Noninvasive tests for liver disease, fibrosis, and cirrhosis: Is liver biopsy obsolete?

EDUCATIONAL OBJECTIVE: Readers will consider using noninvasive tests instead of liver biopsy, when appropriate

EMILY CAREY, DO

+ Author Affiliations

Digestive Disease Institute, Cleveland Clinic

ADDRESS: Emily Carey, DO, Digestive Disease Institute, A30, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195; e-mail careye2@ccf.org.

WILLIAM D. CAREY, MD

+ Author Affiliations

Abstract

Liver biopsy has been used to diagnose chronic liver disease and to assess the degree of hepatic inflammation and fibrosis. However, it is an invasive test with many possible complications and the potential for sampling error. Noninvasive tests are increasingly precise in identifying the cause of many cases of liver disease and even the amount of liver injury (fibrosis). This review discusses the role of noninvasive tests to diagnose liver disease and to assess hepatic fibrosis and cirrhosis.

KEY POINTS

• Liver biopsy remains an important tool in the evaluation and management of liver disease.
• The role of liver biopsy for diagnosis of chronic liver disease has diminished, owing to accurate blood tests and imaging studies.
• Noninvasive tests for assessing the degree of hepatic fibrosis are showing more promise and may further reduce the need for liver biopsy. Elastography, in particular, shows promise in measuring hepatic fibrosis.
• Liver biopsy is still needed if laboratory testing and imaging studies are inconclusive.

Primary care physicians and specialists alike often encounter patients with chronic liver disease. Fortunately, these days we need to resort to liver biopsy less often than in the past.

 

The purpose of this review is to provide a critical assessment of the growing number of noninvasive tests available for diagnosing liver disease and assessing hepatic fibrosis, and to discuss the implications of these advances related to the indications for needle liver biopsy.

 

WHEN IS LIVER BIOPSY USEFUL?

 

In diagnosis

Needle liver biopsy for diagnosis remains important in cases of:

Diagnostic uncertainty (eg, in patients with atypical features)

Coexisting disorders (eg, human immunodeficiency virus [HIV] and hepatitis C virus infection, or alcoholic liver disease and hepatitis C)

An overlapping syndrome (eg, primary biliary cirrhosis with autoimmune hepatitis).

Fatty liver. Needle liver biopsy can distinguish between benign steatosis and progressive steatohepatitis in a patient with a fatty liver found on imaging, subject to the limitations of sampling error.

Because fatty liver disease is common and proven treatments are few, no consensus has emerged about which patients with suspected fatty liver disease should undergo needle biopsy. Many specialists eschew needle biopsy and treat the underlying risk factors of metabolic syndrome, reserving biopsy for patients with findings that raise the concern of cirrhosis.

Hereditary disorders, eg, hemochromatosis, alpha-1 antitrypsin deficiency, and Wilson disease.

In management

Periodic needle biopsy is also valuable in the management of a few diseases.

In autoimmune hepatitis, monitoring the plasma cell score on liver biopsy may help predict relapse when a physician is considering reducing or discontinuing immunosuppressive therapy.1

After liver transplantation, a liver biopsy is highly valuable to assess for rejection and the presence and intensity of disease recurrence.

PROBLEMS WITH LIVER BIOPSY

Liver biopsy is invasive and can cause significant complications. Nearly 30% of patients report having substantial pain after liver biopsy, and some experience serious complications such as pneumothorax, bleeding, or puncture of the biliary tree. In rare cases, patients die of bleeding.2

Furthermore, hepatic pathology, particularly fibrosis, is not always uniformly distributed. Surgical wedge biopsy provides adequate tissue volume to overcome this problem. Needle biopsy, on the other hand, provides a much smaller volume of tissue (1/50,000 of the total mass of the liver).3

As examples of the resulting sampling errors that can occur, consider the two most common chronic liver diseases: hepatitis C and fatty liver disease.

Regev et al4 performed laparoscopically guided biopsy of the right and left hepatic lobes in a series of 124 patients with chronic hepatitis C. Biopsy samples from the right and left lobes differed in the intensity of inflammation in 24.2% of cases, and in the intensity of fibrosis in 33.1%. Differences of more than one grade of inflammation or stage of fibrosis were uncommon. However, in 14.5%, cirrhosis was diagnosed in one lobe but not the other.

In a study in patients with nonalcoholic fatty liver disease, Ratziu et al5 found that none of the features characteristic of nonalcoholic steatohepatitis were highly concordant in paired liver biopsies. Clearly, needle liver biopsy is far from an ideal test.

Increasingly, liver diseases can be diagnosed precisely with laboratory tests, imaging studies, or both. Thus, needle liver biopsy is playing a lesser role in diagnosis.

ADVANCES IN NONINVASIVE DIAGNOSIS OF LIVER DISEASE
 
Over the past 30 years, substantial strides have been made in our ability to make certain diagnoses through noninvasive means.

Blood tests can be used to diagnose viral hepatitis A, B, and C and many cases of hemochromatosis and primary biliary cirrhosis. For a detailed discussion of how blood tests are used in diagnosing liver diseases, see http://www.clevelandclinicmeded.com/medicalpubs/diseasemanagement/hepatology/guide-to-common-liver-tests/

Imaging studies. Primary sclerosing cholangitis can be diagnosed with an imaging study, ie, magnetic resonance cholangiopancreatography (MRCP) or endoscopic retrograde cholangiopancreatography (ERCP). The value of needle biopsy in these patients is limited to assessing the degree of fibrosis to help with management of the disease and, less often, to discovering other liver pathologies.6

Most benign space-occupying liver lesions, both cystic and solid, can be fully characterized by imaging, especially in patients who have no underlying chronic liver disease, and no biopsy is needed. Whether biopsy should be performed to investigate liver lesions depends on the clinical scenario; the topic is beyond the scope of this paper but has been reviewed in detail by Rockey et al.2

CAN NONINVASIVE TESTS DETECT HEPATIC FIBROSIS?
 
Fibrosis, an accumulation of extracellular matrix, can develop in chronic liver disease. FIGURE 1 shows the typical stages and distribution. 7

Cirrhosis (stage 4 fibrosis) results in nodular transformation of the liver and impedance of portal blood flow, setting the stage for portal hypertension and its sequelae. Knowing whether cirrhosis is present is important in subsequent management.

FIGURE 1.
BASED ON INFORMATION CONTAINED IN BATTS KP, LUDWIG J. CHRONIC HEAPTITIS. AN UPDATE ON TERMINOLOGY AND REPORTING. AM J SURG PATHOL 1995; 19:1409–1417.

In advanced cases, cirrhosis is associated with typical clinical manifestations and laboratory and radiographic findings. In such cases, needle biopsy will add little. However, in most cases, particularly early in the course, clinical, laboratory, and radiologic correlates of cirrhosis are absent. In one study of patients with hepatitis C, 27% had cirrhosis, but in only a small number would cirrhosis have been apparent from clinical signs and laboratory and imaging studies.6
 
Since a major contemporary role for liver biopsy is in assessing the degree of fibrosis, it is reasonable to ask if newer noninvasive means are available to estimate hepatic fibrosis. The remainder of this review focuses on assessing our increasing ability to stage the degree of fibrosis (including the presence or absence of cirrhosis) by noninvasive means.

