Hepatitis C: natural history, biology, treatment monitoring

This article presents the laboratory tests used to diagnose hepatitis C, to evaluate the severity of the chronic fibrosing disease, and to monitor the efficacy of treatment. Histological examination of liver biopsies is of the utmost importance for evaluating the development of fibrosis. Factors that precipitate fibrosis are reviewed. The annual rate of fibrosis progression can be assessed based on the estimated duration of hepatitis C virus contamination and on the fibrosis score established using the METAVIR classification. This allows to distinguish slow, fast, and intermediate fibrosis and to estimate the mean time to cirrhosis development. Combined use of interferon alpha (3 million units three times a week) and of Ribavirine (1000-1200 mg per day orally according to body weight) for 6 to 12 months is currently the standard treatment for hepatitis C. Treatment efficacy varies with a number of virus-related factors (genotype, viral burden) and patient-related factor (hepatic fibrosis, age, sex). In nonresponders, the value of treatment should not be assessed in terms of efficacy but in terms of slowing of fibrosis progression.     

Hepatitis B and C: natural course of disease

Significant progress in the understanding of the natural history of hepatitis B and C has been made in recent years due to molecular diagnosis techniques. The most important biologic feature of hepatitis B and C viruses (HBV, HCV) is their ability to cause chronic hepatitis. The natural course of HBV infection is variable, ranging from inactive HBsAg carrier state to progressive chronic hepatitis that can evolve into liver cirrhosis and hepatocellular carcinoma. HBeAg-negative chronic hepatitis is due to a naturally occurring HBV variant with mutations in the precore or basic core promoter regions. It accounts for the majority of cases in many European countries and is generally associated with a more severe liver disease. The morbidity and mortality in chronic hepatitis B are linked to the evolution to cirrhosis and hepatocellular carcinoma. The progression of fibrosis is strongly associated with persistent active viral replication When the diagnosis is made, the 5-year cumulative incidence of developing cirrhosis ranges from 8% to 20%. The 5-year cumulative incidence of hepatic decompensation is 20%. Hepatocellular carcinoma is one of the most common cancers worldwide, 75% of which are related to chronic HBV infection. Coinfection with hepatitis D virus can lead to a more progressive liver disease in a shorter period of time. Hepatitis C virus infection becomes chronic in 80% of infected persons resulting in different stages of chronic hepatitis, with 20%-30% progressing to cirrhosis within 20 years period. The progression of fibrosis determines the ultimate prognosis. The major factors known to be associated with fibrosis progression are older age, male gender and alcohol consumption. Viral load and genotype do not play a role in the disease progression. Progression to fibrosis is more rapid in immunocompromised patients.     

Hepatitis B virus: From diagnosis to treatment

During the next few decades, vaccination against hepatitis B virus (HBV) will dramatically change the epidemiological profile of this worldwide infection especially when Heath Policies encourage including HBV vaccination program for the newborns. However, it is still estimated that more than 2000 millions living people have met HBV. Symptomatic hepatitis with jaundice is less frequent than asymptomatic infection; however, as much as 350 millions of individuals remain chronically infected by HBV. In these cases, the need for efficient antiviral therapy remains clear when a viral replication is observed to control the risk of progression and the need for liver transplantation, which represents the only end-stage treatment. Indeed, patients having chronic hepatitis B (CHB) can now be successfully treated using nucleos(t)ide analogs (NA) or pegylated interferon (PEG-IFN). Therefore, beside vaccination, prevention of the progression of the disease to cirrhosis and liver decompensation, leading to end-stage liver disease and/or to hepatocellular carcinoma, by inhibiting viral replication seems to represent the best approach to improve survival. At last but not least, co-morbidities and other viral infections, leading also to chronic liver cirrhosis or liver inflammation such as the specific satellite delta virus (HDV), human immunodeficency virus (HIV) and/or hepatitis C (HCV) virus, are able to accelerate the progression and have to be taken in account. Interestingly, in treated infection, the dogma of the irreversibility of the liver fibrosis, when the cirrhosis is constituted, is tumbling down. In this review, we will focus on the clinical, virological and therapeutic aspects of hepatitis B infection in order to expose the proposals to follow-up and treat HBV-infected patients and the prevention of drug-resistant HBV mutants that frequently arise, leading to treatment failure and progression to liver disease.     

