How the concept of biochemical response influenced the management of primary biliary cholangitis over time.

BACKGROUND: Criteria assessing biochemical response to ursodeoxycholic acid (UDCA) are established risk stratification tools in primary biliary cholangitis (PBC). We aimed to evaluate to what extent liver tests influenced patient management during a three decade period, and whether this changed over time. METHODS: 851 Dutch PBC patients diagnosed between 1988 and 2012 were reviewed to assess patient management in relation to liver test results during UDCA treatment. To do so, biochemical response at one year was analysed retrospectively according to Paris-1 criteria. RESULTS: Response was assessable for 687/851 (81%) patients; 157/687 non-responders. During a follow-up of 8.8 years (IQR 4.8-13.9), 141 died and 30 underwent liver transplantation. Transplant-free survival of non-responders (60%) was significantly worse compared with responders (87%) (p < 0.0001). Management was modified in 46/157 (29%) non-responders. The most frequent change observed, noted in 26/46 patients, was an increase in UDCA dosage. Subsequently, 9/26 (35%) non-responders became responders within the next two years. Steroid treatment was started in one patient; 19 patients were referred to a tertiary centre. No trend towards more frequent changes in management over time was observed (p = 0.10). CONCLUSION: Changes in medical management occurred in a minority of non-responders. This can largely be explained by the lack of accepted response criteria and of established second-line treatments for PBC. Nevertheless, the observation that response-guided management did not increase over time suggests that awareness of the concept of biochemical response requires further attention,particularly since new treatment options for PBC will soon become available.

HLA-DRB1*03:01 and HLA-DRB1*04:01 modify the presentation and outcome in autoimmune hepatitis type-1.

The classical human leukocyte antigen (HLA)-DRB1*03:01 and HLA-DRB1*04:01 alleles are established autoimmune hepatitis (AIH) risk alleles. To study the immune-modifying effect of these alleles, we imputed the genotypes from genome-wide association data in 649 Dutch AIH type-1 patients. We therefore compared the international AIH group (IAIHG) diagnostic scores as well as the underlying clinical characteristics between patients positive and negative for these HLA alleles. Seventy-five percent of the AIH patients were HLA-DRB1*03:01/HLA-DRB1*04:01 positive. HLA-DRB1*03:01/HLA-DRB1*04:01-positive patients had a higher median IAIHG score than HLA-DRB1*03:01/HLA-DRB1*04:01-negative patients (P<0.001). We did not observe associations between HLA alleles and alanine transaminase levels (HLA-DRB1*03:01: P=0.2; HLA-DRB1*04:01; P=0.5); however, HLA-DRB1*03:01 was independently associated with higher immunoglobulin G levels (P=0.04). The HLA-DRB1*04:01 allele was independently associated with presentation at older age (P=0.03) and a female predominance (P=0.04). HLA-DRB1*03:01-positive patients received immunosuppressive medication and liver transplantation. In conclusion, the HLA-DRB1*03:01 and HLA-DRB1*04:01 alleles are both independently associated with the aggregate diagnostic IAIHG score in type-1 AIH patients, but are not essential for AIH development. HLA-DRB1*03:01 is the strongest genetic modifier of disease severity in AIH.

Dutch guidance for the treatment of chronic hepatitis C virus infection in a new therapeutic era.

BACKGROUND: A new era for the treatment of chronic hepatitis C is about to transpire. With the introduction of the first-generation protease inhibitors the efficacy of hepatitis C treatment improved significantly. Since then, the therapeutic agenda has moved further forward with the recent approval of sofosbuvir and the expected approval of agents such as simeprevir and daclatasvir. This paper, developed parallel to the approval of sofosbuvir, is to serve as a guidance for the therapeutic management of chronic hepatitis C. METHODS: We performed a formal search through PubMed, Web of Science and ClinicalTrials.gov to identify all clinical trials that have been conducted with EMA-approved new agents in hepatitis C; for this version (April 2014) we focused on sofosbuvir. For each disease category, the evidence was reviewed and recommendations are based on GRADE. RESULTS: We identified 11 clinical trials with sofosbuvir and for each disease category recommendations for treatment are made. Not all disease categories were studied extensively and therefore in some cases we were unable to provide recommendations. CONCLUSION: The recent approval of sofosbuvir will most likely change the therapeutic landscape of chronic hepatitis C. The use of sofosbuvir-containing regimens can shorten the duration of therapy, increase efficacy and result in less side effects, compared with standard of care. The efficacy relative to standard of care needs to be weighed against the increased costs of sofosbuvir. With future approval of the other direct-acting antivirals, the outcome of hepatitis C treatment will likely improve further and this guidance will be updated.

