Kinetics of phytohemaglutinin-induced IFN-γ and TNF-α expression in peripheral blood mononuclear cells from patients with chronic hepatitis B after liver transplantation

AIM: To study the association between host immunity and hepatitis B virus (HBV) recurrence after liver transplantation. METHODS: Peripheral blood mononuclear cells (PBMC) were isolated from 40 patients with hepatitis B and underwent orthotopic liver transplantation (OLT) before and 2, 4, 8 wk after surgery. After being cultured in vitro for 72 h, the levels of INF-gamma and TNF-alpha in culture supernatants were detected with ELISA. At the same time, the quantities of HBV DNA in serum and PBMCs were measured by real time PCR. RESULTS: The levels of INF-gamma and TNF-alpha in PBMC culture supernatants decreased before and 2, 4 wk after surgery in turns (INF-gamma 155.52+/-72.32 ng/L vs 14.76+/-9.88 ng/L vs 13.22+/-10.35 ng/L, F = 6.946, P = 0.027 < 0.05; TNF-alpha 80.839+/-46.75 ng/L vs 18.59+/-17.29 ng/L vs 9.758+/-7.96 ng/L, F = 22.61, P = 0.0001 < 0.05). The levels of INF-gamma and TNF-alpha were higher in groups with phytohemagglutinin (PHA) than in those without PHA before surgery. However, the difference disappeared following OLT. Furthermore, INF-gamma and TNF-alpha could not be detected in most patients at wk 4 and none at wk 8 after OLT. The HBV detection rate and virus load in PBMC before and 2, 4 wk after surgery were fluctuated (HBV detected rate: 51.4%, 13.3%, 50% respectively; HBV DNA: 3.55+/-0.674 log10 copies/mL vs 3.00+/-0.329 log10 copies/mL vs 4.608+/-1.344 log10 copies/mL, F = 7.582, P = 0.002 < 0.05). HBV DNA in serum was 4.48+/-1.463 log10 copies/mL before surgery and <10(3) copies/mL after OLT except for one with 5.72 x 10(6) copies/mL 4 wk after OLT who was diagnosed as HBV recurrence. The levels of INF-gamma and TNF-alpha were lower in patients with a high HBV load than in those with a low HBV load (HBV DNA detected/undetected in PBMCs: IFN-gamma 138.08+/-72.44 ng/L vs 164.24+/-72.07 ng/L, t = 1.065, P = 0.297 > 0.05, TNF-alpha 80.75+/-47.30 ng/L vs 74.10+/-49.70 ng/L, t = 0.407, P = 0.686 > 0.05; HBV DNA positive/negative: IFN-gamma 136.77+/-70.04 ng/L vs 175.27+/-71.50 ng/L, t = 1.702, P = 0.097 > 0.05; TNF-alpha 75.37+/-43.02 ng/L vs 81.53+/-52.46 ng/L, t = 0.402, P = 0.690 > 0.05). CONCLUSION: The yielding of INF-gamma and TNF-alpha from PBMCs is inhibited significantly by immunosuppressive agents following OLT with HBV load increased, indicating that the impaired immunity of host is associated with HBV recurrence after OLT.     

Hepatitis C virus RNA detection in serum and peripheral blood mononuclear cells of patients with hepatitis C

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Does ascorbic acid prevent retinopathy during interferon therapy in patients with chronic hepatitis C?

Purpose. Ascorbic acid was administered to patients with chronic hepatitis C to elucidate the mechanism of onset of retinopathy during interferon (IFN) therapy, and its prevention. Methods. The subjects were 62 patients with chronic hepatitis C who had been admitted to our hospital. For the IFN therapy, 6 MIU of natural IFN-α or 10 MIU of recombinant human IFN-α 2b was administered every day for the first 2 weeks, followed by administration three times a week for 22 weeks. The patients were randomly assigned to a group receiving 600 mg/day of ascorbic acid or a group not receiving ascorbic acid (control group). The optic fundi were examined by ophthalmologists before the IFN therapy began and subsequently at weeks 2 and 4 and then every 4 weeks during the IFN therapy. Results. Retinopathy was found in 9 of the 31 patients (29%) in the ascorbic acid-treated group and in 11 of the 31 patients (35%) in the control group. The cumulative incidence of hemorrhage in the ascorbic acid-treated group was lower than that in the control group during the IFN therapy, but the difference between the two groups was not significant (P = 0.186). The cumulative incidence of cotton-wool spots in the ascorbic acid-treated group was almost same as that in the control group during the IFN therapy. The median platelet counts before the therapy was begun were 11.8 × 10⁴/mm² in the group with hemorrhage and 16.6 × 10⁴/mm² in the group without, and the lowest platelet counts during IFN therapy were 7.3 × 10⁴/mm³ in the group with hemorrhage and 9.5 × 10⁴/mm³ in the group without, indicating significantly lower values in the group with hemorrhage (P = 0.018 and P = 0.020, respectively). The lowest platelet counts during IFN therapy were 7.4 × 10⁴/mm³ in the group with cotton-wool spots and 9.7 × 10⁴/mm³ in the group without, indicating a significantly lower value in the group with cotton-wool spots (P = 0.036). Conclusions. Ascorbic acid was not considered to be useful for the prevention of the retinopathy associated with IFN therapy in patients with chronic hepatitis C. Received: September 14, 2000 / Accepted: January 19, 2001     

