The managment of chronic hepatitis C virus infection in patients coinfected with the human immuno... more The managment of chronic hepatitis C virus infection in patients coinfected with the human immunodeficiency virus poses a significant challenge. Treatment is influenced by a number of viral and host characteristics, including hepatitis C virus genotype, baseline viremia, and adherence to medication regimen. Accelerated progression of liver disease, immunodeficiency, and hepatotoxicity of antiretroviral drugs are additional concerns in coinfected patients. According to the results of 5 randomized clinical trials, 27%-55% of coinfected patients who received therapy with pegylated interferon-alfa and ribavirin attained a sustained virologic response. These studies also confirm the importance of early virologic response as a predictor of treatment outcome and reveal the considerable proportion of patients who experience hematologic tolerability issues. Effective management strategies that encompass patient and viral factors are necessary to improve the long-term outlook for coinfected patients.
Phosphodiesterase 12 (PDE12) is a negative regulator of the type 1 interferon (IFN) response and ... more Phosphodiesterase 12 (PDE12) is a negative regulator of the type 1 interferon (IFN) response and here we show that PDE12 inhibitors (lead compounds 63 and 17) are associated with increased RNAseL activity, are well tolerated at the therapeutic range and inhibit, both in vitro and in vivo, the replication of several RNA viruses including hepatitis C virus (HCV), dengue virus (DENV), West Nile Virus (WNV) and SARS-CoV-2.
The editors have tried to ensure the accuracy of this report but cannot accept responsibility for... more The editors have tried to ensure the accuracy of this report but cannot accept responsibility for any errors or omissions. They would like to thank the referees for their constructive comments on the draft document.
To determine the efficacy of interferona2a in chronic active hepatitis B, 238 patients were rando... more To determine the efficacy of interferona2a in chronic active hepatitis B, 238 patients were randomly divided, into four groups: three groups received either 2.5 MIUm-2. 5.0 MIUm-' or 10.0 MIUm-2, three times weekly by intramuscular injection for 12-24 weeks: and a control group received no treatment. Patients were followed for up to 12 months after treatment was discontinued. There was a statistically significant difference in response [clearance of hepatitis B e antigen (HBeAg) and hepatitis B viral DNA (HBV-DNA)] between treated and untreated patients (3 7 vs 13%) but no statistically significant difference was seen between treatment groups (33% 34% and 43% for the 2.5, 5.0 and 10.0 MIUm-' groups, respectively). A transient rise in transaminases (seroconversion hepatitis) was seen in responders, but levels returned to within the normal range after response to treatment. In patients responding to interferon therapy there was a significant reduction in the severity of the hepatitis. Interferon-a2a was generally well tolerated with respect to vital signs and laboratory parameters.
Seventy-eight patients with congenital coagulation disorders were treated with hepatitis B vaccin... more Seventy-eight patients with congenital coagulation disorders were treated with hepatitis B vaccine either subcutaneously or intradermally. All the children (eight vaccinated subcutaneously and eight vaccinated intradermally) responded. Seventeen of 19 (goo/,) anti-HIV-negative adults vaccinated subcutaneously and 14/25 (56Y0) anti-HIV-negative adults vaccinated intradermally showed an immune response. At 24 months, the anti-HBs level was > 10 IU/I in all children vaccinated subcutaneously, 83% of children vaccinated intradermally, 77% of adults vaccinated subcutaneously, and 55% of adults vaccinated intradermally. Eight of 15 (53%) adult patients who were anti-HIV positive were also anti-HBc positive before vaccination and 6/8 (75%) failed to produce an amnestic response to vaccine. Subcutaneous vaccination with regular monitoring of anti-HBs levels and appropriate boosting is recommended.
