Effect of combined interferon-alpha induction therapy and ribavirin on chronic hepatitis C virus infection: a randomized multicentre study.

BACKGROUND: The efficacy of interferon-alpha (IFN) induction in combination with ribavirin for chronic hepatitis C virus (HCV) infection is not known. METHODS: A total of 256 treatment-naive HCV RNA-positive patients with biopsy-confirmed chronic hepatitis were enrolled in a randomized multicentre study. The patients received either standard combination therapy with 3 MIU interferon-alpha2b thrice weekly for 26 weeks or 6 MIU interferon-alpha2b daily for 4 weeks and 3 MIU 3/7 days for 22 weeks. All patients received ribavirin 1000 mg or 1200 mg (weight dependent) daily during the 26-week treatment period. Patients were monitored for HCV RNA during and following treatment. RESULTS: The sustained virological response rates (26 weeks after end of treatment) were 54% and 47% for patients receiving IFN induction/ribavirin and standard IFN/ribavirin, respectively (P = 0.35). Among patients infected with genotype 1a/1b, the sustained response rates were 32% and 35%. In patients infected with genotype 2b/3a IFN induction/ribavirin led to a sustained response rate of 80% as compared to 65% in the standard combination therapy group (P = 0.073). Steatosis was more frequently seen in liver biopsies from patients infected with genotype 3a as compared to genotypes la/lb. Among genotype 1a/1b infected patients. steatosis was a highly significant predictor of failure to achieve sustained virological response. Logistic regression analysis (multivariate analysis) showed that independent predictors of sustained virological response were low age, female gender, genotype 2b/3a and HCV RNA negativity at 2 weeks. CONCLUSIONS: IFN induction in combination with ribavirin does not increase the sustained virological response rate among patients infected with HCV. Absence of steatosis is an independent predictor of sustained virological response in patients infected with genotypes 1a/1b.

[Tuberculosis among HIV-infected persons in Norway]. / Tuberkulose hos HIV-smittede i Norge.

BACKGROUND: HIV-infected persons have a considerably higher risk of developing active tuberculosis than immunocompetent individuals. Tuberculosis is the only opportunistic infection among HIV-infected persons that presents a potential health risk to the general population. MATERIAL AND METHODS: We present a review on this topic based on relevant literature and clinical experience. RESULTS: Treatment options are limited because of interactions between rifamycins and protease inhibitors and non-nucleoside analogues. When concomitant therapy against HIV infection and tuberculosis is indicated, we suggest a first-line regimen of rifabutin combined with either indinavir or nelfinavir. For patients without severe immunodeficiency, anti-retroviral therapy can be postponed until the end of the initial phase of the anti-tuberculosis treatment. INTERPRETATION: Treatment of concurrent HIV infection and tuberculosis is complex and may involve multiple drug regimens. Treating the latent infection could in many cases prevent active tuberculosis. All HIV-infected persons should be evaluated with respect to active tuberculosis and latent infection.

Treatment with interferon-alpha2a alone or interferon-alpha2a plus ribavirin in patients with chronic hepatitis C previously treated with interferon-alpha2a. CONSTRUCT Group.

