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Randomized study comparing vitamin D3 and 1α-Hydroxyvitamin D3 in combination with pegylated interferon/ribavirin therapy for chronic hepatitis C.
Omori-Mizuno, Y, Nakayama, N, Inao, M, Funyu, J, Asabe, S, Tomita, K, Nishikawa, K, Hosoda, Y, Tanaka, M, Hashimoto, Y, et al
Journal of gastroenterology and hepatology. 2015;(9):1384-90
Abstract
BACKGROUND AND AIM An intention-to-treat prospective randomized study was carried out to compare the potentiation of antiviral efficacies between cholecalciferol, non-activated vitamin D3 supplement, and alfacalcidol, activated 1α-Hydroxyvitamin D3 [1α (OH)-vitamin D3]. METHODS Chronic hepatitis patients with genotype 1b hepatitis C virus (HCV) infection showing serum HCV-RNA levels greater than 5 Log IU/mL received oral administration of cholecalciferol (2000 IU/day) or alfacalcidol (0.5 μg/day) for 4 weeks, and then they were given pegylated interferon (Peg-IFN)-α2a plus ribavirin therapy in combination with either vitamin D3 for 48 or 72 weeks according to the response-guided manner. RESULTS A total of 36 patients were evaluated. Serum 25-hydroxyvitamin D3 [25(OH)-D3] levels were increased only in patients in the cholecalciferol group during the lead-in vitamin D administration, and the levels at 4 weeks were higher in these patients than in those in the alfacalcidol group (P < 0.001), while serum 1α,25-dihydroxyvitamin D3 [1α,25(OH)2 -D3] levels were not different between both groups. Rapid virological response was obtained in six (33%) patients in the cholecalciferol group; the ratio was higher than that in the alfacalcidol group (one patient; 6%, P < 0.05). Serum HCV-RNA level decline at 4 weeks of combined Peg-IFN-α2a plus ribavirin therapy compared with the baseline levels were greater in the cholecalciferol group (4.6 Log IU/mL) than in the alfacalcidol group (3.5 Log IU/mL) (P < 0.05), when four patients showing null response to the therapy was excluded. However, both complete early virological response and sustained viral response rates were not different between both groups. CONCLUSION Cholecalciferol produced superior potentiation of the antiviral activity than alfacalcidol only during the initial periods of combined Peg-IFN-α2a plus ribavirin therapy through upregulation of serum 25(OH)-D3 levels.
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Long-term results of 2 adjuvant trials reveal differences in chemosensitivity and the pattern of metastases between colon cancer and rectal cancer.
Kornmann, M, Staib, L, Wiegel, T, Kron, M, Henne-Bruns, D, Link, KH, Formentini, A, ,
Clinical colorectal cancer. 2013;(1):54-61
Abstract
UNLABELLED Two identical randomized controlled trials designed to optimize adjuvant treatment of colon cancer (CC) (n =855) and rectal cancer (RC) (n = 796) were performed. Long-term evaluation confirmed that the addition of folinic acid (FA) to 5-fluorouracil (5-FU) improved 7-year overall survival (OS) in CC but not in RC and revealed different patterns of recurrence in patients with CC and those with RC. BACKGROUND Our aim was to compare long-term results of adjuvant treatment of colon cancer (CC) and rectal cancer (RC). Adjuvant chemotherapy of CC improved overall survival (OS), whereas that of RC remained at the level achieved by 5-fluorouracil (5-FU). METHODS We separately conducted 2 identically designed adjuvant trials in CC and RC. Patients were assigned to adjuvant chemotherapy with 5-FU alone, 5-FU + folinic acid (FA), or 5-FU + interferon-alfa. The first study enrolled patients with stage IIb/III CC, and the second study enrolled patients with stage II/III RC. All patients with RC received postoperative irradiation. RESULTS Median follow-up for all patients with CC (n = 855) and RC (n = 796) was 4.9 years. The pattern and frequency of recurrence differed significantly, especially lung metastases, which occurred more frequently in RC (12.7%) than in CC (7.3%; P < .001). Seven-year OS rates for 5-FU, 5-FU + FA, and 5-FU + IFN-alfa were 54.1% (95% confidence interval [CI], 46.5-61.0), 66.8% (95% CI, 59.4-73.1), and 56.7% (95% CI, 49.3-63.4) in CC and 50.6% (95% CI, 43.0-57.7), 56.3% (95% CI, 49.4-62.7), and 54.8% (95% CI, 46.7-62.2) in RC, respectively. A subgroup analysis pointed to a reduced local recurrence (LR) rate and an increased OS by the addition of FA in stage II RC (n = 271) but not in stage III RC (n = 525). CONCLUSION FA increased 7-year OS by 12.7 percentage points in CC but was not effective in RC. Based on these results and the pattern of metastases, our results suggest that the chemosensitivity of CC and RC may be different. Strategies different from those used in CC may be successful to decrease the frequency of distant metastases in RC in the future.