Treatment of hepatitis C monoinfection in adults--Dutch national guidelines.

In this new Dutch guideline for hepatitis C virus infection we provide recommendations for the management of hepatitis C infection. Until 2012 the standard for treatment consisted of pegylated interferon alpha (peg-IFNa) and ribavirin. The advent of first-generation direct antiviral agents such as boceprevir and telaprevir has changed the concept of treatment of adult chronic hepatitis C genotype 1 infected patients. There are three benefits of boceprevir and telaprevir. They increase the likelihood of cure in 1) naive genotype 1 patients and 2) in patients who did not respond to earlier treatment with peg-IFNa and ribavirin, while 3) allowing shortening of treatment duration from 48 weeks to 24 or 28 weeks, which is possible in 40-60% of non-cirrhotic naive (boceprevir and telaprevir) and relapsing patients (telaprevir). The use of boceprevir and telaprevir is associated with multiple side effects and awareness of these side effects is needed to guide the patient through the treatment process. This guideline, formulated on behalf of The Netherlands Association of Hepato-gastroenterologists, The Netherlands Association of Internal Medicine, and The Dutch Association for the Study of Liver Disease, serves as a manual for physicians for the management and treatment of acute and chronic hepatitis C virus monoinfection in adults.

The 2012 revised Dutch national guidelines for the treatment of chronic hepatitis B virus infection.

In 2008, the Netherlands Association of Gastroenterologists and Hepatologists (Nederlands Vereniging van Maag-Darm-Leverartsen) published the Dutch national guidelines for the treatment of chronic hepatitis B virus infection. New insights into the treatment of chronic hepatitis B with relevance for clinical practice have been adopted in these concise, revised guidelines. The most important changes include the choice of initial antiviral therapy, licensing of tenofovir for the treatment of chronic hepatitis B and the management of antiviral resistance.

Benchmarking patient experiences in colonoscopy using the Global Rating Scale.

INTRODUCTION: The Global Rating Scale (GRS) is a quality assurance program that was developed in England to assess patient-centered care in endoscopy. The aim of the current study was to evaluate patient experiences of colonoscopy using the GRS in order to compare different departments and to provide benchmarks. The study also evaluated factors associated with patient satisfaction. METHODS: A GRS questionnaire was used both before and after the procedure in outpatients undergoing colonoscopy. The questionnaire assessed the processes associated with the colonoscopy, from making the appointment up until discharge. Mean values and ranges of 12 endoscopy departments were calculated together with P values in order to assess heterogeneity. RESULTS: In total, 1904 pre-procedure and 1532 (80 %) post-procedure questionnaires were returned from 12 endoscopy departments. The mean time patients had to wait for their procedure was 4.3 weeks (range 3.1 - 5.8 weeks), and 54 % (range 35 - 64 %; P < 0.001) reported being given a choice of appointment dates/times. Discomfort during colonoscopy was reported by 20 % (range 8 - 40 %; P < 0.001). Recovery room privacy was satisfactory for 76 % of patients (range 66 - 90 %; P < 0.05). The majority of patients reported being sufficiently informed about what to do in case of problems after discharge (79 %, range 43 - 98 %; P < 0.001), and 85 % of individuals stated that they would be willing to repeat the colonoscopy procedure (range 72 - 92 %; P < 0.001). Factors associated with a decreased willingness to return were the burdensome bowel preparation (odds ratio [OR] = 0.25; P < 0.001), "rushing staff" attitude (OR = 0.57; P < 0.05), low acceptance of the procedure (OR = 0.42; P < 0.01), and more discomfort than expected (OR = 0.54; P < 0.05). CONCLUSION: Overall patient experiences with colonoscopy were satisfactory, but they also showed considerable variation. This study shows that use of a GRS patient questionnaire is feasible in the Dutch endoscopy setting for the assessment of patient experience. The significant variability between endoscopy units can be used to benchmark services and enable shortcomings to be identified.