BACKGROUND: Preliminary results from combination therapy with interferon-alpha and ribavirin (IFN/Rib) in patients with chronic hepatitis C have been promising, with up to 50% sustained hepatitis C virus (HCV) RNA response. The aim of this study was to investigate whether a sustained HCV RNA response could be obtained with combination therapy in patients who were non-responders or relapsers after IFN treatment. METHODS: In a multicenter study we randomized 53 HCV RNA-positive patients into 2 treatment groups. They all had biopsy-confirmed chronic hepatitis C, and all were recruited from a previous IFN study: 26 were previous non-responders and 27 responders with relapse. Group A received interferon-alpha2a, 4.5 MIU thrice weekly for 6 months, and group B received ribavirin, 1000-1200 mg/day, in combination with the same dose of interferon-alpha2a for 6 months. Median Knodell index was 5.0 in both groups. Genotype 1 was found in 24 (45%), type 2 in 3 (6%), and type 3 in 26 (49%). RESULTS: Sustained clearance of HCV viremia 6 months after interferon-alpha2a treatment stop was obtained in 12 of 53 patients (23%): 6 of 27 in the IFN group (22%) and 6 of 26 (23%) in the IFN/Rib group (NS). Nine of 27 (33%) former responders with relapse, compared with 3 of 26 (12%) non-responders, obtained a sustained HCV RNA response (P = 0.054). In previous relapse patients sustained loss of viremia was more frequent in genotype 3 (50%) than in genotype 1 (11%) patients (P = 0.022). CONCLUSIONS: In a group of previous IFN-alpha2a-treated chronic HCV patients we obtained a similar sustained clearance of viremia when retreated either with IFN-alpha2a alone or with a combination of IFN-alpha2a and ribavirin for 6 months. Previous relapse patients with HCV genotype 3 obtained sustained loss of viremia significantly more often (50%) than type-patients (11%). Previous IFN responders with relapse responded better than previous non-responders.

[Tularemia after tick bite in Vestfold]. / Tularemi etter flåttbitt i Vestfold.

Direct contact with rodents or their faeces is a well-known risk factor for contracting tularaemia in Norway. Both insects and ticks can act as vectors of tularaemia, but transmission by this route has not previously been described in this country. We report three cases of serologically confirmed ulceroglandular tularaemia on a small island in Southern Norway, an area in which tularaemia has not previously been known to occur. Tick bites preceded infection in two of the patients. The third patient may also have become infected through a tick or insect bite. Diagnosis was made late in all cases, causing a delay in appropriate treatment. Two of the patients were successfully treated with ciprofloxacin. Our experience and previous reports suggest that quinolones should be considered as the first choice of drugs in the treatment of tularaemia in Norway.

The effect of treatment with alpha-interferon on hepatitis G/GBV-C viraemia. The CONSTRUCT Group.

BACKGROUND: Hepatitis G virus (HGV) or GBV-C is frequently detected in patients co-infected with hepatitis C virus (HCV). This study investigated host and virologic factors influencing the response to HGV/GBV-C to alpha-interferon treatment. METHODS: HGV/GBV-C was detected and quantified by nested polymerase chain reaction. The influence of variables such as liver biopsy appearance, liver function abnormalities, and response of HCV to interferon treatment was monitored. RESULTS: Fourteen of the 25 HGV/GBV-C-infected patients treated with interferon (3-6 MIU three times a week for 6 months) became non-viraemic during treatment, although all relapsed after treatment withdrawal at 6 months, with no net change in virus load between 0 and 12 months. CONCLUSIONS: Predictive factors for clearance of HGV/GBV-C viraemia by interferon were pre-treatment severity of liver disease (median Knodell score of 4, compared with 7 for non-responders; P = 0.030) and alanine aminotransferase levels (median, 114, 182 for non-responders; P = 0.039). Clearance was associated with the treatment response of HCV. Nine of 13 who cleared HGV/GBV-C also cleared HCV, compared with 3 of 11 HGV/GBV-C non-responders; P = 0.05). The shared susceptibility of HGV/GBV-C and HCV to interferon treatment suggests a link between the mechanism of clearance of the two viruses.

[Endemic typhus imported to Norway]. / Endemisk flekktyfus importert til Norge.

Murine typhus, caused by Rickettsia typhi, is an important zoonosis in all parts of the world. The disease is transmitted from rodents to humans by fleas. In this article we describe the first three cases of serologically proven murine typhus imported into Norway during the 1990s. The patients were Norwegian tourists who had visited respectively Guinea-Bissau, Crete and Thailand. They all became acutely ill with fever, chills and severe headache 1-10 days after return to Norway. None of them had a rash. Two patients were admitted to hospital, and one was treated with ciprofloxacin for suspected typhoid fever. All the patients recovered without sequelae. The diagnosis of murine typhus was based on detection of IgM-anti-bodies against R typhi in serum samples during reconvalescence.