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Hepatitis C virus selectively perturbs the distal cholesterol synthesis pathway in a genotype-specific manner.
Clark, PJ, Thompson, AJ, Vock, DM, Kratz, LE, Tolun, AA, Muir, AJ, McHutchison, JG, Subramanian, M, Millington, DM, Kelley, RI, et al
Hepatology (Baltimore, Md.). 2012;(1):49-56
Abstract
UNLABELLED Hepatitis C virus (HCV) subverts host cholesterol metabolism for key processes in its lifecycle. How this interference results in the frequently observed, genotype-dependent clinical sequelae of hypocholesterolemia, hepatic steatosis, and insulin resistance (IR) remains incompletely understood. Hypocholesterolemia typically resolves after sustained viral response (SVR), implicating viral interference in host lipid metabolism. Using a targeted cholesterol metabolomic platform we evaluated paired HCV genotype 2 (G2) and G3 patient sera for changes in in vivo HCV sterol pathway metabolites. We compared HCV genotypic differences in baseline metabolites and following antiviral treatment to assess whether sterol perturbation resolved after HCV eradication. We linked these metabolites to IR and urine oxidative stress markers. In paired sera from HCV G2 (n = 13) and G3 (n = 20) patients, baseline sterol levels were lower in G3 than G2 for distal metabolites (7-dehyrocholesterol (7DHC) 0.017 versus 0.023 mg/dL; P(adj) = 0.0524, cholesterol 140.9 versus 178.7 mg/dL; P(adj) = 0.0242) but not the proximal metabolite lanosterol. In HCV G3, SVR resulted in increased levels of distal metabolites (cholesterol [Δ55.2 mg/dL; P(adj) = 0.0015], 7DHC [Δ0.0075 mg/dL; P(adj) = 0.0026], lathosterol [Δ0.0430 mg/dL P(adj) = 0.0405]). In contrast, lanosterol was unchanged after SVR (P = 0.9515). CONCLUSION HCV G3, but not G2, selectively interferes with the late cholesterol synthesis pathway, evidenced by lower distal sterol metabolites and preserved lanosterol levels. This distal interference resolves with SVR. Normal lanosterol levels provide a signal for the continued proteolysis of 3-hydroxyl-3-methylglutaryl coenzyme A reductase, which may undermine other host responses to increase cholesterol synthesis. These data may provide a hypothesis to explain why hypocholesterolemia persists in chronic HCV infection, particularly in HCV G3, and is not overcome by host cholesterol compensatory mechanisms.
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Upfront, randomized, phase 2 trial of sorafenib versus sorafenib and low-dose interferon alfa in patients with advanced renal cell carcinoma: clinical and biomarker analysis.
Jonasch, E, Corn, P, Pagliaro, LC, Warneke, CL, Johnson, MM, Tamboli, P, Ng, C, Aparicio, A, Ashe, RG, Wright, JJ, et al
Cancer. 2010;(1):57-65
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Abstract
BACKGROUND The objective of this study was to independently evaluate the objective response rate of sorafenib and sorafenib plus low-dose interferon-alfa 2b (IFN) as frontline therapy in patients with metastatic renal cell carcinoma (mRCC). METHODS Untreated patients with clear cell mRCC were randomized to receive sorafenib 400 mg orally twice daily or sorafenib 400 mg orally twice daily plus subcutaneous IFN 0.5 million U (MU) twice daily. Primary endpoints included the objective response rate (ORR) and safety. Secondary endpoints included progression-free survival (PFS) and overall survival (OS). Exploratory endpoints included the predictive value of tumor tissue biomarkers. RESULTS Eighty patients were enrolled. The median follow-up was 19.7 months (range, 0-34.2 months). The ORR was 30% (95% confidence interval [CI], 16.6%-46.5%) in the sorafenib arm and 25% (95% CI, 12.7%-41.2%) in the combination arm. The median PFS was 7.39 months in the sorafenib-alone arm (95% CI, 5.52-9.20 months) and 7.56 months in the sorafenib plus IFN arm (95% CI, 5.19-11.07 months). The median OS was 27.04 months in the combination arm (95% CI, from 22.31 to not attained) and was not reached in the sorafenib arm. Toxicities were comparable in both arms. In a multivariate model, increased phosphorylated protein kinase B (pAKT) levels were associated with poorer PFS (hazard ratio, 1.04; 95% CI, 1.00-1.08; P = .0411) and OS (hazard ratio, 1.15; 95% CI, 1.02-1.29; P = .0173). CONCLUSIONS The addition of low-dose IFN to sorafenib resulted in efficacy outcomes that were comparable to those achieved with sorafenib monotherapy. The current results indicated that pAKT levels may predict for clinical outcome, but further mechanistic study is required.
