Ribavirin dosage in patients with HCV genotypes 2 and 3 who completed short therapy with peg-interferon alpha-2b and ribavirin.

BACKGROUND: The optimal dose of ribavirin to be used in combination with Peg-IFN in patients with HCV genotypes 2 and 3 undergoing short treatment has not been established. AIM: To explore the relationship between starting ribavirin doses, expressed as mg/kg body weight and both rapid viral response at treatment week 4 (RVR) and sustained virological response (SVR) in patients treated for 12-14 weeks with peg-interferon alpha-2b and ribavirin. METHODS: A post hoc analysis of data collected from two multicenter clinical trials was performed. Multiple regression analyses were employed to identify independent baseline and on-treatment predictors of RVR and SVR. For each dose of ribavirin, the empirical estimated probability of response was computed and the continuous exposure index was dichotomized by using a recursive partitioning and amalgamation method. RESULTS: A nonlinear relationship was ascertained between ribavirin dose and RVR, but not SVR. A dose of 15.2 mg/kg was selected as the best splitting value for discriminating RVR vs. non-RVR. Regression analysis identified low baseline viraemia, genotype 2 and high ribavirin dose as independent prognostic factors for RVR. The likelihood of an SVR was not correlated with baseline ribavirin dose, but was independently predicted by adherence to the full dose throughout treatment and normal platelet counts. CONCLUSIONS: Starting high ribavirin doses appears capable of increasing the rate of RVR in patients with HCV genotypes 2 and 3 undergoing short treatment. Maintenance of the full planned dose throughout treatment is essential for achieving optimal SVR rates.

Vasoconstrictor therapy for hepatorenal syndrome in liver cirrhosis.

Hepatorenal syndrome is a severe, but not uncommon complication of decompensated liver cirrhosis. In particular, the rapidly progressive form of hepatorenal syndrome (type 1) is associated with a dismal prognosis. Established hepatorenal syndrome has a spontaneous reversibility below 5%. Hepatorenal syndrome is involved in more than 50% of cirrhosis-related mortality. Thus, any treatment capable of reversing hepatorenal syndrome would be expected to reduce morbidity and mortality from liver cirrhosis. A pathophysiological hallmark of hepatorenal syndrome is arterial underfilling due to an extreme splanchnic vasodilatation. Consequently, potent vasoconstrictors capable of reversing this vasodilatation have been investigated in hepatorenal syndrome. Several vasoconstrictors including the alpha-adrenergic agonists, midodrine and noradrenalin, and the vasopressor analogues, ornipressin and terlipressin, have all been associated with a significant improvement in renal function in 57 to 100% of cases and even reversal of hepatorenal syndrome in 42 to 100% of cases. The majority of recent studies are on terlipressin. A randomized, controlled trial showed a significant effect of terlipressin on reversal of hepatorenal syndrome. The contribution of volume expansion to the beneficial effects of vasoconstrictors on hepatorenal syndrome remains to be determined. In general, reversal of hepatorenal syndrome was associated with an improved survival. However, it remains to be determined if vasoconstrictor therapy should be used in hepatorenal syndrome in general, or if it should be reserved for potential candidates for liver transplantation. In conclusion, evidence for a beneficial effect of vasoconstrictor therapy for the treatment of hepatorenal syndrome is steadily accumulating. Confirmation of the preliminary data in larger randomized, controlled trials looking at long-term survival is required.

Interferon alfa-2b alone or combined with recombinant granulocyte-macrophage colony-stimulating factor as treatment of chronic hepatitis C.