Clinical features point to cirrhosis, but not earlier fibrosis

Clinical manifestations help point to the diagnosis of cirrhosis but not to earlier stages of fibrosis.

For example, if a patient is known to have liver disease, the findings of ascites, splenomegaly, or asterixis mean that cirrhosis is highly probable. Similarly, hypersplenism (splenomegaly with a decrease in circulating blood cells but a normal to hyperactive bone marrow) in a patient with liver test abnormalities almost always represents portal hypertension due to cirrhosis, although other, nonhepatic causes are possible, such as congestive heart failure and constrictive pericarditis.

These features generally emerge late in the course of cirrhosis. The absence of such stigmata certainly does not preclude the presence of cirrhosis. Thus, these clinical signs have a high positive predictive value but a low negative predictive value, making them insufficient by themselves to diagnose or stage liver disease.

Laboratory tests are of limited value in assessing the degree of fibrosis

Standard liver tests are of limited value in assessing the degree of fibrosis.

Usual laboratory tests. At one end of the spectrum, anemia, thrombocytopenia, and leukopenia in the presence of liver disease correlate with cirrhosis. At the other end, a serum ferritin concentration of less than 1,000 mg/mL in a patient with hemochromatosis and no confounding features such as hepatitis C, HIV infection, or heavy alcohol use strongly predicts that the patient does not have significant hepatic fibrosis.8

Bilirubin elevation is a late finding in cirrhosis, but in cholestatic diseases bilirubin may be elevated before cirrhosis occurs.

Albumin is made exclusively in the liver, and its concentration falls as liver function worsens with progressive cirrhosis.

The prothrombin time increases as the liver loses its ability to synthesize clotting factors in cirrhosis. Coagulopathy correlates with the degree of liver disease.

Hyponatremia due to impaired ability to excrete free water is seen in patients with cirrhosis and ascites.

In summary, the usual laboratory tests related to liver disease are imprecise and, when abnormal, often indicate not just the presence of cirrhosis, but impending or actual decompensation.

Newer serologic markers, alone or in combination, have been proposed as aids in determining the degree of fibrosis or cirrhosis in the liver. Direct markers of fibrosis measure the turnover or metabolism of extracellular matrix. Indirect markers of fibrosis reflect alterations in hepatic function (see below).

Parkes et al9 reviewed 10 different panels of serum markers of hepatic fibrosis in chronic hepatitis C. Only 35% of patients had fibrosis adequately ruled in or ruled out by these panels, and the stage of fibrosis could not be adequately determined.

These serologic markers have not been validated in other chronic liver diseases or in liver disease due to multiple causes. Thus, although they show promise for use by the general internist, they need to be validated in patients with disease and in normal reference populations before they are ready for “prime time.”

Direct serologic markers of fibrosis

Direct serologic markers of fibrosis include those associated with matrix deposition—eg, procollagen type III amino-terminal peptide (P3NP), type I and IV collagens, laminin, hyaluronic acid, and chondrex.

P3NP is the most widely studied marker of hepatic fibrosis. It is elevated in both acute and chronic liver diseases; serum levels reflect the histologic stage of hepatic fibrosis in various chronic liver diseases, including alcoholic, viral, and primary biliary cirrhosis.10–12 Successful treatment of autoimmune hepatitis has been shown to lead to reductions of P3NP levels.13

Other direct markers of fibrosis are those associated with matrix degradation, ie, matrix metalloproteinases 2 and 3 (MMP-2, MMP-3) and tissue inhibitors of metalloproteinases 1 and 2 (TIMP-1, TIMP-2). Levels of MMP-2 proenzymes and active enzymes are increased in liver disease, but studies are inconsistent in correlating serum levels of MMP-2 to the degree of hepatic fibrosis.14,15 These tests are not commercially available, and the components are not readily available in most clinical laboratories.

Indirect serologic markers of fibrosis

Some indirect markers are readily available:

The AST:ALT ratio. The normal ratio of aspartate aminotransferase (AST) to alanine aminotransferase (ALT) is approximately 0.8. A ratio greater than 1.0 provides evidence of cirrhosis. However, findings have been inconsistent.

The AST:platelet ratio index (APRI), a commonly used index, is calculated by the following formula:

In studies of hepatitis C and hepatitis C-HIV, the APRI has shown a sensitivity of 37% to 80% and a specificity of 45% to 98%, depending on the cutoff value and whether a diagnosis of severe fibrosis or cirrhosis was being tested.16–19 These sensitivities and specificities are disappointing and do not provide information equal to that provided by needle liver biopsy in most patients with chronic liver disease.

The combination of prothrombin, gamma glutamyl, and apolipoprotein AI levels (PGA index) has been validated in patients with many types of chronic liver disease, and its accuracy for detecting cirrhosis is highest (66%–72%) in patients with alcoholic liver disease.20,21

FibroIndex uses the platelet count, AST level, and gamma globulin level to detect significant fibrosis in chronic hepatitis C, but its accuracy has yet to be validated.22

The FIB-4 index is based on four independent predictors of fibrosis, ie, age, the platelet count, AST level, and ALT level. It has shown good accuracy for detecting advanced fibrosis in two studies in patients with hepatitis C.23,24

Fibrometer (based on the platelet count; the prothrombin index; the levels of AST, alfa-2 macroglobulin, hyaluronate, and blood urea nitrogen; and age) predicted fibrosis well in chronic viral hepatitis.25,26

Fibrotest and Fibrosure are proprietary commercial tests available in many laboratories. They employ a mathematical formula to predict fibrosis (characterized as mild, significant, or indeterminate) using the levels of alpha-2 macroglobulin, alpha-2 globulin, gamma globulin, apolipoprotein A1, gamma glutamyl transferase, and total bilirubin. For detecting significant fibrosis, these tests are reported to have a sensitivity of about 75% and a specificity of 85%.27–29

ActiTest incorporates the ALT level into the Fibrotest to reflect liver fibrosis and necro-inflammatory activity.

A meta-analysis showed that Fibrotest and ActiTest could be reliable alternatives to liver biopsy in patients with chronic hepatitis C.30 The area under the receiver operator characteristic curve for the diagnosis of significant fibrosis ranged from 0.73 to 0.87; for the diagnosis of significant histologic activity it ranged from 0.75 to 0.86. Fibrotest had a negative predictive value for excluding significant fibrosis of 91% with a cutoff of 0.31. ActiTest’s negative predictive value for excluding significant necrosis was 85% with a cutoff of 0.36. None of these serum tests have become part of standard of practice for diagnosing fibrosis or cirrhosis.