The mRNA expression of apolipoprotein B mRNA-editing enzyme-catalytic polypeptide-like 3G in peripheral blood mononuclear cells in patients with chronic hepatitis C and its regulation by interferon-α

Objective To study the mRNA expression of apolipoprotein B mRNA-editing enzyme-catalytic polypeptide-like 3G(APOBEC3G) in the peripheral blood mononuclear cells(PBMC) in patients with chronic hepatitis C(CHC) and its regulation by exogenous interferon-α     

Kinetics of phytohemaglutinin-induced IFN-γ and TNF-a expression in peripheral blood mononuclear cells from patients with chronic hepatitis B after liver transplantation

AIM:To study the association between host immunity and hepatitis B virus (HBV) recurrence after liver transplantation. METHODS:Peripheral blood mononuclear cells (PBMC) were isolated from 40 patients with hepatitis B and underwent orthotopic liver transplantation (OLT) before and 2,4,8 wk after surgery. After being cultured in vitrofor 72 h, the levels of INF-γ and TNF-a in culture supernatants were detected with ELISA. At the same time, the quantities of HBV DNA in serum and PBMCs were measured by real time PCR. RESULTS:The levels of INF-γ and TNF-a in PBMC culture supernatants decreased before and 2, 4 wk after surgery in turns (INF-γ 155.52±72.32 ng/L vs 14.76±9.88 ng/L vs 13.22±10.35 ng/L, F=6.946, P=0.027<0.05; TNF-α 80.839±46.75 ng/L vs 18.59±17.29 ng/L vs 9.758±7.96 ng/L, F=22.61, P=0.000K0.05). The levels of INF-γ and TNF-a were higher in groups with phytohemagglutinin (PHA) than in those without PHA before surgery. However, the difference disappeared following OLT. Furthermore, INF-y and TNF-a could not be detected in most patients at wk 4 and none at wk 8 after OLT. The HBV detection rate and virus load in PBMC before and 2,4 wk after surgery were fluctuated (HBV detected rate:51,4%, 13.3%, 50% respectively; HBV DNA:3.55±0.674 log(10) copies/mL vs 3.00±0.329 log(10) copies/mL vs 4.608±1.344 log(10) copies/mL, F=7.582, P=0.002<0.05). HBV DNA in serum was 4.48±1.463 log(10) copies/mL before surgery and <10~3 copies/mL after OLT except for one with 5.72xl0~6 copies/mL 4 wk after OLT who was diagnosed as HBV recurrence. The levels of INF-γ and TNF-α were lower in patients with a high HBV load than in those with a low HBV load (HBV DNA detected/undetected in PBMCs:IFN-γ 138.08±72.44 ng/L vs 164.24±72.07 ng/L, t=1.065, P=0.297>0.05, TNF-α 80.75±47.30 ng/L vs74.10±49.70 ng/L, t=0.407, P=0.686> 0.05; HBV DNA positive/negative:IFN-γ 136.77±70.04 ng/L vs 175.27±71.50 ng/L, t=1.702, P=0.097>0.05; TNF-α 75.37±43.02 ng/L vs 81.53±52.46 ng/L, t=0.402, P=0.690>0.05). CONCLUSION:The yielding of INF-γ and TNF-α from PBMCs is inhibited significantly by immunosuppressive agents following OLT with HBV load increased, indicating that the impaired immunity of host is associated with HBV recurrence after OLT.     