BACKGROUND: To compare the effect of combination therapy with interferon-alpha (INF-alpha) and granulocyte-macrophage colony-stimulating factor (GM-CSF) to monotherapy with INF-alpha in patients with chronic hepatitis C infection. METHODS: Forty-five consecutive patients with chronic hepatitis C, all presenting with elevated serum alanine aminotransferases and viremia, were randomized to receive either 1) INF-alpha + GM-CSF for 3 months followed by INF-alpha alone for 9 months (n = 23) or 2) INF-alpha for 12 months (n = 22). Both drugs were administered 3 times weekly in doses of 3 mU (INF-alpha) and 50-100 microg depending on body weight (GM-CSF). RESULTS: At baseline, there was no difference between the treatment groups in terms of age, sex, ALT level, viral load, genotype or histological activity and fibrosis in a pretreatment liver biopsy. After 12 months' treatment, more patients treated with GM-CSF+ INF-alpha compared to patients receiving monotherapy had normalized ALT, 65% and 32%, respectively (P = 0.03), but there was no difference in percentages of patients with viral clearance between the 2 groups, 48% and 32%, respectively (P = 0.27). At 6 months' follow-up, the biochemical response had declined to 35% in the combination therapy group and to 23% in the monotherapy group (P = 0.37); viral clearance had declined to 22% and 27%, respectively (P = 0.67), and the overall sustained response rate was 22% and 23%, respectively (P = 1.00). CONCLUSIONS: Even though patients receiving INF-alpha + GM-CSF had a significant better biochemical response during treatment compared to patients receiving monotherapy, the sustained biochemical and virological response was not increased. Thus, GM-CSF hardly plays any role in the future treatment of chronic hepatitis C.

Dynamics of albumin in plasma and ascitic fluid in patients with cirrhosis.

BACKGROUND/AIMS: To determine dynamics of albumin in plasma and ascitic fluid of patients with cirrhosis. METHODS: Forty-seven patients were classified in four groups: I--patients without fluid retention; II--patients with ascites not resistant to subsequent diuretic treatment; III--recompensated patients during diuretic treatment; and IV--patients with diuretic-resistant ascites. Transvascular and transperitoneal albumin transports were quantified by 131I-/125I-labelled human albumin. RESULTS: TER(P) (i.e. the fraction of intravascular albumin (IVM) passing from plasma into the interstitial space per hour) was increased in all groups. In group IV patients the transport rate of albumin from plasma into the ascitic fluid (TER(PA)) was significantly higher than the transport rate from the ascitic fluid back into the plasma: TER(AP) (0.45 vs. 0.26% IVM/h, P < 0.002). In group II patients TER(PA) was similar to TER(AP) (0.27 vs. 0.25% IVM/h, ns). A direct correlation was found between TER(PA) and TER(AP) in both groups of patients (r = 0.78, P < 0.001). CONCLUSION: In non-resistant ascites, there is a steady state between the transport of albumin into the peritoneal cavity and back into the plasma, but in resistant ascites the former transport is elevated. Thus, local factors may be important to treatment of ascites.

Natural history and etiology of liver disease in patients with previous community-acquired acute non-A, non-B hepatitis. A follow-up study of 178 Danish patients consecutively enrolled in The Copenhagen Hepatitis Acuta Programme in the period 1969-1987.

BACKGROUND/AIMS: Consecutive patients originally diagnosed with acute non-A, non-B hepatitis were followed up to assess the long-term morbidity and mortality and to re-evaluate the etiology in surviving patients. METHODS: Follow-up was performed in 178 patients with acute non-A, non-B hepatitis enrolled in the Copenhagen Hepatitis Acuta Programme in the period 1969-1987. Mortality and morbidity were assessed using: i) death certificates and ii) diagnoses at discharge following all somatic admissions. All patients who were alive were offered a re-examination encompassing clinical, biochemical and virological evaluation. RESULTS: After a median of 23 years, 71 (40%) had died and seven (4%) were untraceable. Overall mortality and mortality due to cirrhosis and accidents, mainly intoxication with drugs, were significantly higher compared to those of an age- and sex-matched Danish population. Chronic hepatitis had been diagnosed in 19 (11%) and cirrhosis in 16 (9%). Of 100 patients who were alive, 57 accepted a re-examination. Anti-HCV was detected in 24 (42%) and 19 (33%) were HCV-RNA positive. Of the viremic patients, 11 (58%) had elevated P-ALT, but only three (16%) had already been diagnosed with HCV infection. A history of intravenous drug use was tantamount to anti-HCV positivity. CONCLUSIONS: Danish patients with community-acquired acute non-A, non-B hepatitis had an increased mortality due to liver cirrhosis during the first years after the acute infection. Alcohol was the etiological agent in several cases, but HCV infection may also have been present. However, the long-term HCV-related morbidity and mortality were low.