Genotype, viral load and age as independent predictors of treatment outcome of interferon-alpha 2a treatment in patients with chronic hepatitis C. Construct group.

Patients with chronic hepatitis C respond differently when treated with interferon. We randomized 116 patients with chronic hepatitis C in order to compare two dosage regimens of recombinant interferon alpha 2a:3 MIU x 3 per week for 6 months (arm A) or 6 MIU x 3 per week for 3 months and then 3 MIU x 3 per week for 3 months (arm B). There were no significant differences concerning outcome between the two dose regimens: sustained clearance of HCV viremia 6 months after the end of treatment was obtained in 12/59 (20%) in group A compared with 18/57 (32%) in group B (p = 0.24). In patients with genotype 1a, 4/31 (13%), in genotype 1b, none of 9 (0%), 9/15 (60%) in genotype 2, and 17/58 (29%) in genotype 3, showed sustained clearance of HCV viremia 6 months after the end of treatment (p = 0.002). In a stepwise logistic regression analysis, only pretreatment viral load (p = 0.0001), genotype (p = 0.001) and age (p = 0.04) were identified as independent predictors of sustained clearance of HCV viremia. Liver histology as assessed by Knodell index was significantly improved in patients with sustained HCV RNA response 6 months after the end of treatment (5.2 +/- 2.2 vs 2.6 +/- 2.2, p < 0.001), but not in responders with relapse or in non-responders. In conclusion, stepwise logistic regression analysis showed that viral load, HCV genotype and age were the only independent predictors for sustained HCV RNA response.

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.

[Q-fever imported into Norway]. / Q-feber importert til Norge.

Q fever is an important zoonosis that occurs throughout the world. In contrast to most other European countries, there has been no evidence of endemic Q fever in Norway up to now. The disease is caused by Coxiella burnetii, a rickettsia-like bacterium. Humans are infected mainly by inhalation of contaminated aerosols from cattle, sheep and goats. Clinical manifestations are protean, ranging from asymptomatic infection to life-threatening endocarditis. In this article we present the first four cases of serological proven acute Q fever imported into Norway. The patients were Norwegian tourists who had visited Bhutan, the Canary Islands, and Morocco. Two patients had fever with maculopapular exanthema, one had pneumonia, and one had biopsy-proven granulomatous hepatitis. Three were treated with tetracyclines. All four patients recovered well.

[Treatment of hepatitis C]. / Behandling av hepatitt C.

Hepatitis C virus (HCV) has been a major cause of post transfusion hepatitis, and is still an important cause of chronic liver disease throughout the world. How to treat patients with chronic HCV infection has been brought into focus in recent years, and a substantial amount of data has been obtained about the development of hepatitis C with and without treatment. This survey considers the diagnosis of hepatitis C, and present treatment modalities and their potential. The patients most likely to respond to treatment are described, and the authors finally discuss why treatment of hepatitis C still should take place in controlled studies.

Prevalence of hepatitis C genotypes among patients with chronic hepatitis C in Norway. Construct Group.

Among 116 patients with biopsy-confirmed chronic hepatitis C (Riba 2 or Riba 3 positive) in a multicenter study in southern Norway on interferon, we determined hepatitis C virus genotype by restriction fragment length polymorphism (RFLP) of the 5' NCR. The RFLP method was supplemented by and compared with a serological typing method based on the detection of type-specific antibody to peptide from the NS-4 region. A total of 102/106 (96%) patient sera showed detectable type-specific antibody to NS-4 peptides and corresponded in all cases, except two, to the genotype detected by polymerase chain reaction. Combining the results from RFLP genotyping and serotyping, genotype 1 was found in 40 (35%) (27 with 1a and 10 with 1b, 3 subtypes not determined), genotype 2 in 15 (13%) (subtype 2b in 14 and 1 subtype not determined), and genotype 3 in 58 (50%) of patients. The low mean age of the patients (34 years), the low prevalence of cirrhosis (3.5%), the short duration of the disease, and a high prevalence of intravenous-drug abusers may account for the low prevalence of infection with genotype 1b (9%). The epidemiological features of hepatitis C patients are markedly different from patient groups described in southern Europe in terms of risk factors, age, and genotype distribution.