The role of mycophenolate mofetil in the management of autoimmune hepatitis and overlap syndromes.

BACKGROUND: Treatment failure occurs in 20% of autoimmune hepatitis patients on prednisolone and azathioprine (AZA). There is no established second line treatment. AIM: To assess the efficacy of mycophenolate mofetil as second line treatment after AZA-intolerance or AZA-nonresponse in autoimmune hepatitis and overlap syndromes. METHODS: Consecutive patients from the Dutch Autoimmune Hepatitis Group cohort, consisting of 661 patients, with autoimmune hepatitis or overlap syndromes, AZA-intolerance or AZA-nonresponse and past or present use of mycophenolate mofetil were included. Primary endpoint of mycophenolate mofetil treatment was biochemical remission. Secondary endpoints were biochemical response (without remission), treatment failure and prevention of disease progression. RESULTS: Forty-five patients treated with mycophenolate mofetil were included. In autoimmune hepatitis remission or response was achieved in 13% and 27% in the AZA-nonresponse group compared to 67% and 0% in the AZA-intolerance group (P = 0.008). In overlap-syndromes remission or response was reached in 57% and 14% in the AZA-nonresponse group and 63% and 25% of the AZA-intolerance group (N.S.); 33% had side effects and 13% discontinued mycophenolate mofetil. Overall 38% had treatment failure; this was 60% in the autoimmune hepatitis AZA-nonresponse group. Decompensated liver cirrhosis, liver transplantations and death were only seen in the autoimmune hepatitis AZA-nonresponse group (P < 0.001). CONCLUSIONS: Mycophenolate mofetil induced response or remission in a majority of patients with autoimmune hepatitis and azathioprine-intolerance and with overlap syndromes, irrespective of intolerance or nonresponse for azathioprine. In autoimmune hepatitis with azathioprine nonresponse mycophenolate mofetil is less often effective.

Treatment of chronic hepatitis B virus infection - Dutch national guidelines.

