Would you trust a surrogate respondent?
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Clinical Trials as Topic↗
Biomedical subjects
K Krogsgaard
Publications and source records attributed to K Krogsgaard.
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.
Adolescent↗
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.
Adult↗
[Acute viral hepatitis--a constant threat].
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Acute Disease↗
Occurrence of hepatocellular carcinoma and decompensation in western European patients with cirrhosis type B. The EUROHEP Study Group on Hepatitis B Virus and Cirrhosis.
To examine the morbidity of compensated cirrhosis type B, a cohort of 349 Western European, white patients (86% men; mean age, 44 years) with biopsy-proven cirrhosis was followed up for a mean period of 73 months and was studied for occurrence of hepatocellular carcinoma (HCC) and decompensation. At entry into the study all patients were tested for hepatitis B e antigen (HBeAg; 34% of patients were HBeAg-positive) and antibody to hepatitis delta virus (anti-HDV; 20% of patients were anti-HDV-positive); 48% of 252 patients tested were hepatitis B virus (HBV)-DNA-positive. During follow-up HCC developed in 32 (9%) of the 349 patients and decompensation was observed in 88 (28%) of 317 tumor-free patients. Five years after diagnosis, the probability of HCC appearance was 6% and the probability of decompensation was 23%. After the first episode of decompensation the probability of survival was 35% at 5 years. Cox's regression analysis identified three variables that independently correlated with HCC: age, serum levels of platelets, and liver firmness on physical examination. HBV (HBeAg or HBV-DNA) and HDV (anti-HDV) markers at presentation had no prognostic value for the development of HCC. In conclusion, a high proportion of patients with HBsAg-positive compensated cirrhosis do not experience worsening of their condition for several years, but once decompensation occurs life expectancy is poor. European, white patients with compensated cirrhosis type B are at consistent risk for HCC. Prognostic factors for HCC reflect an advanced stage of cirrhosis and support the hypothesis that development of a tumor could be the likely consequence of long-standing hepatic disease.
Aged↗
Voiding problems in patients with HIV infection and AIDS.
The prevalence and type of urinary voiding problems were prospectively investigated in 77 men and four women (median age 36 years) with HIV infection or AIDS consecutively attending an outpatient clinic. Urologic symptoms were registered from replies to a questionnaire and urologic evaluation was made when indicated. All patients were neurologically examined. In addition, urodynamic data from ten consecutively referred HIV/AIDS patients were retrospectively analyzed. Two of the 81 prospectively studied patients had severe, and eight had moderate voiding problems, while 19 had pathologic findings at neurologic examination. Of three patients referred for urodynamic investigation, two were found to have neurogenic bladder dysfunction. In three of the total 13 urodynamically studied patients the findings suggested neurogenic bladder dysfunction secondary to the infection. We conclude that HIV/AIDS infection affects voiding only in minor degree, and when it does the disease is often advanced and dominated by symptoms from other organs. The relevance of urologic/urodynamic investigation in HIV/AIDS patients thus seems limited.
Acquired Immunodeficiency Syndrome↗
[Hepatitis C].
Hepatitis C virus (HCV) was recognized in 1989 as the main cause of transfusion-related hepatitis non-A, non-B (HNANB) as well as sporadically-acquired HNANB infections. The HCV genome has been sequenced but the virus has not yet been visualized. Anti-HCV antibody tests have been developed, namely enzyme-linked immunosorbent assays (ELISA) for screening and recombinant immunoblot assay (RIBA) for confirmative testing of ELISA positive results. Since May 1991 all Danish blood donations have been tested for anti-HCV antibodies. Approximately 0.04% of Danish blood donors are 4-RIBA positive and have signs of chronic HCV infection based on ALT, HCV-RNA or histological findings. High-risk groups are intravenous drug abusers, haemophiliacs, haemodialysis patients and recipients of multiple blood transfusions. Approximately one third of the cases are sporadic, i.e. without obvious risk factors. Sexual transmission of HCV may occur, but this route is uncommon. More than half of the patients with acute HCV infection progress to chronic hepatitis C. Of these a considerable proportion develops cirrhosis and some eventually hepatocellular carcinoma. At present interferon (IFN) is the only registered therapy against chronic hepatitis C. Approximately half of the patients respond to treatment. The majority, however, relapse after stopping IFN treatment and only 20% maintain their response.