Two dose regimens of recombinant interferon-alpha-2b in chronic hepatitis C virus infection. Biochemistry, hepatitis C virus RNA, and liver histology as response indices.

BACKGROUND: Recombinant interferon remains the cornerstone of treatment of chronic hepatitis C virus (HCV) infection. Still, evaluation of treatment on the basis of response indicators and long-term effect of the treatment raises several questions. METHODS: Seventy-four patients with chronic HCV infection were randomized to a high (3 MIU, 3/7 days) or low (1 MIU, 3/7 days) dose of recombinant interferon-alpha-2b for 48 weeks after a 4-week course of 3 MIU, 3/7 days. Response to treatment was assessed by means of liver enzymes (transaminases), HCV RNA, and liver histology. RESULTS: The higher maintenance dose was associated with a significantly higher rate of sustained alanine aminotransferase (ALAT) response (45% versus 19%) and with a significantly better chance of becoming HCV RNA-negative during therapy (47% versus 23%). In the high maintenance dose group 14 of the 29 (48%) patients with available HCV RNA data were negative at the 3-month follow-up, compared with 4 of 27 (15%) in the low maintenance dose group. Significantly more patients had improved liver biopsy findings after interferon in the high maintenance dose group (79%) than in the low maintenance dose group (36%). There was a close correlation between ALAT response and HCV RNA response. Of 17 patients who were HCV RNA-negative 3 months after the end of treatment, 10 remained HCV RNA-negative 2-4 years later. CONCLUSION: The study demonstrates a higher response rate as assessed by biochemistry, HCV RNA, and liver histology in the higher dose group.

Susceptibilities of Norwegian Candida albicans strains to fluconazole: emergence of resistance. The Norwegian Yeast Study Group.

All Candida albicans isolates in Norwegian microbiological laboratories in 1991 judged clinically important (except vaginal isolates) were collected. The isolates were tested for susceptibility to fluconazole with an agar dilution test and a commercially available agar diffusion test. A total of 212 strains (95%) were susceptible to fluconazole, and MICs for most of the strains (92%) were < or = 1.56 micrograms/ml. The agar diffusion test using a 15-micrograms tablet and a 48-h incubation period separated resistant from susceptible strains with a wide margin. The only exception was a strain for which the MIC was 6.25 micrograms/ml. The difference in zone size between the resistant and the susceptible populations of strains was 11 mm. Accordingly, it appears that the agar diffusion test is an appropriate method for detecting fluconazole resistance. The 12 fluconazole-resistant isolates originated from eight AIDS patients with oral or esophageal Candida infections. Seven of the patients had been given fluconazole for 1 month or more, often as self medication. Four had infections that were clinically resistant to fluconazole; one additional patient responded only when the dose was increased. All isolates recovered from these patients were analyzed by multilocus enzyme electrophoresis. The 12 C. albicans isolates belonged to five electrophoretic types, but three of four patients attending one hospital had isolates belonging to one electrophoretic type. One possible explanation for this finding could be that a nosocomial spread of resistant strains has occurred.

Handwriting and perceptual-motor skills in clumsy, dysgraphic, and 'normal' children.