The development of this guideline was initiated and coordinated by the Netherlands Association of Gastroenterologists and Hepatologists (Nederlandse Vereniging van Maag-Darm-Leverartsen). The aim is the establishment of national standards in the evaluation and antiviral treatment of patients with chronic hepatitis B virus (HBV) infection. This includes recommendations on the initial evaluation of patients, choice and duration of antiviral therapy, follow-up after antiviral therapy and monitoring of patients not currently requiring antiviral therapy. The initial evaluation of chronic HBV-infected patients should include testing of liver biochemistry, virus serology and abdominal imaging. In patients without cirrhosis, antiviral treatment is recommended for those with a serum HBV DNA of at least 1.0 x 105 c/ml (>or=2.0 x 10(4) IU/ml) in combination with: a) elevation of serum alanine aminotransferase (ALAT) level above twice the upper limit of normal during at least three months, and/or b) histological evidence of porto-portal septa or interface hepatitis on liver histology. In patients with cirrhosis, antiviral treatment is recommended if serum HBV DNA is 1.0 x 10(4)c/ml (>or=2.0 x 10(3) IU/ml) or higher, independent of ALAT levels or histological findings. If the patient has decompensated cirrhosis, antiviral treatment is recommended if serum HBV DNA is 1000 c/ml (>or=200 IU/ml) or higher. Patients who do not have an indication for antiviral treatment should be monitored because there is a risk of (re)activation of disease activity. Monitoring every three to six months is recommended for HBeAg-positive and HBeAg-negative patients with high viraemia (HBV DNA >or=1.0 x 10(5) c/ml or >or=2.0 x 10(4) IU/ml) and normal ALAT levels. For patients with serum HBV DNA below 1.0 x 10(5) c/ml (<2.0 x 10(4) IU/ml) the recommended frequency of monitoring is every three to six months for HBeAg-positive patients and every six to 12 months for HBeAg-negative patients. Peginterferon (PEG-IF N) therapy should be considered as initial therapy in both HBeAg-positive and HBeAg-negative patients without contraindications for treatment with this drug because of the higher chance of achieving sustained response compared with nucleos(t)ide analogue therapy. In patients starting nucleos(t)ide analogue therapy, the use of lamivudine is not preferred if long-term antiviral treatment is expected due to the high risk of antiviral resistance against this drug. Of the currently licensed nucleos(t)ide analogues, entecavir has the lowest risk of antiviral resistance (compared with lamivudine, adefovir and telbivudine), while suppression of viral replication seems most profound with either entecavir or telbivudine. The recommended duration of treatment with PEG-IF N is one year for both HBeAg-positive and HBeAg-negative patients. In HBeAg-positive patents, nucleos(t)ide analogue therapy should at least be continued until HBeAg seroconversion and a decline in HBV DNA to below 400 c/ml (80 IU/ml) has been achieved and maintained for six months during therapy. Whether nucleos(t)ide analogue therapy can be safely discontinued in HBeAg-negative patients is unknown; usually prolonged or indefinite antiviral treatment is necessary. Patients receiving PEG-IF N should be monitored once a month, while three monthly monitoring suffices for those receiving nucleos(t)ide analogues. Genotypic analysis of the HBV polymerase is indicated if an increase in serum HBV DNA of at least 1 log(10) c/ml (IU/ml) compared with the nadir value is observed during nucleos(t)ide analogue therapy. Antiviral therapy should be changed as soon as possible in case of confirmed genotypic resistance. Adding a second antiviral agent seems beneficial over switching to another agent. With the availability of multiple new antiviral drugs for the treatment of chronic hepatitis B, effective treatment is now possible for more patients and for longer periods. However, the complexity of HBV therapy has also increased. Nowadays, virtually all chronic HBV-infected patients can be effectively managed, either by inducing sustained off-treatment response or by maintaining an on-treatment response.

Treatment of chronic hepatitis C virus infection - Dutch national guidelines.

The development of this guideline was initiated and coordinated by the Netherlands Association of Gastroenterologists and Hepatologists (Nederlandse Vereniging van Maag-Darm-Leverartsen). The aim is the establishment of practical guidelines in the evaluation and antiviral treatment of patients with chronic hepatitis C virus (HCV) infection. This includes recommendations for the initial evaluation of patients, the choice and duration of antiviral therapy and the follow-up after antiviral therapy. Hepatitis C is a slowly progressive disease. The initial evaluation of chronically HCV-infected patients should include liver biochemistry testing, virological testing and abdominal ultrasound imaging. Liver biopsy is no longer a routine procedure. Antiviral treatment should be considered for all HCV-infected patients. Current antiviral treatment is a long-term process and is associated with substantial side effects. When deciding whether to start treatment or not, the chance of successful treatment (80% with hepatitis C genotype 2 and 3 and 50% with hepatitis C genotype 1 and 4), the fibrosis stage, the expected side effects and the compliance of the patient should be taken into consideration. In the absence of significant fibrosis and necroinflammation in liver biopsy, postponing treatment is an option. Current antiviral treatment is contraindicated in patients with Child-Pugh-class B or C cirrhosis. The possibility of a liver transplantation should be investigated in these patients. Significant comorbidity with a limited life expectancy is an absolute contraindication for antiviral treatment Treatment of chronic hepatitis C consists of administration of peginterferon and ribavirin for 24 or 48 weeks. Patients with hepatitis C genotype 1 or 4 are treated for 48 weeks. Patients with hepatitis C genotype 2 or 3 are treated for 24 weeks. In patients with undetectable HCV RNA after four weeks (28 days) of treatment, a shorter treatment is equally effective (12 to 16 weeks for hepatitis C genotype 2 or 3; 24 weeks for hepatitis C genotype 1 or 4). Outpatient clinic visits are recommended at the start and after 2, 4, 8, and 12 weeks of treatment, and thereafter every four to six weeks until the end of treatment. It is recommended to stop treatment if the HCV RNA level has not decreased by at least 2 log10 IU/ml (c/ml) after 12 weeks of treatment or when HCV RNA is still detectable after 24 weeks of treatment. The recommended frequency of outpatient clinic visits for patients who are not being treated is once every six months in patients with cirrhosis, otherwise every 12 months. It is expected that new anti-HCV-medication (STAT-C, specifically targeted antiviral therapy for HCV) will become available in the near future. Therefore treatment of chronic HCV infection will probably be more effective in the future.