Multicystic peritoneal mesothelioma in an octogenarian: diagnosis, natural history, and treatment

Multicystic peritoneal mesothelioma (MCPM) is a rare cystic proliferation most often seen in women of reproductive age with a history of prior abdominal surgery. This is a case report of an 83-year-old woman diagnosed with MCPM during an exploratory laparotomy for presumed peritoneal carcinomatosis from colon cancer. After complete removal of all visible MCPM, the patient remains free of both colon cancer and MCPM. This article reviews the literature with regards to the pathology, natural history, risk of malignant transformation, and current options for management of MCPM, including cytoreductive surgery and hyperthermic intraperitoneal chemotherapy.     

Asthma in older adults: observations from the epidemiology and natural history of asthma: outcomes and treatment regimens (TENOR) study.

BACKGROUND: The Epidemiology and Natural History of Asthma: Outcomes and Treatment Regimens (TENOR) was a 3-year, multicenter, observational study of 4,756 patients 6 years or older with severe or difficult-to-treat asthma by physician evaluation. More than 280 pulmonologist and allergist sites across the United States participated. OBJECTIVE: To compare health care utilization (HCU), medication use, asthma control, and quality of life (QoL) in older (> or =65 years; n = 566) and younger (18-64 years; n = 2,912) adult patients in TENOR. METHODS: Patients had to be under a physician's care for at least 1 year and have high medication use or HCU in the past year. Heavy smokers (> or =30 pack-years) and patients with cystic fibrosis were excluded. RESULTS: Although older patients in TENOR had worse lung function as measured by decreased percent predicted forced expiratory volume in 1 second (FEV1) (P < .001), they had significantly lower HCU compared with younger patients. They also had higher use of inhaled corticosteroids and better QoL than younger patients. Older patients reported fewer problems controlling their asthma (P < .001) but reported worse communication with their physicians (P = .02). CONCLUSIONS: Older patients in TENOR appeared to do better than younger patients, despite having worse lung function. Older patients in TENOR may have received more aggressive care than older asthmatic patients in other studies, based on a higher use of inhaled and oral corticosteroids. Whether differences in treatment or disease influenced other physiologic or inflammatory outcomes that contribute to the disconnect between HCU and FEV1 awaits further study.     