POSTERS mitochondrial isobutyryl-CoA dehydrogenase was located. Genomic DNA sequencing revealed a... more POSTERS mitochondrial isobutyryl-CoA dehydrogenase was located. Genomic DNA sequencing revealed a single nucleotide mutation at −17 of the first intron of Acad8 in affected mice. cDNA sequencing revealed an intronic 28-base-pair insertion at the site of the mutation, which caused a frame shift with a premature stop codon. In vitro splicing assay confirmed that the mutation was sufficient to activate an upstream, aberrant 3 splice site. There was a reduction in the expression of Acad8 at both the mRNA and protein levels. The mutant mice grew normally but demonstrated cold intolerance at young age with a progressive hepatic steatosis. Homozygous mutant mice hepatocytes had abnormal mitochondria with crystalline inclusions, suggestive of mitochondriopathy. This is the first mouse model of isobutyryl-CoA dehydrogenase deficiency; an inborn error of valine metabolism provides us a better understanding of the pathophysiology and the anticipated results of untreated severe cases during metabolic stress.
In a Phase II clinical trial, 14 consecutive, unselected patients with primary hepatocellular car... more In a Phase II clinical trial, 14 consecutive, unselected patients with primary hepatocellular carcinoma were treated with a new inhibitor of thymidylate synthase, CB3717. On the basis of previously reported criteria, 6 patients were considered to have a good prognosis (Grade A) and 8 a poor prognosis (Grade B). Three Grade B patients died after only one treatment. Six patients responded (4 Grade A and 2 Grade B) with a decrease in tumour size and greater than 50% fall in serum alphafetoprotein levels; 3 of these had a greater than 1 log fall in alphafetoprotein. A further patient (Grade B) showed static disease during treatment. Thus, of 11 patients receiving two or more treatments 7 showed clinical benefit, with a median survival from start of CB3717 therapy of 46 weeks (2 still alive at 33 and 67 weeks). Our results suggest that CB3717 will be a useful new therapeutic agent in hepatocellular carcinoma. Further controlled trials are indicated to confirm these preliminary findings, using the drug both as a single agent and in combination with inhibitors of thymidine uptake by cells, which may further increase efficacy.
From the two mutations discovered in the HFE gene, only C282Y is involved in patienls with geneti... more From the two mutations discovered in the HFE gene, only C282Y is involved in patienls with genetic hemochromatosis (GH) while the other (H63D) remains of unclear significance. The aims were lo appreciate the prevalence of the two identified HFE mutations in hvo groups-of patients with or without iron overload. Patients and methods: 2 I I unrelated
We constructed an "SVR Calculator" for estimating the probability that an individual patient will... more We constructed an "SVR Calculator" for estimating the probability that an individual patient will achieve an SVR after treatment with PEGASYS/ COPEGUS. The probability can be calculated at baseline, or after 12 weeks' treatment, and can include assumptions about adherence. Methods: Data included were from patients treated with PEGASYS 180mcg/week and COPEGUS 800 or 1000/1200mg/day in two phase III trials (Fried NEJM 2002; Hadziyannis 2002). The influence of pretreatment factors (gender, age, race, BMI/weight, viral load, ALT quotient, histology, adherence) on SVR rates was examined by a logistic regression model. Data falling outside the 5th-95th percentiles were excluded; thus, data from 736 of 1037 genotype 1 patients with these characteristics were used in the model: Caucasian men and women, aged 18-65yrs, BMI 18-32 kg/m 2 , ALT quotient 1-8, HCV RNA 0.1-24 million copies/mL. Results: Factors that significantly modified the probability of an SVR included: age, viral load, ALT quotient, histology, BMI. The effect of age on the probability of achieving an SVR in a patient treated according to current recommendations is tabulated. Probability (%) of achieving an SVR (95% CI) after 48 wks combination therapy (RBV dose: 1000/1200 mg/d) Patient age 25 years 35 years 45 years 50 years Standard genotype 1 patient (at baseline)* 66 (58-74) 58 (52-65) 50 (44-56) 45 (39-52) Assuming >80% adherence (i.e. for >39 wks) 77 (69-84) 69 (63-75) 60 (53-65) 54 (47-61) Standard genotype 1 patient* (with an EVR at wk 12) 73 (65-81) 66 (59-73) 58 (52-66) 54 (46-61) Assuming >80% adherence (i.e. for >39 wks) 80 (72-86) 73 (66-78) 64 (58-70) 59 (52-66) *Baseline characteristics: noncirrhotic, baseline ALT quotient=2, BMI=26 kg/m 2 , HCV RNA=3.27x10 6 /mL; EVR: undetectable og ≥2-log1decrease in HCV RNA at wk 12; SVR: HCV RNA <50 IU/mL on/after wk60. Conclusion: By varying the input parameters the individual probability of achieving an SVR with PEGASYS/COPEGUS can be calculated. This tool can be used to make treatment decisions and to motivate patients to stay on therapy.
