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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.

To optimize standard treatment of chronic hepatitis C in responder patients who have achieved undetectable viral load, a prospective study was conducted to determine the factors and kinetics of virologic relapse. Responder patients were monitored 2, 4, 8, 12, 16, and 24 weeks after the end of treatment with pegylated interferon and ribavirin. Forty-seven of the 154 patients (30.5%) relapsed. Relapse was significantly associated with absence of rapid virologic response (RVR), retreatment, higher baseline viral load, older age, and lower weight-based dose of pegylated interferon. Relapse was more frequent in patients failing to achieve a RVR after receiving pegylated interferon alpha 2a < 2.5 µg/week or alpha 2b < 1.5 µg/week (P = 0.002). Among patients infected with hepatitis C virus (HCV) genotype 1 with non-CC IL-28B polymorphism (rs12979860), viral decay during treatment was lower in relapsers (P = 0.003 at week 4). Relapse was detected at weeks 2, 4, 8, and 12 after the end of treatment for 5, 8, 10, and 6 patients infected with HCV genotype 1, respectively. Positive predictive values for sustained virologic response were 70.9%, 80.2%, 91.9%, and 98.8% at weeks 2, 4, 8, and 12, respectively. Only one patient relapsed beyond 24 weeks. Closer follow-up and treatment adaptation in patients failing to achieve RVR may decrease the relapse rate in slower responders and heavier patients. Monitoring viral load as early as 1 month after the end of treatment could be useful to assess virologic response., (Copyright © 2013 Wiley Periodicals, Inc.)

The current treatment of chronic hepatitis C is based on pegylated alpha interferon (PEG-IFN-α) and ribavirin. The aim of this study was to identify biological and clinical variables related to IFN therapy that could predict patient outcome. The study enrolled 47 patients treated with PEG-IFN and ribavirin combined therapy. The interferon concentration was measured in serum by a bioassay. The expression of 93 interferon-regulated genes in peripheral blood mononuclear cells was quantified by real-time quantitative reverse transcription-PCR (RT-PCR) before and after 1 month of treatment. The interferon concentration in the serum was significantly lower in nonresponders than in sustained virological responders. Moreover, a significant correlation was identified between interferon concentration and interferon exposition as well as body weight. The analysis of interferon-inducible genes in peripheral blood mononuclear cells among the genes tested did not permit the prediction of treatment outcome. In conclusion, the better option seems to be to treat patients with weight-adjusted PEG-IFN doses, particularly for patients with high weight who are treated with PEG-IFN-α2a. Although the peripheral blood mononuclear cell samples are the easiest to obtain, the measurement of interferon-inducible genes seems not be the best strategy to predict treatment outcome.

Background: Today, treatment of chronic hepatitis C is based on a synergistic combination of pegylated interferon and ribavirin with antiprotease inhibitors. Haemolytic anaemia, which is the major side effect of ribavirin treatment, disrupts ribavirin treatment compliance and varies significantly from one patient to another. There is an individual susceptibility to ribavirin haemolysis. With a view to studying haemolysis, and thus optimizing the treatment response, we have developed a new in vitro tool for analysing the ribavirin-induced lysis of red blood cells., Methods: Resuspended red blood cells were incubated with isotonic buffer and a range of concentrations of ribavirin. Haemolysis was quantified by spectrophotometric measurement of the supernatant at 540 nm. The assay was used to test the effects of various compounds and to investigate the susceptibility of patients to haemolytic anaemia., Results: In our assay, the degree of haemolysis is dependent on the ribavirin concentration used and can be inhibited by the addition of dipyridamole (50% inhibitory concentration [IC(50)] 30 μM), ATP or glutathione (IC(50) 1.63 mM and 767 μM, respectively). We observed a strong decrease in red blood cell haemolysis in the presence of the ribavirin prodrug viramidine (Taribavirin(®)). When testing the performance of this assay with blood from 24 patients before treatment, we observed a strong correlation between in vitro haemolysis before treatment and the decrease in haemoglobin levels seen in vivo during subsequent treatment (P<0.001)., Conclusions: With this new tool it is possible to better evaluate individual susceptibility to ribavirin-induced haemolysis before the start of treatment. In addition, this model will enable the mechanism of ribavirin-induced anaemia to be further explored and allow molecules that could reduce ribavirin haemolysis to be screened and tested in vitro. This approach could help optimize current and future therapeutic strategies involving ribavirin in the treatment of chronic hepatitis C.

The standard treatment of HCV infection with pegylated interferon-alpha2a or -alpha2b and ribavirin is effective in <50% of HCV genotype-1-infected patients. To improve this figure, it might be desirable to obtain optimal plasma concentrations of the drug by increasing the dose. Unfortunately, there is great interpatient variability in ribavirin pharmacokinetics. In the present review, we describe the mechanism of ribavirin-induced anaemia in detail, evaluate host predictive factors for this harmful side effect and assess the literature data on attempts to improve the sustained virological response rate by increasing the dose of ribavirin. We suggest an optimal steady-state concentration range for ribavirin in monoinfected and coinfected patients. Lastly, we propose that it would be of particular value to monitor ribavirin concentrations in HCV genotype-1-infected patients and (regardless of the genotype) coinfected patients, haemodialyzed patients and obese patients.