Intraocular complications of IFN-α and ribavirin therapy in patients with chronic viral hepatitis C

We report a panel of severe inflammatory and vascular intraocular disorders occurring during interferon-alpha (IFN-a) treatment in eight hepatitis C virus (HCV)-infected patients. These events include three cases of Vogt-Koyanagi-Harada like (VKH) disease (an association of panuveitis, retinal detachment, ear and meningeal detachment and skin and hair changes), two cases of central retinal vein occlusion, one case of central retinal artery occlusion, one case of severe hypertensive retinopathy and one case of bilateral ischemic optic neuropathy with severe visual impairment. Rare as they are, such severe ophthalmological complications require a close follow-up of HCV-infected patients under IFN-a treatment with ophthalmological monitoring if any ocular manifestation occurs.     

Intraocular complications of IFN-α and ribavirin therapy in patients with chronic viral hepatitis C

We report a panel of severe inflammatory and vascular intraocular disorders occurring during interferon-alpha (IFN-α) treatment in eight hepatitis C virus (HCV)-infected patients. These events include three cases of Vogt-Koyanagi-Harada like (VKH) disease (an association of panuveitis, retinal detachment, ear and meningeal detachment and skin and hair changes), two cases of central retinal vein occlusion, one case of central retinal artery occlusion, one case of severe hypertensive retinopathy and one case of bilateral ischemic optic neuropathy with severe visual impairment. Rare as they are, such severe ophthalmological complications require a close follow-up of HCV-infected patients under IFN-α treatment with ophthalmological monitoring if any ocular manifestation occurs.     

Effect of in vitro interferon-beta administration on hepatitis C virus in peripheral blood mononuclear cells as a predictive marker of clinical response to interferon treatment for chronic hepatitis C

AIM:To test whether in vitro incubation of peripheral bloodmononuclear cells (PBMC) with interferon (IFN) couldefficiently decrease hepatitis C virus-RNA (HCV-RNA) amountand to analyze whether this effect was associated with clinicalresponse to IFN.METHODS:Twenty-seven patients with histologically provenchronic hepatitis C were given intravenous administrationof 6 million units (MU) IFN-β daily for 6 weeks followed bythree times weekly for 20 weeks.PBMC collected beforeIFN therapy were incubated with IFN-β and HCV-RNA inPMBC was semi-quantitatively determined.RESULTS:Twenty-five patients completed IFN therapy.Eight patients (32%) had sustained loss of serum HCV-RNAwith normal serum ALT levels after IFN therapy (completeresponders).HCV-RNA in PBMC was detected in all patients,whereas it was not detected in PBMC from healthy subjects.In vitro administration of IFN-β decreased the amount ofHCV-RNA in PMBC in 18 patients (72%).Eight of thesepatients obtained complete response.On the other hand,none of the patients whose HCV-RNA in PBMC did notdecrease by IFN-β was complete responders.Multiple logisticregression analysis revealed that the decrease of HCV-RNAamount in PBMC by IFN-β was the only independent predictorfor complete response (P<0.05).CONCLUSION:The effect of in vitro IFN-β on HCV in PBMCreflects clinical response and would be taken into accountas a predictive marker of IFN therapy for chronic hepatitis C.     

Immunological predictors of different responses to combination therapy with interferon α and ribavirin in patients with chronic hepatitis C

Background: This study aimed to investigate peripheral blood CD4+ T-helper (Th) and CD8+ cytotoxic T-lymphocyte (CTL) responses to combination treatment with interferon (IFN) α and ribavirin in 59 patients with chronic hepatitis C, and to correlate the results with the therapy outcome. Methods: The expression of activation molecules on the surface of CD8+ T cells and cytokine production by in-vitro activated CTLs and Th lymphocytes were examined before and at the end of the therapy, using flow cytometry. Results: There were 36 complete responders to the treatment and 23 transient responders who relapsed after withdrawal of the therapy. A significant increase in the production of Th1-type cytokines [IFNγ, interleukin 2 (IL2), and tumor necrosis factor-α (TNFα)] was found at the end of the treatment in complete responders compared with baseline values (P < 0.001). In contrast, transient responders had a marked decrease in the percentage of activated CD8+ T cells expressing CD28 or HLA-DR costimulatory molecules in peripheral blood, and a lower production of TNFα by CTLs and Th cells at the end of the therapy with respect to pretreatment values (P < 0.001). Conclusions: The efficacy of IFNα and ribavirin combination therapy for chronic hepatitis C is associated with a vigorous response of peripheral blood Th1 cells, whereas weak CTL responses at the end of the therapy might predict a further relapse of the disease. Received: March 26, 2002 / Accepted: August 30, 2002 Acknowledgments. This work was supported by grants MZd CzR 5740-3, 6015-3/00. Reprint requests to: R. Amaraa Editorial on page 302     

Predictors of the efficacy of interferon therapy for patients with chronic hepatitis C before and during therapy: how does this modify the treatment course?