Background & Aims: Cholangiocarcinomas (CC) can be subdivided into intrahepatic (IHCC) or extrahe... more Background & Aims: Cholangiocarcinomas (CC) can be subdivided into intrahepatic (IHCC) or extrahepatic (EHCC). Hilar or 'Klatskin' tumours are anatomically extrahepatic. Most international studies, also from the UK, report increasing IHCC and decreasing EHCC incidence. The second edition of the International Classification of Diseases for Oncology (ICD-O-2) assigned 'Klatskin' tumours a unique histology code (8162/3), but this was cross-referenced to the topography code for intrahepatic (IHBD) rather than extrahepatic bile duct tumours (EHBD). Under the third ICD-O edition, 'Klatskin' tumours are cross-referenced to either IHBD or EHBD. New editions of the ICD-O classification are adopted at different time points by different countries. We investigated the impact of changing ICD-O classifications and the potential misclassification of hilar/'Klatskin' tumours on bile duct tumour and CC incidence rates in England and Wales and the US. We also examined whether coding practices by cancer registries in England and Wales could be influencing these rates. Methods: We analysed age-standardised incidence rates (ASIR) in England and Wales for IHBD and EHBD tumours between 1990 and 2008, then transferred all 'Klatskin' tumours from IHBD to EHBD and reanalysed rates from 1995, when ICD-O-2 was introduced in the UK. We also compared trends in IHBD, EHBD, and 'Klatskin' tumours in England and Wales with those in the USSEER (Surveillance, Epidemiology and End Results) database. Coding practice at Cancer registry level in England and Wales was investigated via a questionnaire completed by all national cancer registries. Results: In England and Wales, 1990-2008, ASIR of IHBD cancers rose (0.43-1.84/100,000 population in males; 0.27-1.51 in females) but fell for EHBD (0.78-0.51/100,000 population in males; 0.62-0.39 in females). After transferring all 'Klatskin' tumours from IHBD to EHBD, there remained a marked increase in ASIR of IHBD cancers and a decrease in ASIR for EHBD, as only 1% of CC were reportedly 'Klatskin'. The US SEER data showed that ASIR for IHBD gradually rose from 0.59/100,000 population in 1990 to 0.91 in 2001, then sharply fell before plateauing at 0.60 by 2007. ASIR for EHBD remained relatively stable at around 0.80/100,000 population until 2001, then began increasing, to 0.97 by 2007. Annually, between 1995 and 2008, the vast majority of 'Klatskin' tumours in England and Wales were coded as IHBD. This was also the case in the SEER data until 2001, when the situation was reversed and subsequently most 'Klatskin' tumours were coded as EHBD. US trends coincide with a switch from ICD-O2 to ICD-O-3 in 2001. In the UK, the switch to ICD-O-3 only occurred in 2008. On questioning, cancer registries in England and Wales stated they would not code a CC described as 'hilar' with the designated 'Klatskin' histology code. If the tumour site is unspecified, most registries classify CC as intrahepatic. Conclusions: Changes in ICD-classification may be influencing observed changes in IHBD and EHBD incidence rates. Coding misclassification is likely to have been skewing CC registration to an intrahepatic site, thereby contributing to the previously reported rise in intrahepatic tumours.
INTRODUCTION Interactions between human immunode®ciency virus (HIV) infection and concurrent infe... more INTRODUCTION Interactions between human immunode®ciency virus (HIV) infection and concurrent infections may alter the natural history and treatment out-comes of both diseases. Theoretical molecular interactions between HIV and hepatitis viruses may potentiate HIV replication ...