Interferon alfa for chronic hepatitis B infection: increased efficacy of prolonged treatment. The European Concerted Action on Viral Hepatitis (EUROHEP).

Interferon alfa (IFN-alpha) is the primary treatment for chronic hepatitis B. The standard duration of IFN-alpha therapy is considered 16 weeks; however, the optimal treatment length is still poorly defined. We evaluated the efficacy and acceptability of prolonged IFN-alpha treatment in patients with chronic hepatitis B. To investigate whether treatment prolongation could enhance the rate of hepatitis B e antigen (HBeAg) seroconversion, we conducted a prospective, controlled, multicenter trial in which all patients were treated with a standard regimen of 10 million units IFN-alpha 3 times per week over 16 weeks. Patients who were still HBeAg-positive after 16 weeks of therapy were randomized to prolongation of the identical regimen up to 32 weeks (prolonged therapy) or discontinuation of treatment (standard therapy). Among the 162 patients who entered the study, 27 (17%) were HBeAg-negative after the first 16 weeks of treatment, and 118 were randomized to standard or prolonged therapy. After randomization, a response (HBeAg seroconversion and sustained hepatitis B virus [HBV]-DNA negativity) was observed in 7 of the 57 (12%) patients assigned to standard therapy versus 17 of the 61 (28%) patients assigned to prolonged therapy (P =.04). A low level of viral replication after 16 weeks of treatment, as indicated by serum HBV-DNA values under 10 pg/mL, was found to be the only independent predictor of response (52% vs. 0%; P <.001) during prolonged therapy. The prolonged IFN-alpha schedule was well tolerated in the large majority of patients. In chronic hepatitis B, prolongation of IFN-alpha therapy up to 32 weeks is superior to a standard course of 16 weeks. Those patients who exhibit a low level of viral replication at the end of the standard regimen benefit most from prolonged treatment.

[Pretreatment with prednisolone enhances the effect of human lymphoblastoid interferon in chronic hepatitis B]. / Prednisolon-forbehandling øger effekten af humant lymfoblastinterferon ved kronisk hepatitis B. INTERPRED Trial Group.

Patients (n = 213) with chronic hepatitis B were randomised to prednisolone (two weeks of 0.6 mg/kg/day, one week of 0.45 mg/kg/day and one week of 0.25 mg/kg/day) or placebo followed by two weeks rest, and were then given human lymphoblastoid interferon 10 MU daily for five days followed by 10 MU thrice weekly for 11 weeks. There were statistically significant effects of prednisolone pre-treatment on both HBeAg disappearance and HBeAg to anti-HBe seroconversion (log rank test statistics 5.43; p = 0.02 and 4.75; p = 0.03). HBeAg disappearance and HBeAg to anti-HBe seroconversion rates were 28 vs. 44% and 23 vs. 38% (placebo vs. prednisolone). Fifteen patients (7.5%) lost HBsAg. Three out of 22 cirrhotic patients (14%), one of whom received prednisolone pre-treatment, developed hepatic decompensation with a fatal outcome. Prednisolone pre-treatment, enhances the effect of lymphoblastoid interferon in chronic hepatitis B. Interferon treatment (with and without prednisolone) should be used with caution in patients with cirrhosis and avoided in patients with evidence of hepatic decompensation.

Single-dose pharmacokinetics of citalopram in patients with moderate renal insufficiency or hepatic cirrhosis compared with healthy subjects.