Antiviral therapy for hepatitis C virus (HCV) infection should be based on the natural history of HCV infection; there is a sequential, but slow, progression from chronic hepatitis to cirrhosis, leading to death from either liver failure or hepatocellular carcinoma (HCC). The risk of HCC development increases in association with the advance of fibrosis, and antiviral therapy can reduce this risk. More than 30 indices have been proposed as ‘predictors’ of favourable response to IFN therapy: host factors (age, gender, duration of HCV‐infection, alcohol intake, hepatic iron stores, platelet count, histological staging of the liver disease), viral factors (HCV RNA levels in serum, HCV subtype, diversity of the hypervariable region, mutation of non‐structure 5A gene), and IFN factors (dose, duration of treatment, type, treatment regimens i.e. every day vs three times a week, escalating dose regimen). Before starting IFN therapy, HCV subtype and pretreatment HCV RNA load, as well as the fibrotic stage of the liver, should be determined. The response to IFN therapy should be monitored by the HCV RNA status in serum during therapy, and the treatment regimen modified, or discontinued as required. A sustained virological response should be checked at more than 3 months after the completion of therapy. Even though the risk of HCC is markedly reduced in sustained responders, it is possible to develop HCC several years after completion of IFN therapy.     

Does interferon therapy prevent hepatocellular carcinoma in patients with chronic viral hepatitis?

Chronic hepatitis C and B are well-recognized and potentially preventable risk factors for hepatocellular carcinoma (HCC) development. Clinical and epidemiological studies suggest that therapy with interferon-α may reduce the overall risk of HCC development in patients with chronic hepatitis C, who achieve sustained virological response, but even in those who fail to eradicate the infection. In chronic hepatitis B, interferon therapy reduces the risk of HCC development in HBeAg-positive and cirrhotic patients who achieve persistent suppression of viral replication, while in HBeAg-negative patients the beneficial effect of interferon-α is not definitively confirmed. The preventive role of interferon-α after potentially curative treatment for HCC in both chronic hepatitis B and C is uncertain due to methodological flaws of the existing studies and prospective randomized controlled trials with pegylated interferon-α are needed to clarify this issue.     

Interferon-α improves bone resorption and osteopenia in patients with chronic hepatitis C

Background

Interferon (IFN)-β is known to be involved in the regulation of bone homeostasis. As IFN-α and -β share the same receptor complex and signaling pathway, we speculated that treatment with IFN-α for chronic hepatitis C (CHC) may provide a beneficial effect on bone loss.

Methods

Urinary deoxypyridinoline (uDPD) of 41 patients with CHC who had been receiving IFN-α for 24 weeks was examined during the period of observation. Among them, eight patients showed a bone mineral density (BMD) of less than 0.850 g/cm² before IFN therapy and they were examined a BMD again after completion of IFN administration. Relationships between the percentage difference of uDPD after discontinuation of IFN and various factors related to CHC were also examined.

Results

A mean uDPD of 7.1 ± 3.4 nM/mM creatinine before IFN therapy decreased to 4.5 ± 2.4 in the 4th week and 4.2 ± 2.7 in the 24th week of IFN therapy, respectively (p < 0.0001). The reduction in uDPD was more prominent in cases with a lower viral load (p = 0.0266). The BMD of the eight patients, which was less than 0.850 g/cm² before IFN therapy, showed significant increase after the end of therapy (p = 0.0172).

Conclusion

IFN-α can improve bone resorption in CHC patients, especially in those with a lower viral load, and increased BMD. These effects are thought to be a result of direct action of IFN on bone homeostasis.     