Hepacivirus↗
Does corticosteroid pretreatment enhance the effect of alfa interferon treatment in chronic hepatitis B?
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Adrenal Cortex Hormones↗
The treatment effect of alpha interferon in chronic hepatitis B is independent of pre-treatment variables. Results based on individual patient data from 10 clinical controlled trials. European Concerted Action on Viral Hepatitis (Eurohep).
Alpha interferon induces HBeAg seroconversion in about one third of treated patients and has become an established treatment of chronic hepatitis B. A number of smaller studies have suggested that response to treatment is more likely to occur in patients with higher levels of transaminases, with recent (adult) onset, a history of acute hepatitis, low levels of HBV DNA and in heterosexual males. The aim of this European co-operative study was to estimate the effect of alpha interferon more accurately and to evaluate the influence of host pre-treatment variables on the effect of interferon. Individual data were collected from 751 patients from 10 controlled clinical trials on alpha interferon (lymphoblastoid or recombinant) treatment for chronic hepatitis B. Alpha interferon was administered to 496 patients, while 255 were untreated controls. Individual patient data were analysed by survival analysis (log rank test and Cox regression analysis), stratified by trial, with the disappearance of HBeAg as the major endpoint. The results showed that the HBeAg disappearance rate with or without interferon treatment was higher in patients with high aminotransferase levels, with a history of acute hepatitis and in male heterosexual patients disregarding HIV status. If HIV-positive patients were excluded, the effect of sexual orientation was not significant. Therapy with alpha interferon increased the a priori HBeAg disappearance rate by a factor of 1.76; the relative treatment effect of alpha interferon was independent of the tested pretreatment host variables, but dependent on the total (intended) interferon dose (low dose < or = 200 MU/m2 increased HBeAg disappearance by a factor 1.37; medium/high dose > or = 200 MU/m2 increased HBeAg disappearance by a factor 2.05). In conclusion, this meta-analysis suggests that the effect of alpha interferon is less than previously assumed and independent of pretreatment host variables tested. It confirms the higher therapeutic benefit of a total dose exceeding 200 MU/m2 and of selection of patients based on disease activity and immune reactivity. Although all patient seem to have the same relative benefit, the absolute benefit of alpha interferon treatment seems to be greatest in patients with high transaminase levels and with a history of acute hepatitis.
Adult↗
HTLV-I and -II in intravenous drug users from Sweden and Denmark.
693 IVDU (intravenous drug user) sera from Copenhagen, Malmö and Stockholm were tested, 247 retro- and 446 prospectively, for antibodies to human T-lymphotropic virus (HTLV), types I and II, by means of a commercial whole-virus EIA and/or an HTLV-I/-II peptide-based EIA. Positive EIA reactions were checked and typed by electrophoretic immunoblotting, a differential peptide-based EIA and nucleic acid amplification/hybridization with HTLV-I and -II specific primers and probes. 3 (0.7%) of the prospectively tested IVDUs from Malmö, none of 100 from Stockholm and none of 45 from Copenhagen were HTLV-seropositive. The 3 Malmö IVDU cases were a female immigrant from South America, her male native Swedish spouse (both HTLV-I), and a male immigrant Italian heroinist (HTLV-II). We conclude that HTLV was uncommon among intravenous drug users, a sentinel population, in Sweden and Denmark during 1986 and 1989. However, the occurrence of 3 HTLV-positive cases in Malmö 1993 indicates that the situation can change rapidly.
Adult↗
Cytomegalovirus infection rate among heart transplant patients in relation to anti-thymocyte immunoglobulin induction therapy. Copenhagen Heart Transplant Group.