OBJECTIVE: To compare the pharmacokinetics of the antidepressant citalopram and its metabolites demethylcitalopram and didemethylcitalopram in subjects with moderate renal insufficiency and subjects with hepatic cirrhosis with that in healthy subjects. METHODS: Pharmacokinetic parameters from three individual, open-label, phase I trials were derived following single oral or intravenous citalopram dose (40 mg) to healthy subjects and a single oral dose (20 mg) to patients. Serum and urine concentrations of citalopram and metabolites were determined using a validated HPLC method. RESULTS: The absolute bioavailability of citalopram tablets in healthy subjects was 80%. The renal clearance was a minor component (<20%) of the total elimination of citalopram. Serum Cmax and t(max) for citalopram were essentially unaffected by the occurrence of renal or hepatic disease. In comparison with healthy subjects, renal impairment was associated with a significant reduction in the renal elimination of citalopram and its two metabolites and a slight prolongation of serum citalopram t1/2 (49.5 h vs 36.8 h in healthy subjects). Cirrhosis resulted in significant decrease in citalopram CLoral (0.21 vs 0.331 x h(-1) x kg(-1) in healthy subjects) and increase in Vz x f(-1) with an approximately twofold increase in t1/2 (83.4 h vs 36.8 h in healthy subjects). Indices of renal (creatinine or 51Cr-EDTA clearances) and hepatic (galactose elimination capacity or Child-Pugh score) function were poor predictors of the changes in the pharmacokinetics of citalopram and its metabolites in these populations. CONCLUSION: No reduction of citalopram dosage is warranted in patients with moderately impaired renal function. However, that may not apply for patients with severe renal failure. In patients with impaired hepatic function, prescription of a lower dosage of citalopram may be appropriate.

Interferon-alpha 2b therapy in low-activity hepatitis C: a pilot study.

BACKGROUND: Many patients with chronic hepatitis C have long periods of normal or near-normal liver enzyme levels, even though histologic alterations have been confirmed. The recommendation today is not to treat this patient group. METHODS: In a pilot study 23 hepatitis C virus (HCV) RNA-positive patients with alanine aminotransferase (ALAT) levels less than 1.5 times upper normal limits for at least 6 months on more than three occasions and with histologic liver abnormalities compatible with chronic hepatitis C were treated with 3 MU of interferon-alpha 2b three times a week for 6 months. RESULTS: Nine patients (39%) became HCV RNA-negative in serum during treatment, but only two (8.7%) remained so after 6 months' follow-up. Significantly more patients with genotype other than type 1 became HCV RNA-negative than patients with genotype 1 during treatment (P = 0.005). CONCLUSIONS: Patients with low-activity chronic hepatitis C have a response to interferon-alpha treatment similar to that of patients with increased ALAT levels. Genotype seems to influence the rate of response.

Relation between treatment efficacy and cumulative dose of alpha interferon in chronic hepatitis B. European Concerted Action on Viral Hepatitis (Eurohep).

BACKGROUND/AIMS: Alpha interferon (IFN) is an established treatment of chronic hepatitis B. The effect has been shown to be dose related, recommended dose regimens being associated with a doubling of the spontaneous, baseline HBeAg to anti-HBe seroconversion rate. However, the efficacy of IFN treatment in relation to the dose of IFN actually received remains to be established. The aim of this study was to estimate the relative efficacy of IFN as a function of the cumulative IFN dose. In addition we determined if and when a patient returns to his baseline chance of seroconversion after stopping IFN therapy. MATERIALS AND METHODS: Individual patient data from 10 clinical controlled trials were available for the present analysis, in all, 746 patients, of whom 491 received IFN and 255 were untreated controls. The data were analyzed performing a time-dependent Cox regression analysis of the relative efficacy of IFN using the cumulative IFN dose administered up to any given time during the observation period and the time after termination of therapy as explanatory variables. RESULTS: In the proposed model, the chance of HBeAg disappearance for a treated patient relative to no therapy was estimated to 2.1 at a cumulative dose of 100 MU and leveled out at about 2.8 at a cumulative dose of 500 MU. The effect of IFN was shown to decay rapidly after discontinuation and after 3 months a patient could be considered to be back to his baseline chance of HBeAg disappearance. These findings show that IFN administered at a dose of 15-30 MU/week should be considered effective (relative efficacy approximately 2) already after 1-2 months of treatment. CONCLUSIONS: The present findings do not lend any support to the concept that IFN treatment becomes less effective when a certain total dose of IFN has been administered or that the treatment effect reaches beyond 3 months after stopping IFN.

Prednisolone withdrawal therapy enhances the effect of human lymphoblastoid interferon in chronic hepatitis B. INTERPRED Trial Group.