The management of tuberculosis: epidemiology, resistance and monitoring

This PhD thesis is based on 5 studies conducted in the period 2006-2010 during my employment at the International Reference Laboratory of Mycobacteriology, Statens Serum Institut. The overall aim was to assess tuberculosis (TB) treatment in Denmark with specific focus on the risk of relapse of TB disease, and to analyse treatment outcome of patients with multidrug-resistant (MDR) or isoniazid-resistant TB. The project established the need for rapid methods to detect resistance and follow-up of treatment. A rapid method to detect drug resistance was optimised and evaluated for use directly in clinical specimens. The studies were based on data from the Mycobacterial registry in the period 1992-2007, which included the results from microscopy, culture, drug-susceptibility and restriction fragment length polymorphism (RFLP). Information on dates of death/emigration were taken from the CPR-registry and treatment from surveillance data and patient records. The rate of recurrent TB was found to be low in Denmark, during 13.5 years of follow-up. Relapse accounted for 1.3% of the recurrent cases and reinfection was rare, only in 0.5% cases. The relapse hazard increased up to four years after diagnosis. Cavitary disease was associated with relapse as opposed to reinfection and may need prolonged treatment and closer monitoring. The incidence of MDR-TB and isoniazid resistance was confirmed to be low. Successful short- and long-term treatment outcome of MDR-TB and isoniazid-resistant TB was high. High- and low-level isoniazid resistance did not affect treatment outcome. A multiplex PCR hybridization mutation analysis, that simultaneously detects the most frequent rpoB and katG gene mutations conferring rifampin and high-level isoniazid resistance, was optimized for direct use and evaluated in smear-positive specimens as opposed to slow conventional drug-susceptibility testing (DST). The second-generation rifampin and isoniazid resistance mutation assay additionally included detection of mutations within the inhA gene conferring low-level isoniazid resistance. This assay was found to be rapid (< 48 h) and easy to perform in isolates and clinical specimens. A high concordance between mutation and conventional DST results was found for rifampin, while results varied for isoniazid . The mutation analysis identified all MDR-TB cases and the majority of isoniazid-resistant cases in Denmark. Standard 6-month multiple anti-TB drug therapy is necessary to treat drug-susceptible TB. Drug-resistant TB often requires therapy adjustments and extended treatment. MDR-TB particularly poses therapeutic challenges. Rapid detection of resistance mutations directly in smear-positive patient specimens may improve MDR-TB patient treatment, although the impact on isoniazid-resistant TB treatment outcome remains to be determined. The mutation assay is a rapid supplement to the gold standard conventional DST in high-income countries such as Denmark, while in low-income countries it can be used for preliminary DST. The assay may be applied to smear-positive samples from patients suspected of treatment failure, recurrent TB, drug-resistant TB exposure or originating from countries with high levels of DR. The new extended mutation assay has proved to be a useful tool, which has now been included in the World Health Organization's policy to combat and prevent new cases of MDR and extensively drug-resistant TB.     

Hepatitis B virus core-related antigens as markers for monitoring chronic hepatitis B infection

A sensitive chemiluminescence enzyme immunoassay has been developed for hepatitis B virus (HBV) core-related antigen (HBcrAg) detection. We aimed to investigate the usefulness of HBcrAg measurement for monitoring chronic hepatitis B disease. HBcrAg levels were measured by a chemiluminescence enzyme immunoassay in 54 untreated patients and 39 patients treated with either entecavir or lamivudine. The HBcrAg concentration correlated positively with the levels of serum HBV DNA (r = 0.820), intrahepatic total HBV DNA (r = 0.700), and covalently closed circular DNA (cccDNA) (r = 0.664; for all, P values were <0.001). A higher HBcrAg concentration was associated with a greater proportion of hepatitis B core antigen immunostaining. Although the differences were not statistically significant, patients with higher Knodell necroinflammation and fibrosis scores tended to have higher serum HBcrAg concentration levels. In the treated patients, the logarithmic reduction in HBcrAg at week 48 correlated positively with the logarithmic reduction of serum HBV DNA, intrahepatic total HBV DNA, and cccDNA. Of the 31 patients with undetectable serum HBV DNA (<300 copies/ml) at the end of treatment, 20 (65%) still had detectable HBcrAg. A greater reduction in posttreatment HBcrAg concentration was associated with histological improvement and a decrease in hepatitis B core antigen immunostaining. HBcrAg concentrations of <40,000 kU/ml at baseline and <200 kU/ml at week 24 were associated with a higher chance of having undetectable HBV DNA at week 48. In conclusion, serum HBcrAg levels correlated with HBV virological markers and reflected the chronic hepatitis B disease activity in the liver.     