Effect of interferon and ribavirin combined with amantadine in interferon and ribavirin non-responder patients with chronic hepatitis C （genotype 1）

AIM: To evaluate the efficacy of amantadine plus interferon-alpha and ribavirin in non-responder patients with chronic hepatitis C. METHODS: Twenty-six non-responder patients received the regimen of IFN-α-2a at a dose of 6 million units three times a week, 1 000-1 200 mg of ribavirin daily, and 200 mg of amantadine daily in divided doses over 48 wk. After the end of treatment, at the 72nd wk, a sustained viral response rate was determined. RESULTS: An early (after 12 wk of therapy) response was seen in 34.6% (9/26) of patients. Response rate at the 24th wk was 42.3% (11/26). End of treatment response (ETR) was 53.8% (14/26). Sustained viral response (SVR) was 42.3% (11/26). There was a statistically significant difference between 0 and 12 wk (P= 0.04), 0 and 24 wk (P= 0.01), 0 and 48 wk (P= 0.00), and 0 and 72 wk (P= 0.001). No patient had severe adverse effects during the treatment. CONCLUSION: Combination regimen of interferon-α, ribavirin and amantadine can enhance sustained viral response on IFN-α and ribavirin non-responder patients with HCV. Triple therapy with amantadine should be evaluated in further studies.     

Pulmonary embolism in a 30 year-old man with chronic hepatitis C during therapy with pegylated interferon-α and ribavirin

The authors described a case of a 30 year-old man with chronic hepatitis C (G1,S1) complicated by pulmonary embolism (PE), preceded by symptoms of respiratory system infection, which occurred after 6 months of combination therapy with pegylated interferon-α and ribavirin. Right sided nonbacterial thrombotic endocarditis as a source of segmental/subsegmental PE was found. Hemostatic work up showed increased activated protein C resistance, elevated factor VIII activity and fibrinogen concentration as well as hyperhomocysteinaemia (all these disturbances returned to normal 3-6 months later). The patient's clinical status improved during anticoagulation therapy. Antiviral treatment was not continued as virological response was achieved.     

Entecavir and interferon-α sequential therapy in Japanese patients with hepatitis B e antigen-positive chronic hepatitis B

Background

The outcomes of sequential therapy with lamivudine followed by interferon have been unsatisfactory in Japanese patients with hepatitis B envelope antigen (HBeAg)-positive chronic hepatitis B. However, the efficacy of sequential therapy with entecavir and interferon remains unclear.

Methods

Twenty-four HBeAg-positive patients (23 men and 1 woman; mean age 39 ± 7 years) received entecavir 0.5 mg alone for 36–52 weeks, followed by entecavir plus interferon-α for 4 weeks, and lastly by interferon-α alone for 20 weeks. Twenty-three patients had genotype C infection, and one had genotype A infection.

Results

No entecavir-resistant mutant variants emerged in any patient. Hepatitis flare occurred in three patients during interferon-α treatment after the withdrawal of entecavir, but none had hepatic decompensation. Serum hepatitis B surface antigen levels did not change during or after therapy. Serum hepatitis B core-related antigen levels were significantly decreased at the start (P < 0.0001) and at the end of interferon-α treatment (P < 0.0001), but returned to baseline levels after treatment. Twenty-four weeks after the completion of the sequential therapy, a sustained biochemical, virological, and serological response was achieved in 5 (21 %) patients. The proportion of patients in whom HBeAg was lost during entecavir treatment was significantly higher among those with a sustained response than among those with no response (P = 0.015).

Conclusions

The rate of response to sequential therapy with entecavir and interferon-α in Japanese patients with HBeAg-positive chronic hepatitis B was not higher than the rate in previous studies of lamivudine followed by interferon.     

Interleukin 2 and γ/δ T-cell receptors in peripheral blood of patients with chronic hepatitis C virus infection

Studies were conducted to determine if CD3 (T-cell) associated antigen receptors (R) such as interleukin 2 (IL-2) and γδ participate in the pathogenesis of hepatitis C virus (HCV) infection. Peripheral blood T-cells bearing IL-2R α (CD25) or β (CD122) chain, and αβ or γδ were examined using two-color flow cytometry in 92 patients with various chronic HCV infection. CD25-positive T-cells were increased with the progression of the disease; patients with hepatocellular carcinoma (HCC) had the highest percentage of CD25 + T-cells, while CD 122 + T-cells were significantly higher in asymptomatic HCV carriers with normal serum ALT levels and mild to moderate chronic hepatitis. In HCC patients, a decrease in CD25 + cells and increase in CD 122+ cells were noted after hepatic resection or percutaneous ethanol injection. Asymptomatic carriers had higher γδ T-cells than in controls, and patients with chronic liver disease. The percentage of γδ T-cells became higher during IFN treatment in responders compared with nonresponders. The absolute number of T-cells studied here showed comparable results to those expressed as percentage in each patient group. There was no correlation between serum ALT values, HCV RNA levels, and the incidence of T-cell subsets. The findings suggest that IL-2R αβ chains on T-cells and γδ T-cell are associated with the pathogenesis of chronic HCV infection.     