Among various perceptual-motor tests, only visuomotor integration was significant in predicting accuracy of handwriting performance for the total sample of 59 children consisting of 19 clumsy children, 22 nonclumsy dysgraphic children, and 18 'normal' children. They were selected from a sample of 360 fourth-graders (10-yr.-olds). For groups of clumsy and 'normal' children, the prediction of handwriting performance is difficult. However, correlations among scores on 6 measures showed that handwriting was significantly related to visuomotor integration, visual form perception, and tracing in the total group and to visuomotor integration and visual form perception in the clumsy group. The weakest correlations occurred between tests measuring simple psychomotor functions and handwriting. Moreover, clumsy children were expected to do poorly on tests measuring aiming, tracing, and visuomotor integration, but not on tests measuring visual form perception and finger tapping. Dysgraphic children were expected to do poorly on visuomotor integration only.

Second-generation anti-HCV tests predict infectivity.

Twenty-four blood donors found positive for the first-generation hepatitis C antibody (anti-HCV) test (Ortho EIA-I) and 88 of their recipients over the period from 1972 to 1990 were retrospectively investigated with different first- and second-generation anti-HCV tests. The aim of the study was to identify the infective donors and to evaluate the tests. Seven donors, who probably were infective carriers of HCV, were also second-generation test (EIA-II) positive, compared to only 3 out of 17 noninfective donors. Among the infected recipients, 14 out of 29 (48%) were positive for the second-generation test only. The second-generation test identified the infective donors in our study and was more sensitive than the first-generation test. We therefore recommend that blood donors are screened with EIA-II. Positive test results should be confirmed by the recombinant immunoblot assay (RIBA-II), and persons with positive or not conclusive RIBA-II should not be accepted as blood donors.

[Cutaneous leishmaniasis]. / Kutan leishmaniasis.

Cutaneous leishmaniasis is endemic in certain tropical and sub-tropical regions, and is sometimes encountered as an imported disease in Norway. The disease is characterized by chronic and painless, but often disfiguring, ulcers that regress after some months to years, leaving atrophic scars. Diagnosis is established by demonstrating amastigote Leishmania bodies by microscopy of Giemsa-stained smears from the periphery of the lesions. This report presents six cases seen in our department in the course of the last 14 years.

[Viral hepatitis and blood transfusion]. / Virushepatitt og blodtransfusjon.

Our findings show that hepatitis B-virus was transmitted by blood from two hepatitis B-surface-antigen (HBsAg)-negative but hepatitis B-coreantibody (anti-HBc)-positive donors. Blood donors and recipients were also tested for antibodies against the recently identified hepatitis C-virus (HCV). We found that two anti-HCV-positive donors with no known history of clinical hepatitis were chronic, infective carriers of HCV. The prevalence of anti-HCV in our blood donor population was 0.47% and ALT and anti-HBc testing was of no help for tracing the anti-HCV positives. We recommend that, in addition to HBsAg screening at each donation, donors are tested for anti-HBc and anti-HCV once. Individuals with a history of parenteral virus hepatitis should not be accepted as blood donors.

Infective, chronic carriers of hepatitis C virus among blood donors with no history of clinical hepatitis.

We investigated the infectivity of three hepatitis C virus antibody (anti-HCV) positive blood donors with either hepatitis B core antibodies (anti-HBc) (Nos 1 and 2) or raised alanine aminotransferase (ALT) (No. 3). The 57 recipients of blood products from these donors during the period 1971-1990 were identified and the living 23 were tested for anti-HCV. Among these, 11 out of 14 (78%) recipients from Nos 1 and 2, and 1 out of 9 (11%) recipients from No. 3 were anti-HCV positive. The former donors had high titres of anti-C100-3 and high rating scores in the HCV recombinant immunoblot assay (RIBA). They were evidently infective, chronic carriers of HCV but had no clinical signs or medical history of hepatitis. The latter donor had low titres of anti-C100-3 and a low RIBA rating score. She had clinical signs of chronic hepatitis and persistently elevated ALT, but only one of her recipients was anti-HCV positive.