[A man who contracted hepatitis E in the Netherlands]. / Een man met in Nederland opgelopen hepatitis E.

A 55-year-old man was admitted to our hospital because of malaise, jaundice en cholestatic liver function impairment, 4 days after his return from vacation in Surinam. Serological tests were positive for IgG and IgM antibodies to hepatitis E virus (HEV) and serum PCR was positive, consistent with HEV infection. The infection was acquired in the Netherlands and not abroad, considering the incubation period. The patient recovered spontaneously. HEV infection is rare in the Netherlands and is associated with travel to tropical or subtropical areas. The virus is transmitted by the faecal-oral route through contaminated water or food. Since 2000 there have been cases reported in the Netherlands, without any association with travelling abroad and in which the infection might be related to zoonotic transmission. The diagnosis is primarily based upon serologic tests for the detection of IgM and IgG antibodies to HEV in serum confirmed by immunoblot. It is important that HEV infection is considered in patients with acute hepatitis in whom no other cause can be found for hepatitis, even without any travel history to endemic areas.

Monitoring intrahepatic CD8+ T cells by fine-needle aspiration cytology in chronic hepatitis C infection.

Infection of the liver with hepatitis C virus (HCV) causes compartmentalization of CD8+ cytotoxic T cells to the site of disease. These cells are thought to be involved in viral clearance during interferon therapy. The repetitive analysis of the intrahepatic immune response is hampered by the difficulty to obtain the intrahepatic T cells. The fine-needle aspiration biopsy (FNAB) technique was evaluated for its use to obtain liver-derived CD8+ T cells in a minimally invasive way. In 26 chronic HCV patients who were evaluated for Peg-interferon and ribavirin combination therapy, pre-treatment FNABs and peripheral blood specimens were obtained simultaneously with liver tissue biopsies, and CD3+ and CD8+ T cells were quantified by immunocytochemistry. The CD8+/CD3+ ratio was significantly higher in the FNABs than in peripheral blood (P < 0.01), and similar to those in portal areas in the tissue biopsies. A significant correlation was observed between numbers of CD3+CD8+ T lymphocytes in the FNABs and the numbers of CD8+ cells in the lobular fields or in the portal tracts of the liver tissue biopsies, but not with CD3+CD8+ T lymphocytes in peripheral blood. Finally, the ratio of CD8+/CD3+ T lymphocytes in FNABs was significantly higher in those patients who responded rapidly to therapy when compared with slow responders at 4 weeks of treatment (P = 0.02). These findings demonstrate that the intrahepatic T-cell composition is reflected in FNABs, and that the FNAB technique can be used for predicting early virological response to therapy of patients chronically infected with HCV.

Hyperpigmentation during interferon-alpha therapy for chronic hepatitis C virus infection.

Many types of skin disorders concomitantly occur with hepatitis C virus infection. These skin lesions may be induced or worsened during antiviral therapy with interferon-alpha (IFN). To our knowledge, hyperpigmentation of the skin--and especially of the tongue--has not been reported so far. We describe two dark-skinned patients who developed hyperpigmented skin and tongue lesions during combination therapy with IFN and ribavirin. Immunohistochemical analysis of tongue biopsies confirmed the suspicion of melanin deposits in these areas of hyperpigmentation. We hypothesize that during interferon therapy, melanocytes may produce more melanin pigment in the presence of alpha-melanocyte stimulating hormone and sufficient amounts of tyrosine, leading to melanin deposits and clinical hyperpigmentation.