The Sequential Algorithm for Fibrosis Evaluation (SAFE) combines the APRI and Fibrotest-Fibrosure tests in a sequential fashion to test for fibrosis and cirrhosis. In a large multicenter study31 validating this algorithm to detect significant fibrosis (stage F2 or greater by the F0–F4 METAVIR scoring system32), its accuracy was 90.1%, the area under the receiver operating characteristic curve was 0.89 (95% CI 0.87–0.90), and it reduced the number of liver biopsies needed by 46.5%. When the algorithm was used to detect cirrhosis, its accuracy was 92.5%, the area under the curve was 0.92 (95% CI 0.89–0.94), and it reduced the number of liver biopsies needed by 81.5%.

FIGURE 2.
Magnetic resonance elastography for detecting hepatic fibrosis

Magnetic resonance elastography uses a vibrating device to induce shear waves in internal organs, which are detected by a modified magnetic resonance imaging machine. In this color-coded image, areas toward the red end of the spectrum are stiffer and therefore contain more fibrosis than areas toward the violet end of the spectrum.
FROM TALAWALKAR JA. ELASTOGRAPHY FOR DETECTING HEPATIC FIBROSIS : OPTIONS AND CONSIDERATIONS. GASTROENTEROLOGY 2008; 135:299–302; USED WITH PERMISSION FROM THE AMERICAN GASTROENTEROLOGICAL SOCIETY; WWW.SCIENCEDIRECT.COM/SCIENCE/JOURNAL/00165085.

Another algorithm was developed to simultaneously detect significant fibrosis and cirrhosis. It had a 97.4% accuracy, but 64% of patients still required a liver biopsy.31

SAFE algorithms have the potential to reduce the number of needle biopsies needed to assess the degree of hepatic fibrosis.

CONVENTIONAL IMAGING STUDIES ARE NOT SENSITIVE FOR FIBROSIS

Standard imaging studies often show findings of cirrhosis but are not particularly sensitive, with a low negative predictive value.

Ultrasonography can show a small, nodular liver in advanced cirrhosis, but surface nodularity or increased echogenicity can be seen in hepatic steatosis as well as in cirrhosis. In one study,33 ultrasonography identified diffuse parenchymal disease but could not reliably distinguish fat from fibrosis or diagnose cirrhosis.

Often, in cirrhosis, the right lobe of the liver is atrophied and the caudate or left lobes are hypertrophied. Efforts to use the ratio of the widths of the lobes to diagnose cirrhosis have shown varying performance characterstics.34,35

One study of the splenic artery pulsatility index has shown this to be an accurate predictor of cirrhosis.36

Computed tomography provides information similar to that of ultrasonography, and it can identify complications of cirrhosis, including portal hypertension and ascites. On the other hand, it costs more and it exposes the patient to radiation and contrast media.

ELASTOGRAPHY, A PROMISING TEST
 
Hepatic elastography, a method for estimating liver stiffness, is an exciting recent development in the noninvasive measurement of hepatic fibrosis. Currently, elastography can be accomplished by ultrasound or magnetic resonance.

Ultrasound elastography

The FibroScan device (EchoSens, Paris, France) uses a mild-amplitude, low-frequency (50-Hz) vibration transmitted through the liver.37 It induces an elastic shear wave that is detected by pulse-echo ultrasonography as the wave propagates through the organ.

The velocity of the wave correlates with tissue stiffness: the wave travels faster through denser, fibrotic tissue.38,39

Ultrasound elastography (also called transient elastography) can sample a much larger area than liver biopsy can, providing a better understanding of the entire hepatic parenchyma. 40 Moreover, it can be repeated often without risk. This device is in widespread use in many parts of the world, but it is not yet approved in the United States.

A meta-analysis of 50 studies assessed the overall performance of ultrasound elastography for diagnosing liver fibrosis.41 The areas under the receiver operating characteristic curve were as follows:

■For significant fibrosis: 0.84 (95% CI 0.82–0.86)
■For severe fibrosis: 0.89 (95% CI 0.88–0.91)
■For cirrhosis: 0.94 (95% CI 0.93–0.95).

The type of underlying liver disease influenced the diagnosis of significant fibrosis, which was diagnosed most consistently in patients with hepatitis C. The authors concluded that ultrasound elastography had excellent diagnostic accuracy for diagnosing cirrhosis irrespective of the underlying liver disease, while the diagnosis of significant fibrosis had higher variation, which was dependent on the underlying liver disease.

A meta-analysis of nine studies 42 showed ultrasound elastography to have a sensitivity of 87% (95% CI 84%–90%) and a specificity of 91% (95% CI 89%–92%) for the diagnosis of cirrhosis. In seven of the nine studies, it diagnosed stage II to IV fibrosis with 70% sensitivity (95% CI 67%–73%) and 84% specificity (95% CI 80%–88%).

Limitations. Ultrasound elastography is less effective in obese patients, as the adipose tissue attenuates the elastic wave, and it has not been reliable in patients with acute viral hepatitis.43 Male sex, body mass index greater than 30, and metabolic syndrome seem to increase liver stiffness, thus limiting the use of this test.44

Until more data are available, the ultimate value of ultrasound elastography in reducing the number of liver biopsies needed remains unknown. However, this test shows potential as a reliable and noninvasive way to assess the degree of fibrosis in patients with liver disease.

Magnetic resonance elastography

Magnetic resonance elastography appears more promising than ultrasound elastography (FIGURE 2).32,37 The technique used is similar to that used in ultrasound elastography in that it uses a vibration device to induce a shear wave in the liver. However, in this case, the wave is detected by a modified magnetic resonance imaging machine, and a color-coded image is generated that depicts the wave velocity, and hence stiffness, throughout the organ.

Studies have shown a magnetic resonance scoring system that distinguishes Child-Pugh grade A cirrhosis from other grades to be 93% sensitive and 82% specific.45

FIGURE 3.

Median values and interquartile ranges (box plots) of values on magnetic elastography, (top), ultrasound elastography, (middle), and the aspartate:platelet ratio index (APRI) (bottom) for each METAVIR fibrosis stage in 96 patients with chronic liver disease. Crosses represent mean values, and error bars indicate the smallest and the largest values that are within 1.5 box-lengths of the 25th and 75th percentiles. Outliers are represented as individual points. In the bottom graph, one outlier has not been represented in the F4 group to maintain the clarity of the graph.
REPRINTED FROM HUWART L, SEMPOUX C, VICAUT E, ET AL. MAGNETIC RESONANCE ELASTOGRAPHY FOR THE NONINVASIVE STAGING OF LIVER FIBROSIS. GASTROENTEROLOGY 2008; 135:32–40; USED WITH PERMISSION FROM THE AMERICAN GASTROENTEROLOGICAL SOCIETY; WWW.SCIENCEDIRECT.COM/SCIENCE/JOURNAL/00165085.

In a recent direct comparison,46 the separation of values for varying stages of fibrosis was poor with the APRI index, fair with ultrasound elastography, and very good with magnetic resonance elastography (FIGURE 3). Indeed, in magnetic resonance elastography, a value greater than 4.46 kPa indicates cirrhosis (and a value less than 4.13 indicates no cirrhosis) with a high degree of likelihood, and a value less than 2.84 appears to exclude the likelihood of significant fibrosis. These findings need to be confirmed, and assurance is needed that the test performs accurately across all liver disease states.