Acute exacerbations of asthma: epidemiology, biology and the exacerbation-prone phenotype

Asthma is a highly prevalent chronic respiratory disease affecting 300 million people world-wide. A significant fraction of the cost and morbidity of asthma derives from acute care for asthma exacerbations. In the United States alone, there are approximately 15 million outpatient visits, 2 million emergency room visits, and 500 000 hospitalizations each year for management of acute asthma. Common respiratory viruses, especially rhinoviruses, cause the majority of exacerbations in children and adults. Infection of airway epithelial cells with rhinovirus causes the release of pro-inflammatory cytokines and chemokines, as well as recruitment of inflammatory cells, particularly neutrophils, lymphocytes, and eosinophils. The host response to viral infection is likely to influence susceptibility to asthma exacerbation. Having had at least one exacerbation is an important risk factor for recurrent exacerbations suggesting an 'exacerbation-prone' subset of asthmatics. Factors underlying the 'exacerbation-prone' phenotype are incompletely understood but include extrinsic factors: cigarette smoking, medication non-compliance, psychosocial factors, and co-morbidities such as gastroesophageal reflux disease, rhinosinusitis, obesity, and intolerance to non-steroidal anti-inflammatory medications; as well as intrinsic factors such as deficient epithelial cell production of the anti-viral type I interferons (IFN-α and IFN-β). A better understanding of the biologic mechanisms of host susceptibility to recurrent exacerbations will be important for developing more effective preventions and treatments aimed at reducing the significant cost and morbidity associated with this important global health problem.     

Hepatitis C virus core antigen: A simplified treatment monitoring tool,including for post-treatment relapse

BackgroundSimple, affordable diagnostic tools are essential to facilitate global hepatitis C virus (HCV) elimination efforts.ObjectivesThis study evaluated the clinical performance of core antigen (HCVcAg) assay from plasma samples to monitor HCV treatment efficacy and HCV viral recurrence.Study designPlasma samples from a study of response-guided pegylated-interferon/ribavirin therapy for people who inject drugs with chronic HCV genotype 2/3 infection were assessed for HCV RNA (AmpliPrep/COBAS Taqman assay, Roche) and HCVcAg (ARCHITECT HCV Ag, Abbott Diagnostics) during and after therapy. The sensitivity and specificity of the HCVcAg assay was compared to the HCV RNA assay (gold standard).ResultsA total of 335 samples from 92 enrolled participants were assessed (mean 4 time-points per participant). At baseline, end of treatment response (ETR) and sustained virological response (SVR) visits, the sensitivity of the HCVcAg assay with quantifiable HCV RNA threshold was 94% (95% CI: 88%, 98%), 56% (21%, 86%) and 100%, respectively. The specificity was between 98 to 100% for all time-points assessed. HCVcAg accurately detected all six participants with viral recurrence, demonstrating 100% sensitivity and specificity. One participant with detectable (non-quantifiable) HCV RNA and non-reactive HCVcAg at SVR12 subsequently cleared HCV RNA at SVR24.ConclusionsHCVcAg demonstrated high sensitivity and specificity for detection of pre-treatment and post-treatment viraemia. This study indicates that confirmation of active HCV infection, including recurrent viraemia, by HCVcAg is possible. Reduced on-treatment sensitivity of HCVcAg may be a clinical advantage given the moves toward simplification of monitoring schedules.     

Diabetic nephropathy--a review of the natural history, burden, risk factors and treatment

The earliest clinical evidence of diabetic nephropathy is microalbuminuria. Progression from microalbuminuria to overt nephropathy occurs in 20-40% within a 10-year period with approximately 20% of these patients progressing to end-stage renal disease. End-stage renal disease develops in 50% of type-1 diabetes patients with overt nephropathy within 10 years and in more than 75% by 20 years in the absence of treatment. In type-2 diabetes, a greater proportion of patients have microalbuminuria and overt nephropathy at or shortly after diagnosis of diabetes. The incidence of diabetes is increasing worldwide, with subsequent increase in the incidence of diabetic nephropathy. The risk factors identified in the development of DN from longitudinal and cross-sectional studies include race, genetic susceptibility, hypertension, hyperglycemia, hyperfiltration, smoking, advanced age, male sex, and high-protein diet. Treatment interventions in diabetic nephropathy include glycemic control, treatment of hypertension, hyperlipidemia, cessation of smoking, protein restriction, and renal replacement therapy. Multifactorial approach includes combined therapy targeting hyperglycemia, hypertension, microalbuminuria, and dyslipidemia.