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Clinicopathologic characteristics and outcomes of transformed diffuse large B-cell lymphoma in hepatitis C virus-infected patients.
Hosry, J, Miranda, RN, Samaniego, F, Economides, MP, Torres, HA
International journal of cancer. 2018;(5):940-948
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Abstract
Hepatitis C virus (HCV) causes a chronic but curable infection associated with the development of marginal zone lymphoma (MZL) and diffuse large B-cell lymphoma (DLBCL). Preliminary data have shown frequent transformation of indolent lymphoma to DLBCL in HCV-infected patients. To compare their clinicopathologic characteristics and oncologic outcomes, we reviewed the medical records and pathology reports of HCV-infected and uninfected patients with DLBCL that transformed from indolent lymphoma seen at The University of Texas MD Anderson Cancer Center (June 2004 to May 2015). To identify predictors of DLBCL relapse, patients with relapse after first-line chemotherapy were compared with those without it using univariate and logistic regression analyses. Compared with the uninfected patients (n = 63), HCV-infected patients (n = 21) were younger (median age =54 years [interquartile range= 49-62 years] vs. 62 years [53-66 years]; p = 0.01) and more often had advanced DLBCL (Ann Arbor stage 3-4; 95% vs. 76%; p = 0.05). Immunophenotypically, more HCV-infected than uninfected patients had CD10-negative B cells (76% vs. 43%; p = 0.008), CD5-positive B cells (39% vs. 7%; p = 0.004) and activated B-cell phenotypes (57% vs. 31%; p = 0.07). Comparison of the patients who had relapse after first-line chemotherapy (n = 42) and those who did not (n = 40) revealed that having CD5-positive B cells was the only factor associated with DLBCL relapse in multivariate analysis (odds ratio= 10.7; p = 0.02). HCV-infected patients with transformed DLBCL have unique clinicopathologic characteristics that make their lymphoma difficult to treat, potentially leading to unfavorable outcome. The impact of HCV eradication should be explored in such patients.
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Pharmacokinetics-Based Adjusted Versus Standard Dose of Ribavirin Does Not Improve Virologic Response Rates in Chronic Hepatitis C Genotype 4 Patients: A Randomized Controlled Trial.
Altraif, IH, Sanai, F, Babatin, MA, Alalwan, AA, Abdo, AA, Alhamoudi, W, Peedikayil, M, Alghamdi, H, Alsohaibani, F, Alswat, KA, et al
Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research. 2017;(11):488-493
Abstract
Optimal doses of Ribavirin (RBV) for hepatitis C virus (HCV) treatment are not known. To assess the safety and efficacy of PegIFNalfa-2a in combination with an adjusted (ADJ) RBV dose based on early pharmacokinetics versus a fixed standard (STD) dose of RBV in chronic HCV genotype (GT) 4-naive patients in a randomized trial. One hundred eighty-one patients were randomized. The baseline variables were similar in both arms and females were 50.3% of the patients, 76.5% had minimal-moderate fibrosis (F0-2). Sustained virologic response (SVR) was achieved in 99 (54.7%) subjects. SVR was seen in 50/90 (55.6%) of ADJ dose of RBV and 49/91 (53.9%) of STD dose subjects. Prematurely withdrawal or discontinuation of treatment prematurely in the ADJ RBV arm occurred in 11/90 patients (12.2%) compared with 6/91 subjects (6.6%) in the STD arm (P = 0.214). Similarly, virologic relapse was seen in 14/90 (15.6%) patients of the ADJ arm and 12/91 (13.2%) of the STD arm. Anemia grade 3-4 was seen in 36.7% in ADJ versus 17.6% in STD arm (P = 0.003). Occurrence of rapid virologic response and absences of F4 fibrosis predicted SVR in a univariate analysis. However, age, gender, weight, presence of diabetes, baseline alanine aminotransferase, and vitamin D levels were not significantly different in patients achieving SVR. ADJ higher doses of RBV based on its early pharmacokinetics-based RBV do not improve SVR rates in HCV GT4 treated in combination with peg-IFN alpha-2-a versus STD therapy. Patients on ADJ higher doses of RBV experienced higher rates of anemia and require more erythropoietin without increasing SVR.
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In vitro and in vivo antiviral activity and resistance profile of the hepatitis C virus NS3/4A protease inhibitor ABT-450.