During a 2-year period, 49 patients underwent heart transplantation at Rigshospitalet, Copenhagen. Nine (18%) were females and the mean age for all patients was 44 years (range 14-56 years). Immunosuppressive therapy included cyclosporin, azathioprine and steroids in all patients. 43 patients received in addition short-term (approx. 4 days) induction treatment with antithymocyte immunoglobulin (ATG). 17 patients received ATG Fresenius, 2.5 mg/kg/day or ATGAM, 12.5 mg/kg/day, whereas the remaining 26 patients received ATG Merieux, 2.5 mg/kg/day. Prophylactic antimicrobial chemotherapy included ceftriaxone, acyclovir (1 g daily), nystatin, and pyrimethamine in toxoplasmosis mismatch patients. Serological assays for cytomegalovirus (CMV), Epstein-Barr virus, varicella-zoster virus, herpes simplex virus, legionella and toxoplasmosis as well as CMV and bacterial culturing were carried out before transplantation, at regular intervals and when clinically indicated. Five patients developed septicaemia. Nine had pulmonary bacterial infections, including 2 cases of legionella pneumonia. Two had Clostridium difficile diarrhoea. Three patients had Pneumocystis carinii pneumonitis. 24 patients (49%) had evidence of CMV infection/reactivation. Seven out of 10 CMV mismatch (pos donor/neg recipient) patients and 3 out of 12 CMV match (pos donor/pos recipient) patients developed clinical CMV disease. The rate of CMV infection/reactivation was significantly higher among patients who had CMV-positive donors (p < 0.01) and among patients receiving ATG Merieux induction treatment (p < 0.0001). Logistic regression analysis showed that both positive CMV donor status and ATG Merieux induction treatment were significant independent predictors of CMV infection. Six patients (12%) died. Two out of 4 infection related deaths could be ascribed to CMV disease.
Adolescent↗
Cytomegalovirus infection rate among heart transplant patients in relation to the potency of antithymocyte immunoglobulin induction therapy. Copenhagen Heart Transplant Group.
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Adolescent↗
Hepatitis C in dialysis patients: relationship to blood transfusions, dialysis and liver disease.
Antibodies to hepatitis C virus (anti-HCV) were determined in an unselected group of 340 patients with chronic renal failure treated with maintenance dialysis. A second generation hepatitis C virus (HCV) enzyme-linked immunosorbent assay (ELISA) was used and confirmation made by a second generation recombinant immunoblot assay (RIBA). Sixteen patients (4.7%) were anti-HCV positive and 8 (2.4%) were anti-HCV indeterminate. All anti-HCV positive and anti-HCV indeterminate patients had received blood transfusions. No statistically significant differences were found between anti-HCV positive and indeterminate patients considering blood transfusions, dialysis and liver disease. The combined group of anti-HCV positive and indeterminate patients had had more blood transfusions (P < 0.005) and had been on dialysis for a longer period (P < 0.01) compared with anti-HCV negative patients. Further, significant correlation with elevation of transaminases and anti-HCV was observed (P < 0.001). Thirty patients (8.8%) had elevated transaminase levels and 13 (43%) of these were anti-HCV positive or indeterminate. In conclusion, HCV infection accounts for a substantial proportion of liver disease in dialysis patients, probably most often transmitted by blood transfusions but other routes of transmission could not be excluded.
Adolescent↗
High prevalence of hepatitis C virus (HCV) RNA in dialysis patients: failure of commercially available antibody tests to identify a significant number of patients with HCV infection. Copenhagen Dialysis HCV Study Group.
Results of serologic tests were correlated with hepatitis C virus (HCV) viremia, determined by a cDNA polymerase chain reaction assay to detect HCV RNA, in 340 Danish dialysis patients; of these, 28 (8.2%) were positive for antibodies to HCV (anti-HCV) with second-generation ELI-SAs. HCV RNA was found in sera from 27 of these 28 anti-HCV-positive patients. However, 8 dialysis patients had detectable levels of HCV RNA but were anti-HCV-negative with second-generation ELISAs. Among the 35 HCV-infected dialysis patients 16 were positive, 7 indeterminate, and 12 negative with the second-generation RIBA. More than 60% of patients with evidence of ongoing liver disease had HCV infection. Thus, current commercially available antibody tests did not accurately reflect the HCV status in dialysis patients. A relatively high prevalence (> 10%) of HCV RNA, closely associated with liver disease, was found among dialysis patients in a low-prevalence area of the world.
Base Sequence↗
Chronic evolution of acute hepatitis B: the significance of simultaneous infections with hepatitis C and D. Copenhagen Hepatitis Acuta Programme.