Cost may limit the use of magnetic resonance elastography, and some patients may be unable to tolerate the procedure because of claustrophobia. It seems clear, though, that this test currently has the most promise in reducing the need for liver biopsy for grading the severity of hepatic fibrosis.

WHERE ARE WE NOW?
 
The importance of liver biopsy in arriving at a diagnosis of diffuse parenchymal liver disease is being diminished by accurate blood testing strategies for chronic viral hepatitis, autoimmune hepatitis, and primary biliary cirrhosis. Further, imaging tests are superior to liver biopsy in the diagnosis of primary sclerosing cholangitis.

However, many cases remain in which diagnostic confusion exists even after suitable laboratory testing and imaging studies. Diagnosing infiltrative disease (eg, amyloidosis, sarcoidosis), separating benign fatty liver disease from steatohepatitis, and evaluating liver parenchyma after liver transplantation are best accomplished by liver biopsy.

While needle biopsy is still the mainstay in diagnosing hepatic fibrosis, its days of dominance seem limited as technology improves. When physical examination or standard laboratory tests reveal clear-cut signs of portal hypertension, liver biopsy will seldom add useful information. Similarly, when imaging studies provide compelling evidence of cirrhosis and portal hypertension, needle biopsy is not warranted.

The SAFE algorithms warrant further evaluation in all chronic liver diseases, as they may help decrease the number of liver biopsies required. And we believe elastography will play an ever-increasing role in the assessment of hepatic fibrosis and will significantly reduce the need for biopsy in patients with liver disease.

■Copyright© 2010 The Cleveland Clinic Foundation

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Source

Retreatment of hepatitis C patients with pegylated interferon combined with ribavirin in non-responders to interferon plus ribavirin. Is it different in real life?

BMC Infect Dis. 2010; 10: 212.

Published online 2010 July 20. doi: 10.1186/1471-2334-10-212.
PMCID: PMC2912909
Copyright ©2010 Gonçales et al; licensee BioMed Central Ltd.

Fernando L Gonçales, Jr,1 Camila A Moma,1 Aline G Vigani,1 Adriana FCF Angerami,1 Eduardo SL Gonçales,1 Raquel Tozzo,1 Maria HP Pavan,1 and Neiva SL Gonçales 1,2

1 Grupo de Estudo das Hepatites, Disciplina de Doenças Infecciosas, Departamento de Clínica Médica, Faculdade de Ciências Médicas, Universidade Estadual de Campinas, UNICAMP, São Paulo, Brazil

2 Centro de Hematologia e Hemoterapia, Universidade Estadual de Campinas, UNICAMP, São Paulo, Brazil

Corresponding author

Fernando L Gonçales, Jr: flgj@uol.com.br; Camila A Moma: cami_atm@yahoo.com.br; Aline G Vigani: aline.vigani@sigmanet.com.br; Adriana FCF Angerami: afcfeltrin@yahoo.com.br; Eduardo SL Gonçales: dugoncales@hotmail.com; Raquel Tozzo: tumoca@uol.com.br; Maria HP Pavan: mariahpavan@uol.com.br; Neiva SL Gonçales: neiva@unicamp.br

Received November 9, 2009; Accepted July 20, 2010

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
 
Abstract
 
Background


More than 50% of hepatitis C viruses (HCV)-infected patients do not respond to the classical Interferon (IFN)/Ribavirin (RBV) combination therapy. The aim of this study was to evaluate the efficacy of retreatment with Peg-Interferon alpha-2b (PEG-IFN alpha-2b) plus RBV, in patients with HCV, genotypes 1 or 3, who were non-responders to the previous standard treatment with IFN/RBV.Methods

In the period 2005-2007, a total of 238 HCV chronic patients were non-responders to previous treatment with IFN plus RBV. Of these 130 agreed to be retreated with PEG-IFN alpha-2b and participated in this evaluation (90 with genotype 1 HCV and 40 with genotype 3 HCV). Patients were retreated at assisted IFN application hubs in compliance with the country's public health system rules. They received subcutaneous PEG-IFN alpha-2b, 1.5 μg, once weekly, associated with RBV, through the oral route, with doses determined according to weight (1,000 mg if weight ≤ 75 kg and 1,250 mg if > 75 kg). Patients with genotype 1 HCV were retreated for over 48 weeks and patients with genotype 3 HCV for over 24 weeks. HCV-RNA was tested by polymerase chain reaction (PCR) at baseline, at week 12, at the end of the treatment, and 6 months thereafter. The predictiveness of week 12 in the development of a sustained virologic response (SVR) was also evaluated. Patients with negative HCV-RNA at week 12 were considered as early virologic responders (EVR).Results

EVR was observed in 25% of the patients with genotype 1 HCV and in 64% of the patients genotype 3 HCV (risk = 2.075 and p-value = 0.0414). SVR was observed in 22.2% of the patients with genotype 1 HCV and in 40% with genotype 3 HCV (intention-to-treat analysis). The positive predictive value (PPV) of the HCV-RNA testing at week 12, in order to obtain the SVR, was 65% for genotype 1 and 56% for genotype 3, and the negative predictive value (NPV) was 88% for genotype 1 and 89% for genotype 3.Conclusions

PEG-IFN alpha-2b plus weight-based ribavirin is effective in re-treating previous interferon-α plus RBV failure; 22.2% of the patients with genotype 1 HCV and 40% of patients with genotype 3 HCV achieved SVR.
 
Background
 
Initially the treatment of chronic hepatitis C (CHC) was carried out with the combination of conventional alpha-interferon (IFN-α) plus ribavirin (RBV) over 24-48 weeks according to the genotype. Progressively, IFN-α was replaced by pegylated interferon (PEG-IFN), because this was the most efficacy regime [1-3]. The primary objective of the treatment is to achieve undetectable HCV-RNA with the polymerase chain reaction (PCR). During therapy, this assay allows testing for the early virologic response (EVR) at week 12, the end of treatment virologic response (ETVR) and the sustained virologic response (SVR) at 24 weeks after therapy suspension. In large international multicentric studies, treatment-naive patients receiving PEG-IFN plus RBV showed 54-63% of SVR when considering all viral genotypes [1-3]. The treatment-naive patients infected by genotype 1 showed lower SVR rates (42-46%), as compared with those infected by genotypes 2 and 3 (76-82%). Some authors who re-treated patients without SVR with combined treatment of IFN-α plus RBV reported that it was better to retreat relapsing patients than non-responders to the previous treatment [4-9]. Authors also observed that patients who were non-responders to monotherapy or combined therapy of IFN-α plus RBV respond better than non-responders to PEG-IFN plus RBV [5,8,10].In Brazil, the public health system (SUS) provides free drugs for the treatment of hepatitis C virus chronic patients, in compliance with a specific Ministry of Health protocol. This protocol determines that PEG-IFN is administered weekly at reference centers called "application hubs" which are outpatient departments. Under this system it is estimated that the patients fully comply with the treatment.The primary objective of this study was to evaluate the efficacy of retreating Brazilian patients with CHC, genotypes 1 or 3, with PEG-IFN α-2b associated with RBV at a public health system university hospital. These patients were non-responders to previous conventional treatment. The secondary objective was to evaluate the early virologic response (EVR), characterized by the negativation of HCV on week 12 and its SVR predictive value.
 