Pilot-Matias, T, Tripathi, R, Cohen, D, Gaultier, I, Dekhtyar, T, Lu, L, Reisch, T, Irvin, M, Hopkins, T, Pithawalla, R, et al
Antimicrobial agents and chemotherapy. 2015;(2):988-97
Abstract
The development of direct-acting antiviral agents is a promising therapeutic advance in the treatment of hepatitis C virus (HCV) infection. However, rapid emergence of drug resistance can limit efficacy and lead to cross-resistance among members of the same drug class. ABT-450 is an efficacious inhibitor of HCV NS3/4A protease, with 50% effective concentration values of 1.0, 0.21, 5.3, 19, 0.09, and 0.69 nM against stable HCV replicons with NS3 protease from genotypes 1a, 1b, 2a, 3a, 4a, and 6a, respectively. In vitro, the most common amino acid variants selected by ABT-450 in genotype 1 were located in NS3 at positions 155, 156, and 168, with the D168Y variant conferring the highest level of resistance to ABT-450 in both genotype 1a and 1b replicons (219- and 337-fold, respectively). In a 3-day monotherapy study with HCV genotype 1-infected patients, ABT-450 was coadministered with ritonavir, a cytochrome P450 3A4 inhibitor shown previously to markedly increase peak, trough, and overall drug exposures of ABT-450. A mean maximum HCV RNA decline of 4.02 log10 was observed at the end of the 3-day dosing period across all doses. The most common variants selected in these patients were R155K and D168V in genotype 1a and D168V in genotype 1b. However, selection of resistant variants was significantly reduced at the highest ABT-450 dose compared to lower doses. These findings were informative for the subsequent evaluation of ABT-450 in combination with additional drug classes in clinical trials in HCV-infected patients. (Study M11-602 is registered at ClinicalTrials.gov under registration no. NCT01074008.).
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Lack of clinically significant pharmacokinetic interaction between the thrombopoietin receptor agonist eltrombopag and hepatitis C virus protease inhibitors boceprevir and telaprevir.
Wire, MB, Fang, L, Hussaini, A, Kleha, JF, Theodore, D
Antimicrobial agents and chemotherapy. 2014;(11):6704-9
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Abstract
Eltrombopag is an orally bioavailable thrombopoietin receptor agonist approved for the treatment of thrombocytopenia associated with chronic immune (idiopathic) thrombocytopenic purpura and chronic hepatitis C virus (HCV) infection. This study evaluated the potential drug-drug interactions between eltrombopag and the HCV protease inhibitors boceprevir and telaprevir. In this open-label, 3-period, single-sequence, and crossover study, 56 healthy adult subjects were randomized 1:1 to cohort 1 (boceprevir) or 2 (telaprevir). The dosing was as follows: period 1, single 200-mg dose of eltrombopag; period 2, 800 mg boceprevir or 750 mg telaprevir every 8 hours (q8h) for 10 days; and period 3, single 200-mg dose of eltrombopag with either 800 mg boceprevir or 750 mg telaprevir q8h (3 doses). All doses were administered with food, and eltrombopag was administered specifically with low-calcium food. There was a 3-day washout between periods 1 and 2 and no washout between periods 2 and 3. Serial pharmacokinetic samples were collected for 72 h in periods 1 and 3 and for 8 h in period 2. The coadministration of eltrombopag increased the rate of boceprevir absorption, resulting in a 20% increase in the maximum concentration in plasma (Cmax), a 1-h-earlier time to Cmax (Tmax) for boceprevir, a 32% decrease in the concentration at the end of the dosing interval (Cτ), and no change in the area under the concentration-time curve over the dosing interval (AUC0-τ). The coadministration of eltrombopag did not alter telaprevir pharmacokinetics, and the coadministration of boceprevir or telaprevir did not alter eltrombopag pharmacokinetics. Dysgeusia, headache, and somnolence occurred in ≥2 subjects. One subject withdrew because of nausea, headache, dizziness, sinus pressure, and vomiting. There were no severe or serious adverse events. Dose adjustment is not required when eltrombopag is coadministered with boceprevir or telaprevir given the lack of clinically significant pharmacokinetic interaction.
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SILEN-C3, a phase 2 randomized trial with faldaprevir plus pegylated interferon α-2a and ribavirin in treatment-naive hepatitis C virus genotype 1-infected patients.