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[Comparison of the mechanisms of intralesional steroid, interferon or verapamil injection in the treatment of proliferative scars].
Xu, SJ, Teng, JY, Xie, J, Shen, MQ, Chen, DM
Zhonghua zheng xing wai ke za zhi = Zhonghua zhengxing waike zazhi = Chinese journal of plastic surgery. 2009;(1):37-40
Abstract
OBJECTIVE To investigate the effects of intralesional steroid, interferon alpha-2b or verapamil injection on proliferation, apoptosis and TGF-beta1 expression in keloid and hypertrophic scar in vivo. METHODS 6 patients with keloids and 6 patients with hypertrophic scar were treated with intralesional injection of triamcinolone acetonide (40 mg/ml) or IFN alpha-2b (15 x 10(5) U/ml) or verapamil (2.5 mg/ml). Samples were collected on the 7th day after intralesional injection. Samples of untreated keloid and hypertrophic scar and normal skin were used as control. Expression of PCNA and TGF-beta1 was detected in situ by immunohistochemical staining, and apoptosis was detected in situ by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick end labeling (TUNEL). RESULTS 1) Triamcinolone acetonide could prohibit proliferative scars through inhibiting cell proliferation and TGF-beta1 expression, as well as inducing apoptosis. 2) IFN alpha-2b could prohibit proliferative scars through inhibiting cell proliferation and TGF-beta1 expression, but not inducing apoptosis; 3) Verapamil could also prohibit proliferative scars through inhibiting proliferation and TGF-beta1 expression in fibroblasts, as well as inducing apoptosis. While the effect of inducing apoptosis was stronger than that of triamcinolone acetonide, the effect of inhibiting TGF-beta1 expression was weaker than those of triamcinolone acetonide and IFN alpha-2b. CONCLUSIONS Although intraleional injection of steroid, interferon alpha-2b or verapamil were all effective in the treatment of keloid and hypertrophic scar, their mechanisms are not similar.
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Incidence of type 2 diabetes mellitus and glucose abnormalities in patients with chronic hepatitis C infection by response to treatment: results of a cohort study.
Giordanino, C, Bugianesi, E, Smedile, A, Ciancio, A, Abate, ML, Olivero, A, Pellicano, R, Cassader, M, Gambino, R, Bo, S, et al
The American journal of gastroenterology. 2008;(10):2481-7
Abstract
BACKGROUND Patients with chronic hepatitis C are at risk of developing type 2 diabetes mellitus (DM) and impaired fasting glucose (IFG), and this risk may increase among hepatitis C virus (HCV) patients not responding to an antiviral therapy. AIM: To compare the incidence of glucose abnormalities (IFG or DM) after an antiviral therapy between HCV+ patients with a long-term virological response (LTR) and nonresponders (NR; persistently positive HCV-RNA). METHODS All 202 HCV+ patients without the baseline glucose abnormalities enrolled by our center in investigational trials or routinely treated with interferon (IFN)/peginterferon (Peg-IFN) (+/- ribavirin) from 1988 to 2001, with the available baseline sera stored at -80 degrees C, were considered. The baseline data included age, sex, body mass index (BMI), viral load, genotype, liver histologic staging and steatosis, glucose, and cholesterol. The homeostatic assessment of insulin resistance (HOMA-IR) was calculated in the baseline serum. The incidence of IFG or DM at the end of follow-up was compared between patients with LTR and NR. RESULTS After a median follow-up of 8.0 yr (range 5-16), the cumulative risk of DM (N = 7) or IFG (N = 33) among the 202 HCV+ included patients was 16.9% (95% confidence interval [CI] 11.3-22.5). The 8-yr risk was not significantly lower between LTRs (14.5%) compared to NRs (18.8%) (hazard ratio [HR] 0.60, CI 0.30-1.20, P= 0.16). The HR adjusted for the baseline risk factors for DM and the predictors of a poor response (age, sex, HOMA-IR, BMI, family history of diabetes, HCV genotype 1, high viral load, cirrhosis, and steatosis) was 0.88 (CI 0.38-2.02, P= 0.76). Among other factors, those more associated to IFG-DM were an increasing age (P= 0.017), a higher BMI (P= 0.054), and a family history of DM (P= 0.065). CONCLUSIONS After adjustment for several baseline risk factors, the incidence of glucose abnormalities was not significantly different between LTRs and NRs. Our data suggest that HCV clearance does not significantly reduce the risk of glucose intolerance.
