The addition of a protease inhibitor increases the risk of infections in patients with hepatitis C-related cirrhosis

Londoño, María-Carlota; Perelló, Christie; Cabezas, Joaquín; Cañete, Núria; Lens, Sabela; Mariñó, Zoe; Gambato, Martina; Rodríguez, Raquel; Menéndez, Susana; Carrión, J.A.; Crespo, Javier; Calleja, José Luís; Forns, Xavier

doi:10.1016/j.jhep.2014.09.025

Cited by 13 publications

(16 citation statements)

References 28 publications

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“…Our study implies that diabetic patients should be monitored for infection during CHC therapy. The only other triple therapy cohort study that assessed risk of infection was restricted to cirrhotics and found that respiratory infections were overrepresented in those on PI therapy [22]. Our cohort supports this finding, as respiratory infections accounted for 41% of severe infections and 19% of moderate infections.…”

Section: Discussionsupporting

confidence: 83%

“…This stems from oncologic research as development of neutropenia following chemotherapy usually heralds a severe clinical situation necessitating admission and prompt administration of antibiotics [38]. There is a wealth of literature that establishes that PegIFN induced neutropenia does not pose an increased risk for infections in CHC patients [12,22,39]. Indeed, in our cohort neutropenia did not increase the risk of infection; it even seemed to be associated with a lower risk for infections.…”

Section: Discussionmentioning

confidence: 68%

“…Real world data furthermore suggest that triple therapy substantially increases the risk of severe infections. However, the current evidence for this association is limited to CHC patients with cirrhosis [22][23][24]. Therefore, the aims of this study were (i) to investigate the occurrence and risk factors for clinically relevant infections and (ii) the relation of ontreatment neutropenia with infections in CHC patients who received triple therapy with boceprevir or telaprevir.…”

Section: Introductionmentioning

confidence: 99%

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High Risk of Infection During Triple Therapy with First- Generation Protease Inhibitors: A Nationwide Cohort Study

Berden

Zwietering

Maan

et al. 2016

JGLD

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Background & Aims: Peginterferon (PegIFN) remains the backbone of therapy for chronic hepatitis C (CHC) in economically constrained regions. However, PegIFN may cause neutropenia and addition of a protease inhibitor can increase the likelihood of neutropenia. The aims of this study were to assess the occurrence of clinically relevant infections during first-generation protease inhibitor based therapy and its risk factors as well as the relation to treatment-induced neutropenia. Methods: This multicenter (n=45) retrospective cohort study included CHC patients treated in the Netherlands. Based on absolute neutrophil count, categories of neutropenia were defined as: severe (<500/μL), moderate (500-750/μL) and mild (750-1500/μL). Likewise, infections were classified as severe (intravenous antibiotics/ hospitalization) and moderate (anti-infective treatment). We assessed risk factors for infections using multivariable regression analysis adjusting for multiple measurements. Results: We included 467 CHC patients, 319 (68%) were male and 111 (24%) had cirrhosis. A total of 185 clinically relevant infections (34 severe) occurred in 145 patients (31%). During treatment 310 patients experienced neutropenia (severe, n=34). Multivariable analysis identified female sex (OR 1.7, 95%CI 1.2- 2.5), chronic obstructive pulmonary disease (COPD) (OR 2.7, 95%CI 1.6- 4.5) and diabetes mellitus (OR 1.7, 95%CI 1.0-3.0) as risk factors for infections. Neutropenia at the previous visit was not associated with infection (univariable analysis: OR 0.9, 95%CI 0.6-1.3). Conclusion: This study shows that therapy with first generation protease inhibitors was complicated by an infection in 31% of patients. Not neutropenia, but female sex, COPD and diabetes mellitus were independent risk factors for infection. These patients should be monitored carefully once a PegIFN regimen is initiated. Abbreviations: ANC: absolute neutrophil count; CHC: chronic hepatitis C; COPD: chronic obstructive pulmonary disease; DAAs: direct acting antivirals; DM: diabetes mellitus; HCV: hepatitis C virus; PegIFN: pegylated interferon alpha; PI: protease inhibitor; UTI: urinary tract infection.

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Section: Discussionsupporting

confidence: 83%

Section: Discussionmentioning

confidence: 68%

Section: Introductionmentioning

confidence: 99%

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High Risk of Infection During Triple Therapy with First- Generation Protease Inhibitors: A Nationwide Cohort Study

Berden

Zwietering

Maan

et al. 2016

JGLD

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“…As described in detail previously [9], there are several mechanisms to explain the increased risk of infections in these patients including liver dysfunction, bacterial translocation, shunting, dysbiosis, immune dysfunction, and polymorphisms in NOD2 or TLR2 [11]. However, the change in the pattern of infections observed in patients receiving antiviral therapy with a PI, prompted us to study other mechanisms.…”