The managment of chronic hepatitis C virus infection in patients coinfected with the human immuno... more The managment of chronic hepatitis C virus infection in patients coinfected with the human immunodeficiency virus poses a significant challenge. Treatment is influenced by a number of viral and host characteristics, including hepatitis C virus genotype, baseline viremia, and adherence to medication regimen. Accelerated progression of liver disease, immunodeficiency, and hepatotoxicity of antiretroviral drugs are additional concerns in coinfected patients. According to the results of 5 randomized clinical trials, 27%-55% of coinfected patients who received therapy with pegylated interferon-alfa and ribavirin attained a sustained virologic response. These studies also confirm the importance of early virologic response as a predictor of treatment outcome and reveal the considerable proportion of patients who experience hematologic tolerability issues. Effective management strategies that encompass patient and viral factors are necessary to improve the long-term outlook for coinfected patients.
Phosphodiesterase 12 (PDE12) is a negative regulator of the type 1 interferon (IFN) response and ... more Phosphodiesterase 12 (PDE12) is a negative regulator of the type 1 interferon (IFN) response and here we show that PDE12 inhibitors (lead compounds 63 and 17) are associated with increased RNAseL activity, are well tolerated at the therapeutic range and inhibit, both in vitro and in vivo, the replication of several RNA viruses including hepatitis C virus (HCV), dengue virus (DENV), West Nile Virus (WNV) and SARS-CoV-2.
The editors have tried to ensure the accuracy of this report but cannot accept responsibility for... more The editors have tried to ensure the accuracy of this report but cannot accept responsibility for any errors or omissions. They would like to thank the referees for their constructive comments on the draft document.
To determine the efficacy of interferona2a in chronic active hepatitis B, 238 patients were rando... more To determine the efficacy of interferona2a in chronic active hepatitis B, 238 patients were randomly divided, into four groups: three groups received either 2.5 MIUm-2. 5.0 MIUm-' or 10.0 MIUm-2, three times weekly by intramuscular injection for 12-24 weeks: and a control group received no treatment. Patients were followed for up to 12 months after treatment was discontinued. There was a statistically significant difference in response [clearance of hepatitis B e antigen (HBeAg) and hepatitis B viral DNA (HBV-DNA)] between treated and untreated patients (3 7 vs 13%) but no statistically significant difference was seen between treatment groups (33% 34% and 43% for the 2.5, 5.0 and 10.0 MIUm-' groups, respectively). A transient rise in transaminases (seroconversion hepatitis) was seen in responders, but levels returned to within the normal range after response to treatment. In patients responding to interferon therapy there was a significant reduction in the severity of the hepatitis. Interferon-a2a was generally well tolerated with respect to vital signs and laboratory parameters.
Seventy-eight patients with congenital coagulation disorders were treated with hepatitis B vaccin... more Seventy-eight patients with congenital coagulation disorders were treated with hepatitis B vaccine either subcutaneously or intradermally. All the children (eight vaccinated subcutaneously and eight vaccinated intradermally) responded. Seventeen of 19 (goo/,) anti-HIV-negative adults vaccinated subcutaneously and 14/25 (56Y0) anti-HIV-negative adults vaccinated intradermally showed an immune response. At 24 months, the anti-HBs level was > 10 IU/I in all children vaccinated subcutaneously, 83% of children vaccinated intradermally, 77% of adults vaccinated subcutaneously, and 55% of adults vaccinated intradermally. Eight of 15 (53%) adult patients who were anti-HIV positive were also anti-HBc positive before vaccination and 6/8 (75%) failed to produce an amnestic response to vaccine. Subcutaneous vaccination with regular monitoring of anti-HBs levels and appropriate boosting is recommended.