Methods
 
This was a retrospective study carried out by the Hepatitis Study Group from the Medical Sciences School at the State University of Campinas (GEHEP). In the period 2005-2007, a total of 238 HCV non-responder patients to previous treatment with interferon plus ribavirin were considered for retreatment with PEG-IFN plus RBV. Of this total, 172 had been treated at our institution of which 152 agreed to receive retreatment with PEG-IFN plus RBV. Of these, 130 met the inclusion criteria and were retreated, in compliance with the rules created by the State of São Paulo Health Secretary and the Brazilian Ministry of Health, which provided the medication. This study was approved by our Ethical Committee. The evaluation included male and female patients, over 18, chronically infected by hepatitis C virus (HCV) genotypes 1 or 3, who were non-responders to the previous treatment with IFN-α plus RBV. Data were collected on age, sex, ethnic group, alcohol abuse and the possible infection route. Patients were considered as potentially contaminated through the parenteral route when they reported receiving transfusions, injections with non-disposable syringes or needles, or sharing materials used for manicures, acupuncture or application of tattoos given in less than optimal conditions. Patients were considered as intravenous drug users (IVDU) when reporting the use of illegal drugs or stimulants (Glucoenergan®) through the intravenous route, in groups, and sharing syringes or needles.
 
At baseline, all patients showed positive serum test for HCV-RNA by polymerase chain reaction (PCR-Cobas Amplicor® HCV Test - Roche Molecular Systems Inc.). All patients were negative for HBsAg and anti-HIV.
 
The previous treatment for HCV was carried out with IFN-α 2a or 2b (3,000,000 UI, subcutaneous, three times a week) plus RBV (administered through oral route, twice a day, weight-based dose: 1,000 mg/day for patients under 75 kg and 1,250 mg/day for those weighing over 75 kg. In Brazil this drug is provided free by the Ministry of Health in capsules of 250 mg. All patients were treated at outpatients departments. Patients with genotype 1 had been treated for over 48 weeks and those with genotype 3 were treated for over 24 weeks. Therapy was discontinued for all patients infected with genotype 1 who had positive HCV-RNA (PCR qualitative, PCR Amplicor HCV test - Roche molecular systems) at week 24. So, only non-responder patients (positive HCV-RNA at week 24) were screened for this study. Patients relapsing or who had a breakthrough in the first treatment were excluded. We included in our sample only patients who had attended every clinical evaluation of the first treatment, who had received all the drugs from the hospital pharmacy and had done all the biochemical and molecular tests requested.
 
Before starting the retreatment, all patients had hemoglobin > 10 g/dL, neutrophils > 1,500 cells/mm3, platelet > 70,000/mm3, albumin > 3.5 mg/dL and INR < 1.2. The bilirubin and creatinine levels were within normal values. All patients had a liver biopsy performed no more than 18 months before the start of the study, and the diagnosis was consistent with HCV. The inflammatory activity and the fibrosis grade were evaluated by the Metavir score. Patients were considered as carriers of non significant fibrosis when classified as F0, F1 and F2. Patients with F3 and F4 were considered as significant fibrosis carriers. Patients on hemodialysis, and heavy drug and alcohol users unable to comply with the treatment, were excluded. Other patients excluded had auto-immune, degenerative, renal and hematological diseases, or had other liver metabolic diseases, or those who had hypersensitivity reaction or other contraindications to the PEG-IFN plus RBV combination.
 
All patients were retreated with PEG-IFN α-2b associated with RBV. PEG-IFN α-2b was administered through the subcutaneous route, with a once weekly dose of 1.5 μg. All doses were administered at reference centers called "application hubs" which are outpatient departments. The 250 mg tablets of RBV were administered through the oral route, twice a day, with the dose varying according to the weight: 1,000 mg/day if the weight was less than 75 kilos and 1,250 mg/day if the weight was over 75 kilos. The retreatment period for genotype 1 was 48 weeks, while for genotype 3 it was 24 weeks.
 
Clinical and biochemical evaluations were performed before starting the treatment and then monthly throughout the treatment (hemogram, AST, ALT, gama-GT, TSH and free T4 dosing) in order to evaluate adverse events, tolerance and efficacy. The AST, ALT and gamma-GT levels were expressed in quotients (qALT, qAST, qGama-GT). Thus, for example, the qALT was obtained by dividing the serum ALT value by the method's highest normal value. Those with qALT > 1 had increased ALT. In the case of patients having severe adverse events or biochemical abnormalities the dose of ribavirin or PEG-IFN α-2b was reduced. In patients with hemoglobin levels lower than 8.5 mg/dL, ribavirin was suspended and when the hemoglobin levels varied between 8.5 and 10 mg/dL, the dose was reduced to half of the initial. The reduction of PEG-IFN α-2b to two-thirds of the initial dose occurred when the platelet count was lower than 30,000/mm3 or when the granulocyte count was lower than 750 cells/mm3.
 
The HCV-RNA was detected by PCR at weeks 12, 24 and 48 for patients infected by genotype 1 and at weeks 12 and 24 for patients infected by genotype 3. The EVR was tested at week 12 by qualitative HCV-RNA (PCR- Cobas Amplicor® HCV Test version 2.0-Roche Molecular Systems Inc.) in 104 patients, 78 (75%) with genotype 1 and 26 (25%) with genotype 3. Patients with negative PCR on this occasion were considered as complete early virologic responders (EVR). The end-of-treatment virologic response (ETVR) was tested at week 24 (genotype 3) or week 48 (genotype 1) by the same qualitative HCV-RNA test. The SVR was evaluated by a HCV-RNA test at 24 weeks after the end of the treatment.
 
The patients' descriptive data analysis was presented in tables for categorical variables. In order to identify risk factors for the treatment responses, uni - and multivariate Cox regression analyses were used. The adopted significance level was 5%. The computer program SAS, System for Windows (Statistical Analysis System), and version 9.1.3 Service Pack 3, SAS Institute Inc, 2002-2003, Cary, NC, USA was used.
 
Results
 
The evaluation included 130 patients with chronic hepatitis C who were non-responders to previous treatment with IFN plus RBV, carried out at our outpatient departments. The main demographic, epidemiological and biochemical data of the 130 patients are presented in Table 1. Most of the patients were males (72%) and white (90%), and the median age was 48. Around 33% of the patients acquired the infection through the parenteral route, 21% were IVDU and in 40% of the cases the acquisition route of HCV was unknown. Alcohol abuse was present in 17% of the studied population. Of the 130 patients, 90 (70%) were infected by genotype 1 and 40 (30%) were infected by genotype 3. Only 1 (0.8%) of the infected patients showed no fibrosis according to the Metavir score (F0); 19 (14.6%) were F1, 58 (44.6%) were F2, 38 (29.2%) were F3, and 14 (10.8%) were F4. The groups, analyzed according to the genotypes, showed similar characteristics, demonstrating that no considerable bias occurred during the data statistical analysis. A small difference, however, was observed in the presence of significant fibrosis (F3 plus F4) in genotype 3 (45% of the patients against 37.8% of genotype 1). Most patients (56%) did not need a reduction in their PEG-IFN or RBV doses.
 