LPS-stimulated production of TNF-α by peripheral blood monocytes in patients with Behcet’s Disease

Tumor necrosis factor alpha (TNF-α) is believed to play a significant role in disease pathogenesis of Behcet’s disease (BD). High serum levels of TNF-α were repeatedly reported in patients with active BD and anti-TNF agents are effective in its treatment. The pathophysiology of TNF-α in BD is still unknown and conflicting results regarding TNF-α overproduction by peripheral blood monocytes (PBM) from patients with BD were reported. The aim of the study is to compare stimulated production of TNF-α by PBM of BD patients with that of healthy volunteers (HV) and to examine correlations between the ability of PBM to produce TNF-α and organ/system involvement in patients with BD. Eighteen patients with BD (mean age 38.4±12.4 years, 12 males) gave informed consent and completed the European BD Current Activity Form. The PBM were separated and treated with lipopolysaccharide (LPS) overnight. TNF-α levels in the supernatants were assayed by ELISA and values were expressed in terms of cell protein contents. The control group included 15 HV (mean age 34.2±9.9 years, seven males). The mean production of TNF-α/cell protein (ng/mg) and in-group dispersion were similar in both groups (p=0.98). In the subgroup analysis, TNF-α production by PBM in BD patients who reported “bad” or “very bad” global well-being over the last month (n=4) was higher compared to other patients with better self-rating (p=0.03). PBM of BD patients in the present study did not overproduce TNF-α upon stimulation with LPS. However, BD patients with a higher TNF-α-producing capacity had worse sense of well-being.     

Risk factors for retinopathy associated with interferon α-2b and ribavirin combination therapy in patients with chronic hepatitis C

AIM: To elucidate the frequency and risk factors for retinopathy in patients with chronic hepatitis C who are treated by interferon-ribavirin combination therapy. METHODS: We prospectively analyzed 73 patients with histologically confirmed chronic hepatitis C, who underwent combination therapy for 24 wk. Optic fundi were examined before, and 2, 4, 12 and 24 wk after the start of combination therapy. RESULTS: Fourteen patients (19%) developed retinopathy, which was initially diagnosed by the appearance of a cotton wool spot in 12 patients. Retinal hemorrhage was observed in 5 patients. No patient complained of visual disturbance. Retinopathy disappeared in 9 patients (64%) despite the continuation of combination therapy. However, retinopathy persisted in 5 patients with retinal hemorrhage. A comparison of the clinical background between the groups with and without retinopathy showed no significant differences in age, gender, viral genotype, RNA level, white blood cell count, platelet count, prothrombin time, complications by diabetes mellitus or hypertension, or pretreatment arteriosclerotic changes in the optic fundi. However, multiple logistic regression analysis revealed that complication by hypertension was observed with a high frequency in the group with retinopathy (P = 0.004, OR = 245.918, 95% CI = 5.6-10786.2). CONCLUSION: Retinopathy associated with combination therapy of interferon alpha-2b and ribavirin tends to develop in patients with hypertension.     

Risk factors for retinopathy associated with interferonα-2b and ribavirin combination therapy in patients with chronic hepatitis C

AIM: To elucidate the frequency and risk factors for retinopathy in patients with chronic hepatitis C who are treated by interferon-ribavirin combination therapy. METHODS: We prospectively analyzed 73 patients with histologically confirmed chronic hepatitis C, who underwent combination therapy for 24 wk. Optic fundi were examined before, and 2, 4, 12 and 24 wk after the start of combination therapy. RESULTS: Fourteen patients (19%) developed retinopathy, which was initially diagnosed by the appearance of a cotton wool spot in 12 patients. Retinal hemorrhage was observed in 5 patients. No patient complained of visual disturbance. Retinopathy disappeared in 9 patients (64%) despite the continuation of combination therapy. However, retinopathy persisted in 5 patients with retinal hemorrhage. A comparison of the clinical background between the groups with and without retinopathy showed no significant differences in age, gender, viral genotype, RNA level, white blood cell count, platelet count, prothrombin time, complications by diabetes mellitus or hypertension, or pretreatment arteriosclerotic changes in the optic fundi. However, multiple logistic regression analysis revealed that complication by hypertension was observed with a high frequency in the group with retinopathy (P = 0.004, OR=245.918, 95% CI=5.6-10786.2). CONCLUSION: Retinopathy associated with combination therapy of interferon a-2b and ribavirin tends to develop in patients with hypertension.