High sustained virological response in chronic hepatitis C by combining induction and prolonged maintenance therapy.

Chronic hepatitis C patients with genotype 1 infection, liver cirrhosis, high viral load, or those who have not responded to anti-viral treatment in the past have limited chances of clearing the virus, even with pegylated interferon-ribavirin therapy. In this study we treated such patients with a treatment schedule that combines high dose induction Interferon (IFN), prolonged daily IFN and ribavirin treatment. Twenty-four consecutive patients were included in this study with either genotype 1 infection, cirrhosis, previous non-response to IFN or a combination of these poor-response characteristics. Patients were treated with 10 million units (MU) of IFN daily for 4 weeks followed by 5 MU/day until week 24, 3 MU/day until week 52 and 3 MU thrice weekly until week 76 in combination with 1-1.2 g ribavirin daily. HCV RNA levels were assessed weekly until week 4 and at least once every 3 months thereafter, by a validated assay with a detection limit below 500 copies/mL. Both intention to treat (ITT) and per protocol (PP) analysis showed a high sustained virological response (ITT 67%, PP 80%). A virological response occurred rapidly (before 8 weeks of treatment) in all patients with a sustained response. Relapse after stopping therapy was observed in only 5%. Side-effects were observed frequently, and six patients had to be hospitalized. With this new treatment regimen that combines induction- and prolonged daily interferon treatment with ribavirin it seems possible to eliminate hepatitis C virus in the majority of patients that have an a priori limited chance of sustained response. Further clinical evaluation of intensive interferon and ribavirin combination therapy (now also including PEG-interferon) is recommended in centres that can provide close patient monitoring and experienced hepatological support.

Prospective comparative study of spiral computer tomography and magnetic resonance imaging for detection of hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is often detected at a relatively late stage when tumour size prohibits curative surgery. Screening to detect HCC at an early stage is performed for patients at risk. AIM: The aim of this study was to compare prospectively the diagnostic accuracy and classification for management of the two state of the art secondline imaging techniques: triphasic spiral computer tomography (CT) and super paramagnetic iron oxide (SPIO) enhanced magnetic resonance imaging (MRI). PATIENTS: Sixty one patients were evaluated between January 1996 and January 1998. Patients underwent CT and MRI within a mean interval of 6.75 days. METHODS: CT and MRI were evaluated blindly for the presence and number of lesions, characterisation of these lesions, and classification for management. For comparison of the data on characterisation, the CT and MRI findings were compared with histopathological studies of the surgical specimens and/or follow up imaging. Data of patients not lost to follow up were available to January 2001. RESULTS: SPIO enhanced MRI detected more lesions and overall smaller lesions than triphasic spiral CT (number of lesions 189 v 124; median diameter 1.0 v 1.8 cm; Spearman rank's correlation coefficient 0.63, p<0.001). There was no significant difference in accuracy between CT and MRI for lesion characterisation. The agreement in classification for management was very good (weighted kappa 0.91, 95% CI 0.83-0.99). CONCLUSION: SPIO enhanced MRI detects more and smaller lesions, but both techniques are comparable in terms of classification for management. SPIO enhanced MRI may be preferred as there is no exposure to ionising radiation.

A psychometric comparison of health-related quality of life measures in chronic liver disease.

Four generic [the Sickness Impact Profile (SIP-68), Short-Form Health Survey (SF-36), EuroQol instrument (EQ-5D), COOP/WONCA charts], two domain-specific health-related quality of life measures [the sexuality scale of the HIV Overview Problems Evaluating System (HOPES), Multi-dimensional Fatigue Index (MFI-20)], and a self-developed 12-item symptom index were compared in terms of feasibility, test-retest reliability, internal consistency reliability, construct validity, and known groups validity in patients with chronic liver disease. All instruments could be completed within 10 min and exhibited a good psychometric performance in patients with chronic liver disease. The SF-36 and the MFI-20 performed relatively best in terms of reliability, construct validity, and discriminative ability. The sexuality scale of the HOPES demonstrated a relatively poor performance, as the missing value rate was higher than 5%. Further research is needed into the sensitivity to important clinical changes of the instruments.