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Interleukin-2/interferon-alpha2a/13-retinoic acid-based chemoimmunotherapy in advanced renal cell carcinoma: results of a prospectively randomised trial of the German Cooperative Renal Carcinoma Chemoimmunotherapy Group (DGCIN).
Atzpodien, J, Kirchner, H, Rebmann, U, Soder, M, Gertenbach, U, Siebels, M, Roigas, J, Raschke, R, Salm, S, Schwindl, B, et al
British journal of cancer. 2006;(4):463-9
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Abstract
We performed a prospectively randomised clinical trial to compare the efficacy of four subcutaneous interleukin-2-(sc-IL-2) and sc interferon-alpha2a (sc-IFN-alpha2a)-based outpatient regimens in 379 patients with progressive metastatic renal cell carcinoma. Patients with lung metastases, an erythrocyte sedimentation rate < or =70 mm h(-1) and neutrophil counts < or =6000 microl(-1) (group I) were randomised to arm A: sc-IL-2, sc-IFN-alpha2a, peroral 13-cis-retinoic acid (po-13cRA) (n=78), or arm B: arm A plus inhaled-IL-2 (n=65). All others (group II) were randomised to arm C: arm A plus intravenous 5-fluorouracil (iv-5-FU) (n=116), or arm D: arm A plus po-Capecitabine (n=120). Median overall survival (OS) was 22 months (arm A; 3-year OS: 29.7%) and 18 months (arm B; 3-year OS: 29.2%) in group I, and 18 months (arm C; 3-year OS: 25.7%) and 16 months (arm D; 3-year OS: 32.6%) in group II. There were no statistically significant differences in OS, progression-free survival, and objective response between arms A and B, and between arms C and D, respectively. Given the known therapeutic efficacy of sc-IL-2/sc-INF-alpha2a/po-13cRA-based outpatient chemoimmunotherapies, our results did not establish survival advantages in favour of po-Capecitabine vs iv-5-FU, and in favour of short-term inhaled-IL-2 in patients with advanced renal cell carcinoma receiving systemic cytokines.
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Comparison of two different regimens of combined interferon-alpha2a and lamivudine therapy in children with chronic hepatitis B infection.
Kansu, A, Doğanci, T, Akman, SA, Artan, R, Kuyucu, N, Kalayci, AG, Dikici, B, Dalgiç, B, Selimoğlu, A, Kasirga, E, et al
Antiviral therapy. 2006;(2):255-61
Abstract
AIM: To evaluate the efficacy of two regimens of combined interferon-alpha2a (IFN-alpha2a) and lamivudine (3TC) therapy in childhood chronic hepatitis B. METHODS A total of 177 patients received IFN-alpha2a, 9 million units (MU)/m2 for 6 months. In group I (112 patients, 8.7 +/- 3.5 years), 3TC (4 mg/kg/day, max 100 mg) was started simultaneously with IFN-alpha2a, in group II (65 patients, 9.6 +/- 3.8 years) 3TC was started 2 months prior to IFN-alpha2a. 3TC was continued for 6 months after antiHBe seroconversion or stopped at 24 months in nonresponders. RESULTS Baseline alanine aminotransferase (ALT) was 134.2 +/- 34.1 and 147.0 +/- 45.3; histological activity index (HAI) was 7.4 +/- 2.7 and 7.1 +/- 2.3; and HBV DNA levels were above 2,000 pg/ml in 76% and 66% of patients in groups I and II, respectively (P > 0.005). Complete response was 55.3% and 27.6% in groups I and II, respectively (P < 0.01). AntiHBe seroconversion was higher and earlier, and HBV DNA clearance was earlier in group I (P < 0.05). HBsAg clearance was 12.5% and 4.6% and antiHBs seroconversion was 9.8% and 6.2% in groups I and II, respectively (P > 0.05). Breakthrough occurred in 17.9% and 24.6%; breakthrough times were 15.9 +/- 4.6 and 14.1 +/- 5.1 months; and relapse rates were 6.8% and none in groups I and II, respectively (P > 0.05, P > 0.05, P > 0.05). Responders had higher HAI (HAI > 6) and higher pre-treatment ALT than non-responders. CONCLUSION Simultaneous 3TC+IFN-alpha2a yields a higher response and earlier antiHBe seroconversion and viral clearance than consecutive combined therapy. Relapse rate is low. Predictors of response are high basal ALT and high HAI scores. 3TC can be administered for 24 months without any side effect and breakthrough rate is comparable with previous studies.