Dieterich, D, Asselah, T, Guyader, D, Berg, T, Schuchmann, M, Mauss, S, Ratziu, V, Ferenci, P, Larrey, D, Maieron, A, et al
Antimicrobial agents and chemotherapy. 2014;(6):3429-36
Abstract
Faldaprevir is an investigational hepatitis C virus (HCV) NS3/4A protease inhibitor which, when administered for 24 weeks in combination with pegylated interferon α-2a and ribavirin (PegIFN/RBV) in treatment-naive patients in a prior study (SILEN-C1; M. S. Sulkowski et al., Hepatology 57:2143-2154, 2013, doi:10.1002/hep.26276), achieved sustained virologic response (SVR) rates of 72 to 84%. The current randomized, open-label, parallel-group study compared the efficacy and safety of 12 versus 24 weeks of 120 mg faldaprevir administered once daily, combined with 24 or 48 weeks of PegIFN/RBV, in 160 treatment-naive HCV genotype 1 patients. Patients with maintained rapid virologic response (HCV RNA of <25 IU/ml at week 4 and undetectable at weeks 8 and 12) stopped all treatment at week 24, otherwise they continued PegIFN/RBV to week 48. SVR was achieved by 67% and 74% of patients in the 12-week and 24-week groups, respectively. Virologic response rates were lower in the 12-week group from weeks 2 to 12, during which both groups received identical treatment. SVR rates were similar in both groups for patients achieving undetectable HCV RNA. Most adverse events were mild or moderate, and 6% of patients in each treatment group discontinued treatment due to adverse events. Once-daily faldaprevir at 120 mg for 12 or 24 weeks with PegIFN/RBV resulted in high SVR rates, and the regimen was well tolerated. Differences in the overall SVR rates between the 12-week and 24-week groups were not statistically significant and possibly were due to IL28B genotype imbalances; IL28B genotype was not tested, as its significance was not known at the time of the study. These results supported phase 3 evaluation. (This study has been registered at ClinicalTrials.gov under registration no. NCT00984620).
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A randomized phase 2b study of peginterferon lambda-1a for the treatment of chronic HCV infection.
Muir, AJ, Arora, S, Everson, G, Flisiak, R, George, J, Ghalib, R, Gordon, SC, Gray, T, Greenbloom, S, Hassanein, T, et al
Journal of hepatology. 2014;(6):1238-46
Abstract
BACKGROUND & AIMS Peginterferon lambda-1a (Lambda) is a type-III interferon with similar antiviral activity to alfa interferons but with a diminished extrahepatic receptor distribution, reducing the risk for extrahepatic adverse events. METHODS This was a randomized, blinded, actively-controlled, multicentre phase 2b dose-ranging study in patients chronically infected with HCV genotypes 1-4. Treatment-naive patients received Lambda (120/180/240 μg) or peginterferon alfa-2a (alfa; 180 μg) once-weekly with ribavirin for 24 (genotypes [GT] 2,3) or 48 (GT1,4) weeks. RESULTS Rates of undetectable HCV-RNA at week 12 (complete early virologic response [cEVR]; primary end point) were significantly higher in GT1,4 patients receiving Lambda vs. alfa (170/304, 56% vs. 38/103, 37%); with similar cEVR rates for GT2,3 (80/88, 91% vs. 26/30, 87%). Rates of undetectable HCV-RNA at week 4 were significantly higher on 180 μg (15/102, 15% GT1,4; 22/29, 76% GT2,3) and 240 μg (17/104, 16% GT1,4; 20/30, 67% GT2,3) Lambda than alfa (6/103, 6% GT1,4; 9/30, 30% GT2,3). Sustained virologic responses (post-treatment week 24) were comparable between Lambda and alfa for GT1,4 (37-46% Lambda; 37% alfa) and GT2,3 (60-76% Lambda; 53% alfa). Aminotransferase and/or bilirubin elevations were the primary dose-limiting abnormalities for Lambda; a sponsor-mandated 240 to 180 μg dose reduction was therefore implemented. Serious adverse events were comparable (3-13% Lambda; 3-7% alfa). Grade 3-4 haemoglobin, neutrophil, and platelet reductions were lower on Lambda than alfa. Among alfa patients, 28/133 (21%) had peginterferon and 31/133 (23%) had ribavirin dose reductions for haematologic abnormalities vs. 0/392 and 8/392 (2%) on Lambda. Lambda demonstrated fewer musculoskeletal (16-28% vs. 47-63%) and influenza-like events (8-23% vs. 40-46%) than alfa. CONCLUSION Lambda was associated with improved or similar rates of virologic response with fewer extrahepatic adverse events than alfa in chronic HCV infection.