Seventy-six of 77 consecutive patients with hepatitis B surface antigen (HBsAg)-positive acute hepatitis were reevaluated using anti-hepatitis C virus (HCV), anti-hepatitis D virus (HDV), and IgM anti-hepatitis B core (HBc) testing. Anti-HCV and/or anti-HDV was found in 32 patients (42%). The presence of these markers was significantly associated with intravenous drug abuse (p less than 10(-6). Sixty-nine patients were IgM anti-HBc-positive, of whom two (3%) (95% confidence limits, 1-12%) became chronic HBsAg carriers with histologically verified chronic liver disease; both were anti-HCV and anti-HDV-negative. Among the remaining 67 IgM anti-HBc-positive patients 8 had HBV and HDV co-infection, 3 had HBV and HCV co-infection, and 1 had HBV, HCV, and HDV co-infection. Twenty-two had evidence of preceding or past HCV infection; two developed chronic active hepatitis in spite of HBsAg clearance. Seven patients with IgM anti-HBc negative. One was a chronic HBsAg carrier with HDV superinfection. One had subclinical acute HBV infection and became a chronic HBsAg carrier. In a further two patients reactivation of replication in a chronic HBV infection could not be disregarded. Three patients could not be classified; all had acute recent onset of symptoms, cleared HBsAg within 6 months, but lacked IgM anti-HBc. It is concluded that HCV and HDV superinfections in HBV carriers mimicking acute HBV infection with chronic evolution are rarely encountered in the present population in spite of high frequency of both HCV and HDV markers.
Adolescent↗
High incidence of hepatitis B infection and evolution of chronic hepatitis B infection in patients with advanced HIV infection.
Two hundred eleven HIV-seropositive patients with AIDS, AIDS-related complex, or a CD4+ cell count less than 200 x 10(6) were examined for the presence of hepatitis B virus markers during the course of their HIV infection (median follow-up of 18 months; range of 1 to 107 months). Anti-HBs was detected initially in 138 patients (65%). Sixteen patients (8%) were HBsAg positive at entry. Fourteen had chronic HBV infection of whom 12 initially were positive for HBeAg and HBV DNA; 11 remained positive during follow-up, whereas one seroconverted to anti-HBe and lost HBV DNA. Two patients with chronic HBV infection were initially negative for HBeAg and HBV DNA: one later had reactivated HBV replication and one cleared HBeAg following onset of hepatitis D infection. The last two HBsAg-positive patients had resolving acute HBV infection. Six of the 57 patients who initially were negative for HBV markers acquired HBV infection during follow-up. Four of these six patients developed chronic infection whereas two patients had acute subclinical resolving hepatitis. In addition, four patients became HBsAg positive with their last serum samples, possibly indicating reactivation of HBV infection following progressive immunological and clinical deterioration. None of the patients developed clinical symptoms that could be ascribed to HBV infection, and transaminase elevations were only sporadically recorded. It is concluded that acquisition of HBV infections is not infrequent in HIV-seropositive patients with immune deficiency. Furthermore, the course of both previously established chronic HBV infection and newly acquired HBV infection is modified in such patients, whereas reactivation of past HBV infection seems to be a rare event.
Adult↗
[Hepatitis C virus].
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Hepatitis Antibodies↗
[Screening of Danish blood donors for hepatitis C virus antibodies].
In Denmark only 1-3 cases of transfusion-associated hepatitis NANB (TAH-NANB) are registered annually or about 1 case per 100,000 units transfused. Thus, the prevalence of blood donors with hepatitis NANB infection is estimated to be very low and measures to prevent TAH-NANB such as surrogate testing have not been considered to be worth while. The incidence of TAH-NANB, however, may be underestimated if cases are overlooked or not identified as transfusion-associated or if registration fails. The appearance of the anti-HCV test (Ortho) has clearly provided a more sensitive and specific tool for identifying blood donors, who may transmit hepatitis NANB. In the present study, we have determined the prevalence of anti-HCV in random Danish blood donors from 1989 (fresh serum samples) and 1982 (frozen serum samples). All donors were tested for ALT and anti-HBc. A prevalence of 0.3% anti-HCV positive blood donors was found in 1989 (2/600) as well as in 1982 (2/595). Thus, no change in the prevalence of HCV infected donors seems to have occurred in Denmark during these years. The anti-HCV prevalence of 0.3% in random blood donors is low but not negligible, and if the majority of the reactive donors identified are true positives, the epidemiologic pressure as to HCV infection probably equalizes the pressure as to HBV infection (0.1-0.2%) in people attending our blood banks to become donors. In a group of donors positive for surrogate markers (ALT greater than 40 U/l and/or anti-HBc) we found only 0.9% (2/225) anti-HCV positives.(ABSTRACT TRUNCATED AT 250 WORDS)
Blood Donors↗