Section: Introductionmentioning

confidence: 97%

“…However, the use of triple therapy (TT) was associated with an important increase in the number of treatment-related adverse events (including infections, clinical decompensation and death) in cirrhotic patients, especially in those with signs of portal hypertension (platelet count <100,000 mm 3 ) or liver dysfunction (albumin levels < 35g/L) [6–8]. Moreover, in a recently published study by our group [9], patients with cirrhosis who received TT presented a significantly higher number of bacterial infections as compared to cirrhotic patients treated with PegIFN and RBV (25% vs. 9%; p = 0.001). We also found that the use of TT changed the pattern of infections with an increase in the number of respiratory tract infections (particularly with gram-positive cocci) in the group of patients treated with this combination.…”

Section: Introductionmentioning

confidence: 99%

Neutrophil and Monocyte Function in Patients with Chronic Hepatitis C Undergoing Antiviral Therapy with Regimens Containing Protease Inhibitors with and without Interferon

et al. 2016

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Real-life data showed an increased incidence of bacterial infections in patients with advanced liver disease receiving a protease inhibitor (PI)-containing antiviral regimen against hepatitis C (HCV). However, the causes of this event are unknown. We hypothesized that PIs might impair innate immune responses through the inhibition of proteases participating in the anti-bacterial functions of neutrophils and monocytes. The aims of the study were to assess phagocytic and oxidative burst capacity in neutrophils and monocytes obtained from patients receiving a PI containing-antiviral regimen, and to determine cytokine secretion after neutrophil stimulation with flagellin. Forty patients with chronic HCV (80% with cirrhosis) were enrolled in the study, 28 received triple therapy (Group A) with pegylated-interferon and ribavirin for 4 weeks followed by the addition of a PI (telaprevir, boceprevir or simeprevir), and 12 patients received an interferon-free regimen (Group B) with simeprevir and sofosbuvir. Phagocytosis and oxidative burst capacity were analyzed by flow cytometry at baseline, week 4, and week 8 of therapy. In neutrophils from Group A patients, oxidative burst rate and oxidative enzymatic activity per cell significantly decreased throughout the study period (p = 0.014 and p = 0.010, respectively). Pairwise comparisons showed a decrease between baseline and week 4 and 8 of therapy. No differences were observed after the introduction of the PI. The oxidative enzymatic activity per cell in monocytes significantly decrease during the study period (p = 0.042) due to a decrease from baseline to week 8 of therapy (p = 0.037) in patients from Group A. None of these findings were observed in Group B patients. Cytokine secretion did not significantly change during the study in both groups. In conclusion, our data suggest that the use interferon (rather than the PI) has a deleterious effect on neutrophil and monocyte phagocytic and oxidative burst capacity in this cohort of patients with HCV-related advanced liver fibrosis.

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Asunaprevir and daclatasvir in hemodialysis patients with chronic hepatitis C virus genotype 1b infection

et al. 2017

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Background and AimPatients requiring hemodialysis show high morbidity with hepatitis C virus (HCV) infection, but there are difficulties associated with interferon‐based therapies. Asunaprevir and daclatasvir could help patients with HCV genotype 1b because the drugs have a nonrenal metabolism and show good viral eradication. We evaluated the efficacy and safety of combined asunaprevir and daclatasvir therapy.MethodsThis was a multicenter prospective trial of patients with chronic hepatitis or compensated cirrhosis from HCV genotype 1b who had end‐stage renal disease requiring chronic hemodialysis. Asunaprevir and daclatasvir were administered orally (100 mg twice daily and 60 mg once daily, respectively) for 24 weeks. The primary end‐point was the proportion of patients achieving sustained virological response 12, defined as HCV RNA <15 IU/mL undetectable at 12 weeks after completion of asunaprevir and daclatasvir treatment.ResultsBetween December 2014 and December 2015, 23 dialysis patients were enrolled, and 22 patients completed the protocol therapy. Sustained virological response 12 rates were 91.3% (95% confidence interval: 72.0–98.9) in the intention‐to‐treat and 95.5% (95% confidence interval: 77.2–99.9) in the per‐protocol populations. Serum aminotransferase significantly decreased after initiation of asunaprevir and daclatasvir (P < 0.01), although the level was low at baseline. Asunaprevir and daclatasvir were well tolerated; however, one patient could not continue because of infective endocarditis and cerebral infarction.ConclusionsAsunaprevir and daclatasvir could help patients with chronic hepatitis C receiving hemodialysis. Close collaboration with dialysis physicians is important when treating these patients because hemodialysis carries life‐threatening risks.

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The addition of a protease inhibitor increases the risk of infections in patients with hepatitis C-related cirrhosis

Cited by 13 publications

References 28 publications

High Risk of Infection During Triple Therapy with First- Generation Protease Inhibitors: A Nationwide Cohort Study

High Risk of Infection During Triple Therapy with First- Generation Protease Inhibitors: A Nationwide Cohort Study

Neutrophil and Monocyte Function in Patients with Chronic Hepatitis C Undergoing Antiviral Therapy with Regimens Containing Protease Inhibitors with and without Interferon

Asunaprevir and daclatasvir in hemodialysis patients with chronic hepatitis C virus genotype 1b infection

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