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Effects of vitamin E on chronic hepatitis C genotype 3: a randomized, double-blind, placebo-controlled study.
Bunchorntavakul, C, Wootthananont, T, Atsawarungruangkit, A
Journal of the Medical Association of Thailand = Chotmaihet thangphaet. 2014;:S31-40
Abstract
BACKGROUND Hepatitis C virus (HCV) infection is associated with chronic inflammation and oxidative damage, with hepatic steatosis being common in genotype 3 cases. Vitamin E, a potent antioxidant protective against oxidative stress-induced liver damage in vitro and in vivo, has beneficial effects on alanine aminotransferase (ALT) and histological outcomes in patients with non-alcoholic steatohepatitis. OBJECTIVE To assess the effect of vitamin E on ALT status in patients with HCV genotype 3. MATERIAL AND METHOD This randomized, placebo-controlled, double-blind trial was conducted in a single tertiary-care hospital (Rajavithi Hospital, Bangkok) between 2010 and 2011. We included patients with HCV genotype 3 infection, unable to receive or tolerate, or did not respond to standard therapy. Responders were defined as patients exhibiting a decrease in serum ALT of at least 5% below the baseline value after 12 weeks of treatment. RESULTS Thirty-seven eligible patients were randomly assigned either to receive vitamin E 400 IU twice daily (n = 19) or placebo (n = 18; 1 dropped outearly) for 12 weeks. In all, 11 of 19 patients in the vitamin E group (57.8%) and 5 of 17 patients in the placebo group (29.4%) were ALT responders. Among responders, serum ALT levels were greatly decreased in the vitamin E group (reducing from 122.6±80.1 IU/L to 68.4±25.3 IU/L, p = 0.016), when compared with the placebo group (reducing from 89.2±40.6 IU/L to 73.6±30.6 IU/L, p > 0.05). Vitamin E treatment was well-tolerated with no serious adverse events in the present study. CONCLUSION Vitamin E treatment decreased serum ALT levels in patients with HCV genotype 3. Because of its good safety profile, vitamin E may be a worthwhile supportive therapy for patients with HCV particularly for those who were unable to achieve viral eradication by standard therapy.
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Vitamin B12 supplementation improves rates of sustained viral response in patients chronically infected with hepatitis C virus.
Rocco, A, Compare, D, Coccoli, P, Esposito, C, Di Spirito, A, Barbato, A, Strazzullo, P, Nardone, G
Gut. 2013;(5):766-73
Abstract
BACKGROUND In vitro, vitamin B12 acts as a natural inhibitor of hepatitis C virus (HCV) replication. OBJECTIVE To assess the effect of vitamin B12 on virological response in patients with chronic HCV hepatitis naïve to antiviral therapy. METHODS Ninety-four patients with chronic HCV hepatitis were randomly assigned to receive pegylated interferon α plus ribavirin (standard-of-care; SOC) or SOC plus vitamin B12 (SOC+B12). Viral response-namely, undetectable serum HCV-RNA, was evaluated 4 weeks after starting treatment (rapid viral response), 12 weeks after starting treatment (complete early viral response) and 24 or 48 weeks after starting treatment (end-of-treatment viral response) and 24 weeks after completing treatment (sustained viral response (SVR)). Genotyping for the interleukin (IL)-28B polymorphism was performed a posteriori in a subset (42/64) of HCV genotype 1 carriers. RESULTS Overall, rapid viral response did not differ between the two groups, whereas the rates of complete early viral response (p=0.03), end-of-treatment viral response (p=0.03) and SVR (p=0.001) were significantly higher in SOC+B12 patients than in SOC patients. In SOC+B12 patients, the SVR rate was also significantly higher in carriers of a difficult-to-treat genotype (p=0.002) and in patients with a high baseline viral load (p=0.002). Distribution of genotype IL-28B did not differ between the two groups. At multivariate analysis, only easy-to-treat HCV genotypes (OR=9.00; 95% CI 2.5 to 37.5; p=0.001) and vitamin B12 supplementation (OR=6.9; 95% CI 2.0 to 23.6; p=0.002) were independently associated with SVR. CONCLUSION Vitamin B12 supplementation significantly improves SVR rates in HCV-infected patients naïve to antiviral therapy.
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Resistance-associated amino acid variants associated with boceprevir plus pegylated interferon-α2b and ribavirin in patients with chronic hepatitis C in the SPRINT-1 trial.
