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Ribavirin has been widely used for antiviral therapy. Unfortunately, ribavirin-induced anemia is often a cause of limiting or interrupting treatment. Our team has observed that dehydroepiandrosterone (DHEA) has a protective effect against in vitro and in vivo ribavirin-induced hemolysis. The aim of this study was to better understand this effect as well as the underlying mechanism(s). DHEA was able to reduce in vitro intraerythrocytic ATP depletion induced by ribavirin. Only 1% of ATP remained after incubation with ribavirin (2 mM) at 37 °C for 24 h vs. 37% if DHEA (200 μM) was added (p < 0.01). DHEA also helped erythrocytes conserve their size, with a shrinkage of only 10% vs 40% at 24 h with ribavirin alone (p < 0.01), and reduced phosphatidylserine exposure at the outer membrane, i.e. 27% vs 40% at 48 h, (p < 0.05). DHEA also inhibits ribavirin-induced hemolysis, i.e. 34% vs 46.5% at 72 h (p < 0.01). DHEA is an inhibitor of glucose-6-phosphate dehydrogenase (G6PD), a key enzyme in the hexose monophosphate shunt connected to the glycolytic pathway which is the only energy supplier of the red blood cell in the form of ATP. We have confirmed this inhibitory effect in the presence of ribavirin. All these observations suggest that ribavirin-induced hemolysis was initiated by ATP depletion, and that the inhibitory effect of DHEA on G6PD was able to rescue enough ATP to limit this hemolysis. This mechanism could be important for improving the therapeutic management of patients treated with ribavirin., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Ribavirin-induced anemia is the major side effect observed during HCV therapy. In an in vitro study, we recently discovered that DHEA can strongly inhibit this adverse event. We also evaluated a possible link between pre-treatment serum DHEA and hemoglobin during HCV therapy. Among the 108 patients of our cohort serum baseline DHEA levels were associated with hemoglobin levels at week 12 of treatment (r = 0.35; P = 0.0021). Patients with low baseline serum DHEA developed severe anemia. A serum level of DHEA less than 1,500 ng/ml had a sensitivity of 94.3% and a positive predictive value of 93.1% for the detection of hemoglobin less than 11 g/dl during the first 12 week of treatment. With pre-treatment DHEA levels below the cutoff, anemia was observed in 24.4% and 60.5% of patients treated with dual therapy and triple therapy, respectively, versus 0% and 15% of patients with higher DHEA levels. At week 12, the mean difference between patients with serum DHEA below and above the cutoff, in terms of absolute hemoglobin for dual and triple therapy groups were 1.2 and 1.7 g/dl, respectively (P = 0.005 and <0.001). Pretreatment DHEA levels are associated with hemoglobin levels during treatment. Based on these data, pretreatment assay of DHEA could be considered systematically in order to propose DHEA supplementation to potentiate the efficacy of the current and future use of ribavirin for HCV and HEV therapy. J. Med. Virol. 89:1033-1039, 2017. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

Anemia is a well-known RBV-related event in HCV therapy which is exacerbated by the addition of telaprevir and boceprevir. This retrospective study evaluated and compared ribavirin exposure and parameters able to influence hemoglobin decrease in a large population of patients treated with dual or triple therapy. Patients on triple therapy had higher ribavirin concentrations at week 12 of treatment (3460 ng/mL vs. 1843 ng/mL; P < .0001). An association was also observed between week 12 eGFR and ribavirin concentration only for patients on triple therapy (P = .002). The proportion of patients with a  >20 mL/min/1.73 m(2) decrease in eGFR at week 12 was higher among patients on triple therapy: 32%, 14%, and 5% for boceprevir, telaprevir, and dual therapy, respectively (P = .025 and .026). No correlation was observed between boceprevir and telaprevir concentrations and hemoglobin or eGFR decrease. Exacerbation of anemia in patients on triple therapy is related to higher ribavirin concentrations. We provide an explanation for this increase in plasma RBV concentration. Triple therapy with PEG-IFN, RBV, and telaprevir or boceprevir will remain the only HCV treatment option for many patients. Our data show that the RBV dose can be decreased while maintaining adequate plasma concentrations and reducing anemia., (© 2015, The American College of Clinical Pharmacology.)

Background: The optimization of combination therapy with ribavirin (RBV) and pegylated interferon alpha has substantially improved sustained virologic response (SVR) rates and lowered virologic relapse rates in patients infected with hepatitis C virus (HCV). In this study, we performed an analysis of the relationship between the end-of-treatment plasma RBV concentration and virologic relapse., Methods: Thirty-four patients with HCV treated with pegylated interferon/RBV and with an end-of-treatment response were assayed for plasma RBV concentration using liquid chromatography assay coupled to tandem mass-spectrometric detection on the last day of the treatment. Clinical data and the concentration of RBV were compared between patients classified as either relapsers or nonrelapsers., Results: Eleven patients (32.4%) relapsed and 23 patients (67.6%) achieved an SVR. The mean plasma RBV concentration on the last day of treatment was 1380 ± 312 ng/mL for relapsers and 2278 ± 569 ng/mL for SVR patients (P < 0.0001). A receiver operating characteristic analysis showed that a threshold of 1960 ng/mL was associated with the greatest sensitivity and specificity (100% and 83%, respectively, with an area under the curve of 0.94; P < 0.0001) for discriminating between patients who relapsed and those who did not. A univariate logistic regression analysis indicated that a plasma RBV concentration of <1960 ng/mL at the end of the treatment was strongly associated with relapse (odds ratio, 55; 95% confidence interval, 7.24-∞; P = 0.0001) independently of age, body weight, RBV dose, baseline viral load, the interleukin-28B genotype, and response to previous courses of treatment., Conclusions: Our study results highlight the relevance of measuring plasma RBV concentrations during and at the end of HCV treatment, with a view to avoiding virologic relapse.