoxon signed rank test, p <0.05). The assessment of the impact of the simplification regimen costs compared with baseline resulted statistically significant (p <0.05). CONCLUSION: Switching to a dual ART regimen with DTG or PI maintains virological efficacy up to 6 months, and is associated with slight improvements of the CD4/CD8 ratio. The increase in total cholesterol can be attributed to the statin-like effect of tenofovir, which is lost in the simplification regimen. The variations of creatinine and the renal filtrate observed in group A are consistent with DTG action as an inhibitor of the renal protein organic cation transporter 2 (OCT2). Finally, the dual therapy is less expensive in economic terms

EVALUATION OF THE SWITCH TO A DUAL ART REGIMEN WITH LAMIVUDINE PLUS DOLUTEGRAVIR OR PROTEASE INHIBITORS IN HIV-INFECTED VIROLOGICALLY SUPPRESSED PATIENTS. A REAL LIFE EXPERIENCE

Evaluation of the switch to a dual ART regimen with lamivudine plus dolutegravir or protease inhibitors in HIV-infected virologically suppressed patients. A real life experience BACKGROUND: Little is known about the durability of dual treatments in HIV-infected virologically suppressed patients. We explored the combination of lamivudine (3TC) + dolutegravir (DTG) and lamivudine + protease inhibitors (PI) as treatment options when switching from standard ART regimens. MATERIAL AND METHODS: We prospectively enrolled 36 HIV-infected patients under a standard ART regimen. Inclusion criteria were: HIV-RNAq < 40 cp/ml for at least 6 months and absence of mutations in the resistance assay. A simplification regimen with 3TC+DTG (13 pts; group A) or 3TC+PI (23; group B) has been adopted. HIV-RNAq, CD4, CD4/CD8 ratio, total cholesterol, triglycerides, creatinine and renal filtrate were compared at baseline and after 6 months from simplification. The same parameters were then evaluated among the groups A and B. A comparison between regimen costs was also investigated. RESULTS: All enrolled patients (36/36) maintained the same viro-immunological pattern after 6 months from the ART regimen simplification (no statistically significant difference was found in the HIV-RNAq and CD4 count), with the exception of an increase in the CD4/CD8 ratio (p<0.05). Total cholesterol was found to be statistically increased after 6 months of dual ART therapy compared with baseline (p<0.05). All the other parameters (triglycerides, creatinine and renal filtrate) were unchanged. The statistical comparison of the group A and B showed no significant difference in CD4 count, CD4/CD8 ratio, total cholesterol and triglycerides. Creatinine levels were statistically increased and decreased in group A and B, respectively (F (1) = 8.144, p = 0.007, repeated measures ANOVA for the interaction between simplification and creatinine). A marked decrease of renal filtrate (vegf) was observed in group A while an increase in group B. The comparison between the two groups at 6 months showed a statistically significance difference (p <0.05), while only group B showed a significantly higher value of VEGF at 6 months compared to baseline (Wilcoxon signed rank test, p <0.05). The assessment of the impact of the simplification regimen costs compared with baseline resulted statistically significant (p <0.05). CONCLUSION: Switching to a dual ART regimen with DTG or PI maintains virological efficacy up to 6 months, and is associated with slight improvements of the CD4/CD8 ratio. The increase in total cholesterol can be attributed to the statin-like effect of tenofovir, which is lost in the simplification regimen. The variations of creatinine and the renal filtrate observed in group A are consistent with DTG action as an inhibitor of the renal protein organic cation transporter 2 (OCT2). Finally, the dual therapy is less expensive in economic terms

COLECISTECTOMIA COME FATTORE DI RISCHIO PER INFEZIONI DEL TRATTO EPATOBILIARE

Background: Nel corso della nostra pratica clinica abbiamo notato una stretta correlazione tra gli interventi di colecistectomia e l’insorgenza di colangiti, anche a distanza di alcuni anni dall’intervento e talvolta con tendenza alla ricorrenza. Obiettivo: Valutare la tendenza allo sviluppo di colangiti nei pazienti colecistectomizzati. Materiali e metodi: Abbiamo valutato retrospettivamente i pazienti trattati presso la U.O. di Malattie Infettive dell’Azienda Ospedaliera Universitaria di Ferrara nel triennio 2013-2015, dimessi con diagnosi di colangite. Di essi, abbiamo valutato l’eventuale pregressa colecistectomia, la tipologia di intervento chirurgico (open vs laparoscopia), la presenza o meno di complicanze intra e perioperatorie, l’andamento degli indici di colestasi nel periodo successivo all’intervento chirurgico e la tendenza alla ricorrenza degli episodi infettivi. Risultati: Tutti i 5 pazienti trattati presso la nostra U.O. per colangite presentavano febbre e rialzo della PCR; 4 pazienti (80%) mostravano incremento degli indici di colestasi, 2 (40%), ALT e bilirubina. In 4 casi (80%), è stato possibile isolare dalle emocolture l’agente eziologico (E. coli ESBL- in tutti). Le indagini strumentali hanno sempre confermato reperti compatibili con la diagnosi; solo in un caso l’ecografia non si è dimostrata valida, mentre la colangio-RM ha evidenziato dilatazione delle vie biliari ed esiti di pregresse colangiti. Tutti i pazienti avevano subito colecistectomia. Di questi, 3 (60%) erano stati trattati per via laparoscopica in assenza di complicanze intra e perioperatorie, 2 (40%) in chirurgia open, con esecuzione di anastomosi bilio-digestiva. Il periodo medio di tempo intercorso tra la colecistectomia ed il ricovero è stato di 6 anni (range: 6/ mesi-20 anni). 3 pazienti (80%) riferivano febbri ricorrenti, nel periodo compreso tra la colecistectomia ed il ricovero. Di questi, 1 paziente presentava anamnesi positiva per ascesso epatico da E. coli , un altro, per sepsi da E. coli. Tutti presentavano rialzi periodici degli indici di colestasi anche in assenza di sintomi clinici. Conclusioni: Nonostante l’esiguità della casistica esaminata e la scarsa numerosità di dati della letteratura, dal nostro lavoro emerge la stretta correlazione tra la colecistectomia e l’insorgenza di colangiti. Riteniamo pertanto opportuno sospettare un coinvolgimento infettivo delle vie biliari nei pazienti con febbre ed anamnesi positiva per colecistectomia, anche se eseguita negli anni precedenti, specialmente quando vi sia il concomitante riscontro di emocolture positive per germi intestinali e rialzo degli indici di colestasi. Nei casi in cui siano documentati ripetuti episodi febbrili, consigliamo inoltre lo studio delle vie biliari tramite Colangio-RM al fine di escludere esiti cicatriziali da insulti ripetuti