Ogert, RA, Howe, JA, Vierling, JM, Kwo, PY, Lawitz, EJ, McCone, J, Schiff, ER, Pound, D, Davis, MN, Gordon, SC, et al
Antiviral therapy. 2013;(3):387-97
Abstract
BACKGROUND Resistance to direct-acting antivirals represents a new challenge in the treatment of chronic hepatitis C. METHODS SPRINT-1 was a randomized study of treatment-naive patients with genotype (G) 1 hepatitis C infection (n=595) that evaluated the safety and efficacy of boceprevir (BOC) when added to pegylated interferon-α2b plus ribavirin (PR). Plasma samples collected at protocol-specified visits were analysed by population sequencing for detection of BOC-associated resistance-associated variants (RAVs). RESULTS A total of 17/24 (71%) patients randomized to BOC with baseline RAVs achieved sustained virological response (SVR). V55A/I (n=14), Q41H (n=11) and T54S (n=9) were the most frequently detected polymorphisms at baseline. Seven non-SVR patients with baseline RAVs had V55A (relapse, n=3; breakthrough, n=1; and non-response, n=1) and/or R155K (non-response, n=2). In total, 63/144 (44%) patients with sequenced post-baseline samples (2 SVR, 61 non-SVR) had detectable RAVs after BOC treatment (G1a: R155K [39/49; 80%], V36M [37/49; 76%] and T54S [24/49; 49%]; G1b: T54S [3/11; 27%], T54A [4/11; 35%], A156S [2/11; 18%] and V170A [2/11; 18%]). RAV frequency varied according to the virological response: 90%, 67%, 27% and 37% of breakthrough, incomplete virological response, relapse and non-responder patients, respectively, had post-baseline RAVs present. Similar RAVs were identified in both the PR lead-in and no-lead-in arms and the frequency of post-baseline RAVs was highest in the low-dose ribavirin arm. CONCLUSIONS SVR rates were not compromised among patients with RAVs at baseline; however, a lower starting mg/kg dose of ribavirin was associated with a higher frequency of post-baseline RAVs.
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Vitamin D improves viral response in hepatitis C genotype 2-3 naïve patients.
Nimer, A, Mouch, A
World journal of gastroenterology. 2012;(8):800-5
Abstract
AIM: To examine whether vitamin D improved viral response and predicted treatment outcome in patients with hepatitis C virus (HCV) genotype 2-3. METHODS Fifty patients with chronic HCV genotype 2-3 were randomized consecutively into two groups: Treatment group [20 subjects, age 48 ± 14 years, body mass index (BMI) 30 ± 6, 65% male], who received 180 μg pegylated α-interferon-2a plus oral ribavirin 800 mg/d (Peg/RBV), together with oral vitamin D3 (Vitamidyne D drops; 2000 IU/d, 10 drops/d, normal serum level > 32 ng/mL) for 24 wk; and control group (30 subjects, age 45 ± 10 years, BMI 26 ± 3, 60% male), who received identical therapy without vitamin D. HCV RNA was assessed by reverse transcription polymerase chain reaction. Undetectable HCV RNA at 4, 12 and 24 wk after treatment was considered as rapid virological response, complete early virological response, and sustained virological response (SVR), respectively. Biomarkers of inflammation were measured. RESULTS The treatment group with vitamin D had higher BMI (30 ± 6 vs. 26 ± 3, P < 0.02), and high viral load (> 400,000 IU/mL, 65% vs. 40%, P < 0.01) than controls. Ninety-five percent of treated patients were HCV RNA negative at week 4 and 12. At 24 wk after treatment (SVR), 19/20 (95%) treated patients and 23/30 (77%) controls were HCV RNA negative (P < 0.001). Baseline serum vitamin D levels were lower at baseline (20 ± 8 ng/mL) and increased after 12 wk vitamin D treatment, to a mean level of (34 ± 11 ng/mL). Logistic regression analysis identified vitamin D supplement [odds ratio (OR) 3.0, 95% CI 2.0-4.9, P < 0.001], serum vitamin D levels (< 15 or > 15 ng/mL, OR 2.2, P < 0.01), and BMI (< 30 or > 30, OR 2.6, P < 0.01) as independent predictors of viral response. Adverse events were mild and typical of Peg/RBV. CONCLUSION Low vitamin D levels predicts negative treatment outcome, and adding vitamin D to conventional Peg/RBV therapy for patients with HCV genotype 2-3 significantly improves viral response.