Table 1
Characteristics of the patient's population according to the genotypes (N = 130)

Eleven out of 130 (8.5%) patients did not conclude the treatment due to side effects resulting from the drugs administered. These 11 patients were infected by HCV genotype 1.Of the 90 patients with genotype 1, 79 (87.7%) performed HCV-RNA testing (PCR) at week 12, while 25 (63%) of 40 patients infected by genotype 3 were also tested in the same week. All of them completed the treatment period and were tested for the presence of HCV-RNA six months after the end of the therapy to estimate the SVR rates. A higher percentage of patients with genotype 3 reached EVR (64%), when compared to genotype 1 (25%) (Figure ​(Figure1).There1).There were no significant differences in the EVR of patients infected by genotypes 1 or 3, when they were analyzed according to sex, race, mean age, alcohol abuse, and the kind of exposure or enzyme alterations of AST, ALT and gamma-GT (Table 2). In both patient groups there were no statistical differences in regard to higher or lower EVR percentages associated with the liver fibrosis grade.

Figure 1
Early virologic response (EVR) and sustained virologic response (SVR) in patients retreated with PEG-IFN alpha 2b plus RBV according to the HCV genotypes (n = 104).

Table 2
Early virologic (EVR) and sustained virologic response (SRV) according to the genotype and population characteristics.

By intention-to-treat (ITT) analysis the SVR was lower in patients with genotype 1(20/90,22.2%) when compared to 40% (16/40) of SVR in patients infected by genotype 3. By per protocol analysis (PPA) the SVR also was lower in patients infected by genotype 3 (20/79, 25.3%) compared to 40% (16/40) of SVR in patients infected by genotype 3. Figure ​Figure11 shows the results of the HCV-RNA testing at week 12 (EVR) in the 104 patients who performed this test and at 24 weeks after the end of the treatment. There was a statistically significant correlation for both genotypes concerning the absence of EVR and the absence of SVR (NPV = Negative Predictive Value). The positive predictive value (PPV) was 65% (13/20) for genotype 1 and 56% (9/16) for genotype 3 and the negative predictive value (NPV) was 88% (52/59) and 89% (8/9), respectively. It is important to note that 7 patients with genotype 1 and only 1 with genotype 3 reached SVR, despite presenting no EVR. In an unvaried Cox regression analysis, the sole risk factor for not obtaining EVR was the presence of infection by the genotype 1, with a risk of 2.075 (CI 95% [1.029; 4.183]) and p value below 5% (0.0414). Regarding the reduction of medication dosage, there was no statistically significant change in the SVR, with the reduction of peg-interferon or ribavirin or both. Additionally, no relation was found between the fibrosis grade and lower response to the treatment. The body mass index (BMI) was also related to EVR and SVR for each genotype, with no statistical differences between the groups.

We observed that all patients with significant fibrosis and infection by genotype 1 who had drug dose reduction did not achieve sustained virologic response, in contrast to those infected by genotype 3. When analyzing patients with non-significant fibrosis (F0, F1 and F2) who had reduced drug doses, no difference was observed in the sustained virologic response between genotypes 1 and 3. Patients with genotype 3 and non-significant fibrosis had a worse response to dose reduction than those with F3 and F4 stages.

Discussion

Overall, our population of non-responders is similar to those of other studies and to the standard population of patients infected by HCV in our country. There was homogeneity regarding demographic, epidemiologic and biochemical characteristics among patients infected by genotypes 1 and 3, except for those who had significant fibrosis (grades 3 and 4 on the Metavir fibrosis score), whose percentage was proportionally higher for genotype 3 than genotype 1 (45% versus 37,8%).This was also seen in other Brazilian studies [4,7]. We observed a higher percentage of IVDU among those infected by genotype 3 (32%) and a higher percentage of cirrhosis carriers (20%), which could reduce the SVR rates.

It is known that patients who have relapses after the standard IFN treatment, whether combined or not with RBV, respond better to the retreatment with PEG-IFN plus RBV than those not responding to the same regimes. Krawitt et al. observed 55% of SVR in 66 relapsing patients when retreated with PEG-IFN alpha 2b (100-150 μg/week) plus RBV (1,000 mg/day) against 20% of SVR in 116 previous non-responder patients treated with the same regime [6]. They also observed SVR in 53% of the relapsing patients infected by genotype 1 and in 59% of the relapsing patients infected by genotypes 2/3. Therefore, there was no significant difference in this group of patients. This was not observed among the previous non-responders when retreated. Of these, only 17% of patients infected by genotype 1 presented SVR, as compared to 57% of the infected by the genotypes 2/3. Therefore, genotype influenced the SVR in previous non-responders. Multicentric studies, sponsored by pharmaceutical companies and conducted in Brazil by Parise et al. with PEG-IFN alpha-2a plus RBV [4] and by Gonçales Jr et al., with PEG-IFN alpha-2b plus RBV [7], in patients who were non-responders to IFN/RBV, found higher SVR percentages (24-38%) when compared to the international studies. Sherman et al. found a SVR percentage of 23% among the non-responders against a SVR of 41% among relapsing patients after retreatment with PEG-IFN alpha-2a and ribavirin [9]. In the present study, with real life patients treated outside clinical trials, we found by intention-to-treat (ITT) analysis 22.2% (20/90) of SVR in the patients infected by genotype 1 and 40% of SVR among the infected by genotype 3. By per protocol analysis the SVR also was lower in patients infected by genotype 3 (20/79, 25.3%) compared to 40% (16/40) of SVR in patients infected by genotype 3. Because patients in this study received all injections of PEG-IFN at a specialized center we should expect better rates of SVR than those treated in their homes. Again, the Brazilian patients who were non-responders to previous treatment with IFN plus RBV, when retreated, obtained good SVR rates, particularly those infected by the HCV genotype 1. The lower SVR rate observed in our Brazilian patients, infected by genotype 3, when compared to that observed by Krawitt et al. (57%) may be associated with the type of patient included by us, as 45% of them showed significant fibrosis. Additionally, Krawitt et al., in contrast to the present study, did not include non-responders to the IFN monotherapy in their retreatment group.