Hepatitis C viral kinetics in difficult to treat patients receiving high dose interferon and ribavirin.

BACKGROUND/AIMS: Hepatitis C viral (HCV) kinetic studies have demonstrated the increased antiviral effect of higher than standard dosages of interferon and of daily treatment schedules. Since interferon has a short half-life, twice-daily administration of interferon may be even more effective. METHODS: We evaluated the HCV kinetics in daily vs. twice-daily high dose interferon (IFN) therapy in combination with ribavirin in 24 difficult to treat patients. Patients were randomised to 10 MU IFN daily or 5 MU twice-daily for 4 weeks. RESULTS: Interferon efficacy (epsilon) was similar and very high for both groups (range 99.83-99.97%). Clearance of infected cells (beta phase) tended to be slightly faster for patients on 5 MU bd (T1/2 70 vs. 90 h, ns). Clearance of infected cells was strongly related to initial viral load (T1/2 103 vs. 53 h, P = 0.002, for above versus below 2 x 10(6) copies/ml). In this study an additional phase with a temporary rise in viral load was observed between the alpha and the beta phase. CONCLUSION: Daily high induction dose is associated with nearly complete inhibition of viral replication even in difficult to treat patients. A twice-daily schedule did not lead to further improvement. Clearance rate of infected cells was significantly correlated with initial viral load.

Estimation of early hepatitis C viral clearance in patients receiving daily interferon and ribavirin therapy using a mathematical model.

Patients with hepatitis C virus (HCV) genotype 1 infection are resistant to standard interferon (IFN) therapy. We used a mathematical model to estimate the duration of daily therapy necessary to maximize the number of patients achieving viral negativity before 12 weeks of therapy. Patients from a study to determine HCV RNA reduction over 4 weeks using 3 million units (MU), 5 MU, or 10 MU of IFN alfa daily plus Ribavirin were compared with a group receiving IFN alfa 3 MU three times a week. By extending the linear regression and prediction interval lines, the estimated time to negativity was greater than 12 weeks for the standard IFN group, 42 to greater than 84 days for the 3 MU IFN daily plus Ribavirin, 39 to 60 days for 5 MU IFN daily plus Ribavirin and 25 to 45 days for the 10 MU IFN daily and Ribavirin group, respectively. Thus, the use of a predictive model based on log transformation and linear regression of the early HCV RNA response suggests daily doses of 5 or 10 million units of IFN plus Ribavirin will be theoretically necessary for longer than 4 weeks to maximize the number of patients who clear virus by 12 weeks of therapy. This model may be useful in predicting response in groups of patients receiving other therapies.

Changes in anti-viral effectiveness of interferon after dose reduction in chronic hepatitis C patients: a case control study.

BACKGROUND: High dose interferon induction treatment of hepatitis C viral infection blocks viral production over 95%. Since dose reduction is often performed due to clinical considerations, the effect of dose reduction on hepatitis C virus kinetics was studied. METHODS: A new model that allowed longitudinal changes in the parameters of viral dynamics was used in a group of genotype-1 patients (N = 15) with dose reduction from 10 to 3 million units of interferon daily in combination with ribavirin, in comparison to a control group (N = 9) with no dose reduction. RESULTS: Dose reduction gave rise to a complex viral kinetic pattern, which could be only explained by a decrease in interferon effectiveness in blocking virion production. The benefit of the rapid initial viral decline following the high induction dose is lost after dose reduction. In addition, in some patients also the second phase viral decline slope, which is highly predictive of success of treatment, was impaired by the dose reduction resulting in smaller percentage of viral clearance in the dose reduction group. CONCLUSIONS: These findings, while explaining the failure of many induction schedules, suggest that for genotype-1 patients induction therapy should be continued till HCVRNA negativity in serum in order to increase the sustained response rate for chronic hepatitis C.