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Effect of intralesional interferon-alpha 2b combined with oral vitamin E for treatment of early stage Peyronie's disease: a randomized and prospective study.
Inal, T, Tokatli, Z, Akand, M, Ozdiler, E, Yaman, O
Urology. 2006;(5):1038-42
Abstract
OBJECTIVES To compare the efficacy and safety of intralesional interferon-alpha 2b combined with oral vitamin E or intralesional interferon-alpha 2b alone or oral vitamin E alone for the treatment of Peyronie's disease. METHODS From January 2000 to March 2002, a total of 30 consecutive men with Peyronie's disease were randomized prospectively into three different treatment groups. All the patients were assessed objectively with penile duplex Doppler ultrasonography for plaque size, location, and presence of calcification before and after treatment. Subjective data were obtained by querying about the improvement in penile pain and by using the "global efficacy question" for the assessment of the quality of sexual intercourse at the end of the study. A total of 5.0 x 10(6) U of interferon-alpha 2b was given once per week directly into the plaque for a period of 12 weeks. Patients received 400 IU of vitamin E orally twice daily for 6 months. RESULTS At the 6-month follow-up visit, we did not find any statistically significant changes in the objective parameters when compared with the initial findings in each group or among the three groups (P >0.05). We did not observe any clinically significant improvement in the subjective parameters among the three groups (P >0.05). However, all patients who were treated with interferon-alpha 2b experienced brief flu-like side effects. CONCLUSIONS Our findings indicate that 5 million units of intralesional interferon-alpha 2b injection therapy either alone or in combination with vitamin E does not appear to be clinically effective in the management of early stage Peyronie's disease compared with only oral vitamin E.
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Interferon alfa-2b [correction of alpha-2b]and ribavirin for patients with chronic hepatitis C and normal ALT.
Jacobson, IM, Ahmed, F, Russo, MW, Lebovics, E, Dieterich, DT, Esposito, SP, Bach, N, Klion, F, Tobias, H, Antignano, L, et al
The American journal of gastroenterology. 2004;(9):1700-5
Abstract
OBJECTIVES Most studies establishing the role of antiviral therapy in patients with chronic hepatitis C (CHC) excluded the patients with normal ALT levels. Small trials with interferon monotherapy suggested a limited efficacy and/or de novo ALT elevations. We sought to evaluate the efficacy of two doses of interferon alfa-2b (IFN) with ribavirin (RBV) in patients with normal ALT [correction]. METHODS Patients with biopsy-proven CHC with detectable HCV RNA and at least two normal ALT levels three or more months apart were randomized to receive either 3 or 5 million units of IFN thrice a week plus RBV 1,000-1,200 mg. Therapy was stopped at 24 wk if HCV RNA remained detectable and continued for an additional 24 wk if HCV RNA was undetectable. A final HCV RNA level was obtained 24 wk after discontinuation of therapy. RESULTS Fifty-six patients were randomized and received at least one dose of treatment. The overall rate of sustained virologic response (SVR) was 32%. SVR rates were higher in genotype 2 and 3 patients (80%) than in genotype 1 patients (24%, p = 0.002). There was a tendency toward higher SVR in genotype 1 patients treated with the higher IFN dose (36%vs 10%, p = 0.07). Five patients had mild, transient ALT elevations. No sustained ALT elevations were noted. CONCLUSIONS Patients with normal ALT had a rate of SVR comparable to that reported in patients with elevated ALT. Higher dose of interferon tended to be more effective in genotype 1 infected patients. De novo ALT elevations were transient and not clinically significant. Patients with CHC should not be excluded from treatment on the basis of ALT alone. Combination therapy with pegylated interferon and ribavirin should be evaluated in these patients.