Two large international studies, HALT-C and EPIC3, that retreated with PEG-IFN α-2a/α-2b plus RBV HCV patients who were non-responders or relapsers to previous treatment with interferon plus RBV, obtained 18% of SVR for non-responders [5,8] and 43% of SVR for relapsers [8]. The retreatment results for EPIC3 were better in relapsers than in non-responders and, mainly, in those who received IFN plus RBV previously as compared to those who received PEG-IFN plus RBV. In EPIC3, the early virologic response (week 12) was an important predictor of SVR, as 56% of the patients with undetectable HCV-RNA obtained SVR, while no individual with decrease ≤ 2log10 in the serum HCV-RNA had SVR. Patients who had a decrease of at least 2 log10 in the viral load obtained SVR of 12%. In our study, 65% of the patients with HCV-genotype 1, with EVR, had SVR. Of the patients infected by HCV-genotype 3, 56% had SVR. It is important to note the poor liver profile of these patients (45% presented F3/F4). The negative predictive value was 88-89% showing the usefulness of carrying out the HCV-RNA testing at week 12 in the retreatment cases. With regard to week 4, there are no clear predictiveness rules for patients on retreatment. Regarding the dose reduction of medications throughout the treatment, variations were observed in the SVR obtained for each genotype. The lower SVR percentage (17%) was found in the patients who had their PEG-IFN doses reduced. It is important to point out, however, that the total sample encompassed only 17 patients who had this medication reduced. In the multivariate analysis, there was no statistically significant difference in the SVR observed among patients with or without the reduction of medications, regardless of whether ribavirin or PEG-IFN was reduced. It is probable that if the sample were more powerful it would be possible to obtain a more reliable value for the outcome of reducing pegylated interferon doses during the treatment. Recent studies have shown that the fibrosis grade is one of the primary predictors of worse therapeutic response [5,8]. When comparing the liver fibrosis grade with the SVR rate we did not find statistically significant differences between the groups of patients. In the initial stages of liver fibrosis, as evaluated by the METAVIR score (F0, F1, F2), 24% of the patients with genotype 1 obtained SVR against 25% with genotype 3, which was not significant. In advanced grades of fibrosis (F3, F4), 30% of SVR was observed in the group infected by HCV-genotype 1 against 35% in the group infected by HCV-genotype 3. In fact, in our study, the fibrosis grade itself did not appear to affect the SVR. Perhaps this may be due to a relatively small sample size of advanced fibrotics enrolled. However, when analyzing the reduction of doses of drugs, it was observed that none of the patients infected with HCV genotype 1 who had significant fibrosis and reduction of drug had a sustained virological response. In EPIC3, SVR predictors included: infection by genotypes 2/3, presence of fibrosis F2/F3, viral load ≤ 600,000 UI/ml, previous treatment with IFN monotherapy and patients relapsing after the first treatment [8]. The results of our study confirmed that the response percentage was good for Brazilian patients infected by HCV who were non-responders to the previous treatment with IFN plus RBV when retreated in real life with PEG-IFN plus RBV.

Conclusions

Our patients, retreated at assisted interferon application hubs, had good virologic response rates. In the present study, intention-to-treat (ITT) analysis showed an SVR of 22.2% (20/90) in those patients infected by genotype 1 and 40% (16/40) among those infected by genotype 3.By per-protocol-analysis the SVR was also lower in patients infected by genotype 1 (20/79, 25.3%) compared to 40% (16/40) of SVR in patients infected by genotype 3.

Competing interests

The authors declare that they have no competing interests.

Authors' contributions

FLGJ participated in the design of the study, performed the statistical analysis, conceived the study, and made substantial contributions to acquisition, analysis, and interpretation. CAM, AGV, ESLG, MHP made substantial contributions to acquisition, analysis, and interpretation of data. AF performed liver biopsies and participated in the design of the study. NSLG coordinated the laboratory analyses carried out the molecular genetic studies and drafted the manuscript. All authors read and approved the final manuscript.

Pre-publication history

The pre-publication history for this paper can be accessed here:
http://www.biomedcentral.com/1471-2334/10/212/prepub

Acknowledgements

The authors would like to thank Stephen Shaw for the English review of the manuscript. Project partially sponsored by a scientific initiation scholarship PIBIC/CNPq.

References

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3. Hadziyannis SJ, Sette H, Morgan TR. Peginterferon alfa-2a (40 kilodaltons) and ribavirin combination therapy in chronic hepatitis C: randomized study of the effect of treatment duration and ribavirin dose. Ann Intern Med. 2004;140:346–355.

4. Parise E, Cheinquer H, Crespo D, Meirelles A, Martinelli A, Sette H, Gallizi J, Silva R, Lacet C, Correa E, Cotrim H, Fonseca J, Paraná R, Spinelli V, Amorim W, Tatsch F, Pessoa M. Brazilian Pegasys Cooperative Study Group. Peginterferon alfa- 2 a(40 KD) (PEGASYS®) plus Ribavirin (COPEGUS®) in retreatment of chronic hepatitis C patients nonresponders and relapsers to previous conventional interferon plus ribavirin therapy. Braz J Infect Dis. 2006;10:11–16.

5. Shiffman ML, Di Bisceglie AM, Lindsay KL, Morishima C, Wright EC, Everson GT, Lok AS, Morgan TR, Bonkovsky HL, Lee WM, Dienstag JL, Ghany MG, Goodman ZD, Everhart JE. The Halt-C Trial Group. Peginterferon alfa-2a and ribavirin in patients with chronic hepatitis C who have failed prior treatment. Gastroenterology. 2004;126:1015–1023. doi: 10.1053/j.gastro.2004.01.014.

6. Krawitt EL, Ashikaga T, Gordon SR, Ashikaga T, Gordon SR, Ferrentino N, Ray MA, Lidofsky SD. New York New England Study Team. Peginterferon alpha-2b and ribavirin for treatment-refractory chronic hepatitis C. J Hepatol. 2005;43:243–9. doi: 10.1016/j.jhep.2005.03.015.

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HIV/AIDS Update -Tentative approval of lamivudine and stavudine Fixed Dose Combination tablets

I received this in my email today from the FDA....

You are receiving this message as a subscriber to the FDA HIV/AIDS electronic list serve. The purpose of the list serve is to relay important information about HIV/AIDS-related products and issues, including product approvals, significant labeling changes, safety warnings, notices of upcoming public meetings and alerts to proposed regulatory guidances for comment.

Please do not reply to this message.

On August 5, 2010, the Food and Drug Administration (FDA) granted tentative approval for lamivudine and stavudine Fixed Dose Combination tablets, 150mg/30mg, indicated in combination with other antiretrovirals for the treatment of HIV-1 infection. This new Fixed Dose Combination is manufactured by Macleods Pharmaceuticals Limited of Daman, India.

FDA's tentative approval means that although a product meets all of the safety, efficacy, and manufacturing quality standards required for marketing in the U.S., existing patents and/or proprietary issues currently prevent marketing of the product in the United States. Tentative approval, however, does qualify the product for consideration for purchase under the President's Emergency Plan for AIDS Relief, or PEPFAR program.

As with all generic applications, FDA conducts an on-site inspection of the manufacturing facilities and of the facilities performing the bioequivalence studies prior to granting approval or tentative approval to evaluate the ability of the manufacturer to produce a quality product and to assess the quality of the bioequivalence data supporting the application.

This Fixed Dose Combination product was reviewed for PEPFAR under the FDA guidance titled Fixed Dose Combinations, Co-Packaged Drug Products, and Single-Entity Versions of Previously approved Antiretrovirals for the Treatment of HIV developed to clarify what regulatory requirements apply to such applications, what issues might be of concern, and how these issues should be addressed. The guidance is intended to encourage sponsors to submit applications for combination and co-packaged products, and to facilitate submission of such applications to FDA.