POSTERS mitochondrial isobutyryl-CoA dehydrogenase was located. Genomic DNA sequencing revealed a... more POSTERS mitochondrial isobutyryl-CoA dehydrogenase was located. Genomic DNA sequencing revealed a single nucleotide mutation at −17 of the first intron of Acad8 in affected mice. cDNA sequencing revealed an intronic 28-base-pair insertion at the site of the mutation, which caused a frame shift with a premature stop codon. In vitro splicing assay confirmed that the mutation was sufficient to activate an upstream, aberrant 3 splice site. There was a reduction in the expression of Acad8 at both the mRNA and protein levels. The mutant mice grew normally but demonstrated cold intolerance at young age with a progressive hepatic steatosis. Homozygous mutant mice hepatocytes had abnormal mitochondria with crystalline inclusions, suggestive of mitochondriopathy. This is the first mouse model of isobutyryl-CoA dehydrogenase deficiency; an inborn error of valine metabolism provides us a better understanding of the pathophysiology and the anticipated results of untreated severe cases during metabolic stress.
In a Phase II clinical trial, 14 consecutive, unselected patients with primary hepatocellular car... more In a Phase II clinical trial, 14 consecutive, unselected patients with primary hepatocellular carcinoma were treated with a new inhibitor of thymidylate synthase, CB3717. On the basis of previously reported criteria, 6 patients were considered to have a good prognosis (Grade A) and 8 a poor prognosis (Grade B). Three Grade B patients died after only one treatment. Six patients responded (4 Grade A and 2 Grade B) with a decrease in tumour size and greater than 50% fall in serum alphafetoprotein levels; 3 of these had a greater than 1 log fall in alphafetoprotein. A further patient (Grade B) showed static disease during treatment. Thus, of 11 patients receiving two or more treatments 7 showed clinical benefit, with a median survival from start of CB3717 therapy of 46 weeks (2 still alive at 33 and 67 weeks). Our results suggest that CB3717 will be a useful new therapeutic agent in hepatocellular carcinoma. Further controlled trials are indicated to confirm these preliminary findings, using the drug both as a single agent and in combination with inhibitors of thymidine uptake by cells, which may further increase efficacy.
From the two mutations discovered in the HFE gene, only C282Y is involved in patienls with geneti... more From the two mutations discovered in the HFE gene, only C282Y is involved in patienls with genetic hemochromatosis (GH) while the other (H63D) remains of unclear significance. The aims were lo appreciate the prevalence of the two identified HFE mutations in hvo groups-of patients with or without iron overload. Patients and methods: 2 I I unrelated
We constructed an "SVR Calculator" for estimating the probability that an individual patient will... more We constructed an "SVR Calculator" for estimating the probability that an individual patient will achieve an SVR after treatment with PEGASYS/ COPEGUS. The probability can be calculated at baseline, or after 12 weeks' treatment, and can include assumptions about adherence. Methods: Data included were from patients treated with PEGASYS 180mcg/week and COPEGUS 800 or 1000/1200mg/day in two phase III trials (Fried NEJM 2002; Hadziyannis 2002). The influence of pretreatment factors (gender, age, race, BMI/weight, viral load, ALT quotient, histology, adherence) on SVR rates was examined by a logistic regression model. Data falling outside the 5th-95th percentiles were excluded; thus, data from 736 of 1037 genotype 1 patients with these characteristics were used in the model: Caucasian men and women, aged 18-65yrs, BMI 18-32 kg/m 2 , ALT quotient 1-8, HCV RNA 0.1-24 million copies/mL. Results: Factors that significantly modified the probability of an SVR included: age, viral load, ALT quotient, histology, BMI. The effect of age on the probability of achieving an SVR in a patient treated according to current recommendations is tabulated. Probability (%) of achieving an SVR (95% CI) after 48 wks combination therapy (RBV dose: 1000/1200 mg/d) Patient age 25 years 35 years 45 years 50 years Standard genotype 1 patient (at baseline)* 66 (58-74) 58 (52-65) 50 (44-56) 45 (39-52) Assuming >80% adherence (i.e. for >39 wks) 77 (69-84) 69 (63-75) 60 (53-65) 54 (47-61) Standard genotype 1 patient* (with an EVR at wk 12) 73 (65-81) 66 (59-73) 58 (52-66) 54 (46-61) Assuming >80% adherence (i.e. for >39 wks) 80 (72-86) 73 (66-78) 64 (58-70) 59 (52-66) *Baseline characteristics: noncirrhotic, baseline ALT quotient=2, BMI=26 kg/m 2 , HCV RNA=3.27x10 6 /mL; EVR: undetectable og ≥2-log1decrease in HCV RNA at wk 12; SVR: HCV RNA <50 IU/mL on/after wk60. Conclusion: By varying the input parameters the individual probability of achieving an SVR with PEGASYS/COPEGUS can be calculated. This tool can be used to make treatment decisions and to motivate patients to stay on therapy.