BACKGROUND/AIMS: The aim of this multicentre, randomised, controlled, clinical trial was to evaluate the effect of prednisolone followed by lymphoblastoid interferon treatment in chronic hepatitis B. METHODS: Two hundred and thirteen patients with chronic hepatitis B were randomised to either prednisolone (2 weeks of 0.6 mg/kg/day, 1 week of 0.45 mg/kg/day and 1 week of 0.25 mg/kg/day) or matching placebo followed by a 2-week rest phase and then human lymphoblastoid interferon 10 MU daily for 5 days followed by 10 MU thrice weekly for 11 weeks. Of 200 evaluable patients, 33 (16.5%) were females, and 50 (25%) were male homosexuals. Thirty three patients (16.5%) had chronic persistent hepatitis, 145 (72.5%) had chronic active hepatitis and 22 (11%) had active cirrhosis. RESULTS: Survival analysis disclosed statistically significant effects of prednisolone pre-treatment on both HBeAg disappearance and HBeAg to anti-HBe seroconversion (log-rank test statistics 5.43; p = 0.02 and 4.75; p = 0.03). Observed HBeAg disappearance and HBeAg to anti-HBe seroconversion rates (placebo vs. prednisolone patients) were 28% vs. 44% and 23% vs. 38%. Six months after stopping interferon, HBV DNA was negative in 51% of prednisolone patients vs. 28% of placebo patients (Chi-square test statistic 6.13; p = 0.013). Prednisolone pre-treatment tended to be more effective in patients with higher transaminase levels and in patients with low levels of HBV DNA. Fifteen patients (7.5%) (13 within 1 year of follow-up) eventually lost HBsAg; 14 of these subsequently developed anti-HBs. Interferon treatment was modified in 102 patients (51%). Three out of 22 patients with cirrhosis (14%), one of whom received prednisolone pre-treatment, developed hepatic decompensation with a fatal outcome while on interferon treatment. CONCLUSIONS: Prednisolone pre-treatment significantly enhanced the treatment effect of lymphoblastoid interferon in terms of HBeAg clearance and seroconversion to anti-HBe. Treatment should be used with caution in patients with cirrhosis and avoided in patients showing signs, or with a history, of decompensated cirrhosis.

[The hepatorenal syndrome]. / Det hepatorenale syndrom.

Renal dysfunction and abnormal sodium-water handling are frequent in liver disease. The term hepatorenal syndrome (HRS) denotes a functional type of renal failure characterized by a progressive decrease in the glomerular filtration rate (GFR), greatly increased sodium retention, a high urine/plasma ratio of solutes, azotaemia, and oliguria. The main pathogenic feature is reduced renal blood flow (RBF), especially in the cortex. The kidney is morphologically intact and has been shown to rapidly regain normal function after transplantation to a recipient with a healthy liver. Three factors should be considered in the pathogenesis of HRS: 1) decreased liver function; 2) deranged haemodynamics, including abnormal blood pressure, blood volume, and blood flow distribution; and 3) deranged neuro-humoral regulation. The prognosis in HRS is very poor, and therapy for HRS has proved disappointing. However future studies should be directed towards the reduced liver function and the haemodynamic abnormalities, especially the abnormal renal vasoconstriction. Implantation of a peritoneovenous shunt, paracentesis with plasma expansion, certain "blockers", and normalization of arterial blood pressure have reversed the HRS only in the more early stages. Liver transplantation is the ultimate treatment for the HRS.

[Poisonings due to analgesics during a period of 14 years in Denmark--a registry study of the period 1979-1992]. / Danske analgetikaforgiftninger i en 14-års periode--en registerundersøgelse for 1979-1992.

The study describes consumption of and poisoning by analgesic drugs in Denmark during the period 1979-1992. During this period, fatal poisonings from analgesics almost doubled to 200 deaths per year (40% of all drug related deaths in Denmark). The annual consumption of opioids increased at the beginning of the period, but during 1985-1992 it was relatively constant at 20 million defined daily doses (DDD) and associated with 600 hospital admissions and 150-170 deaths due to poisoning per year. Within the opioid group dextropropoxyphene consumption and poisonings decreased following a National Board of Health initiative in 1985-1987. As for the weak analgesics, consisting mainly of paracetamol or salicylates, the total consumption increased gradually and reached 145 million DDD in 1992, corresponding to 160 tablets per inhabitant per year. This consumption was associated with approximately 750 hospital admissions and 40 deaths due to poisoning. As judged from the mortality per dose the weak analgesics are 20-30 times safer than the opioids.