Background & Aims: Cholangiocarcinomas (CC) can be subdivided into intrahepatic (IHCC) or extrahe... more Background & Aims: Cholangiocarcinomas (CC) can be subdivided into intrahepatic (IHCC) or extrahepatic (EHCC). Hilar or 'Klatskin' tumours are anatomically extrahepatic. Most international studies, also from the UK, report increasing IHCC and decreasing EHCC incidence. The second edition of the International Classification of Diseases for Oncology (ICD-O-2) assigned 'Klatskin' tumours a unique histology code (8162/3), but this was cross-referenced to the topography code for intrahepatic (IHBD) rather than extrahepatic bile duct tumours (EHBD). Under the third ICD-O edition, 'Klatskin' tumours are cross-referenced to either IHBD or EHBD. New editions of the ICD-O classification are adopted at different time points by different countries. We investigated the impact of changing ICD-O classifications and the potential misclassification of hilar/'Klatskin' tumours on bile duct tumour and CC incidence rates in England and Wales and the US. We also examined whether coding practices by cancer registries in England and Wales could be influencing these rates. Methods: We analysed age-standardised incidence rates (ASIR) in England and Wales for IHBD and EHBD tumours between 1990 and 2008, then transferred all 'Klatskin' tumours from IHBD to EHBD and reanalysed rates from 1995, when ICD-O-2 was introduced in the UK. We also compared trends in IHBD, EHBD, and 'Klatskin' tumours in England and Wales with those in the USSEER (Surveillance, Epidemiology and End Results) database. Coding practice at Cancer registry level in England and Wales was investigated via a questionnaire completed by all national cancer registries. Results: In England and Wales, 1990-2008, ASIR of IHBD cancers rose (0.43-1.84/100,000 population in males; 0.27-1.51 in females) but fell for EHBD (0.78-0.51/100,000 population in males; 0.62-0.39 in females). After transferring all 'Klatskin' tumours from IHBD to EHBD, there remained a marked increase in ASIR of IHBD cancers and a decrease in ASIR for EHBD, as only 1% of CC were reportedly 'Klatskin'. The US SEER data showed that ASIR for IHBD gradually rose from 0.59/100,000 population in 1990 to 0.91 in 2001, then sharply fell before plateauing at 0.60 by 2007. ASIR for EHBD remained relatively stable at around 0.80/100,000 population until 2001, then began increasing, to 0.97 by 2007. Annually, between 1995 and 2008, the vast majority of 'Klatskin' tumours in England and Wales were coded as IHBD. This was also the case in the SEER data until 2001, when the situation was reversed and subsequently most 'Klatskin' tumours were coded as EHBD. US trends coincide with a switch from ICD-O2 to ICD-O-3 in 2001. In the UK, the switch to ICD-O-3 only occurred in 2008. On questioning, cancer registries in England and Wales stated they would not code a CC described as 'hilar' with the designated 'Klatskin' histology code. If the tumour site is unspecified, most registries classify CC as intrahepatic. Conclusions: Changes in ICD-classification may be influencing observed changes in IHBD and EHBD incidence rates. Coding misclassification is likely to have been skewing CC registration to an intrahepatic site, thereby contributing to the previously reported rise in intrahepatic tumours.
INTRODUCTION Interactions between human immunode®ciency virus (HIV) infection and concurrent infe... more INTRODUCTION Interactions between human immunode®ciency virus (HIV) infection and concurrent infections may alter the natural history and treatment out-comes of both diseases. Theoretical molecular interactions between HIV and hepatitis viruses may potentiate HIV replication ...
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