A complete list of all Approved and Tentatively Approved Antiretrovirals in Association with the President's Emergency Plan is available on the FDA web site..

Richard Klein
Office of Special Health Issues
Food and Drug Administration

Kimberly Struble
Division of Antiviral Drug Products
Food and Drug Administration

INTERVIEW-Ignoring Hep C in Thai HIV-positive drug users helps HIV spread

06 Aug 2010 09:06:00 GMT
Written by: Thin Lei Win

BANGKOK (AlertNet) - Thailand's failure to treat the Hepatitis C virus in HIV-positive injecting drug users means that the human immunodeficiency virus remains highly infectious in this group and is more likely to spread to other people, an activist said.

There are roughly between 30,000 and 60,000 injecting drug users in Thailand living with either HIV or AIDS caused by the virus, said Karyn Kaplan who heads Thai AIDS Treatment Action Group.

About 90 percent of such drug users in Thailand also carry the Hepatitis C virus because both viruses are blood-borne and can be transmitted through shared needles and other equipment, even cotton swabs.

The Hepatitis C virus can be cured but if untreated, it develops into a potentially deadly liver disease. At that point anti-retroviral therapy for HIV, which also significantly reduces its infectiousness, stops working, Kaplan said.

"So IDUs (injecting drug users) will continue to be infectious, which is of importance from a national perspective in that (the government) will not be able to control HIV in this population," she told AlertNet.

Thailand's public health service does not cover treatment for the Hepatitis C virus and few people can pay for the costly therapy at a private clinic, according to a recent report by Kaplan's organisation.

Moreover, many Thai doctors would refuse treatment to former or current injecting drug users because they think these patients cannot adhere to treatment regimens, the report said.

Kaplan added that there is a widely held view in Thailand that "this population, their health and lives are less important than other populations or not important at all" even in spite of their role in the spread of HIV.

To limit the spread of the Hepatitis C virus, Thai AIDS Treatment Action Group is calling for several changes in Thailand's health policies.

"The best way to prevent a blood-borne disease in an IDU is to provide them with the tool that they need, which is a clean needle. The government still does not endorse access to clean injecting equipment for people who use drugs," Kaplan said.

The group's other recommendations include the universal provision of free testing and treatment for the virus.

Thailand has been widely praised for its work in containing HIV. The number of new infections fell to 18,000 in 2005 from a peak of around 140,000 a year in 1991, according to UNAIDS. This was achieved mainly because men used condoms more and visited brothels less.

(Additional reporting by Olesya Dmitracova in London)

Reuters AlertNet is not responsible for the content of external websites.

Source

Tattooing linked to higher risk of hepatitis C: UBC study

Public release date: 6-Aug-2010
Contact: Brian Lin
brian.lin@ubc.ca
604-822-2234
University of British Columbia

HAART helps prevent HIV transmission among individuals, reducing HIV diagnoses in the community

Youth, prison inmates and individuals with multiple tattoos that cover large parts of their bodies are at higher risk of contracting hepatitis C and other blood-borne diseases, according to a University of British Columbia study.

The researchers reviewed and analysed 124 studies from 30 countries, including Canada, Iran, Italy, Brazil and the United States, and found the incidence of hepatitis C after tattooing is directly linked with the number of tattoos an individual receives. The findings are published in the current issue of the International Journal of Infectious Diseases.

Tattoos have become increasingly popular in recent years. In the U.S., an estimated 36 per cent of people under 30 have tattoos. In Canada, approximately eight per cent of high school students have at least one tattoo and 21 per cent of those who don't have one want one. During tattooing, the skin is punctured 80 to 150 times a second in order to inject color pigments.

"Since tattoo instruments come in contact with blood and bodily fluids, infections may be transmitted if instruments are used on more than one person without being sterilized or without proper hygiene techniques," says lead author Dr. Siavash Jafari, a Community Medicine Resident in the UBC School of Population and Public Health (SPPH).

"Furthermore, tattoo dyes are not kept in sterile containers and may play a carrier role in transmitting infections," says Jafari. "Clients and the general public need to be educated on the risks associated with tattooing, and tattoo artists need to discuss harms with clients."

Other risks of tattooing identified by the study include allergic reactions, HIV, hepatitis B, bacterial or fungal infections, and other risks associated with tattoo removal.

The researchers are calling for infection-control guidelines for tattoo artists and clients, and enforcement of these guidelines through inspections, reporting of adverse events and record-keeping. They also recommend prevention programs that focus on youth – the population who are most likely to get tattoos – and prisoners – who face a higher prevalence of hepatitis C – to lower the spread of hepatitis infection. In Canada, 12 to 25 per cent of hepatitis C infections among prisoners are associated with tattooed individuals, compared to six per cent of the general population.

The chemical ingredients in tattoo dyes can include house paint, ink from computer printers, or industrial carbon. Toxic contents of some tattoo inks may be entering the kidney, lungs and lympth nodes through the circulatory system. The study also revealed a new trend among youth to get tattooed with glow-in-the-dark ink, the risks of which are not yet known.

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Co-authors of the study include Assoc. Prof. Jane Buxton from SPPH and the BC Centre for Disease Control; Mahyar Etminan, a scientist with the Centre for Clinical Epidemiology and Evaluation at Vancouver General Hospital and the Vancouver Coastal Health Research Institute; Dr. Ray Copes, clinical professor at SPPH and Dr. Souzan Baharlou with the Department of Urology at BC Children's Hospital.

BC Children's Hospital, an agency of the Provincial Health Services Authority, provides expert care for the province's most seriously ill or injured children, including newborns and adolescents. BC Children's is an academic health centre affiliated with the University of British Columbia, Simon Fraser University, and the Child & Family Research Institute. For more information, please visit http://www.bcchildrens.ca/.

BC Centre for Disease Control (BCCDC) is an agency of the Provincial Health Services Authority that provides provincial and national leadership in public health through surveillance, detection, treatment, prevention and consultation services. The Centre provides both direct diagnostic and treatment services for people with diseases of public health importance and analytical and policy support to all levels of government and health authorities. BCCDC investigates and evaluates the occurrence of communicable diseases in BC and is the provincial reporting centre for reportable cases and categories of communicable diseases. In addition, the Centre creates opportunities for scientists, health professionals, university and other partners to contribute their knowledge and experience in resolving the outstanding health challenges facing British Columbians.

The UBC Faculty of Medicine provides innovative education programs in health and life sciences, teaching over 3,000 students at the undergraduate, graduate and postgraduate levels. In addition, over 700 researchers/faculty members representing all of the Faculty's 19 departments, two schools and 15 research centres and institutes received research grants. In 2008/09 the Faculty generated more than one-half of the total research funding of the university ($475.3M). For more information visit http://www.med.ubc.ca/.

The School of Population and Public Health became UBC's newest school in 2008, housed within the Faculty of Medicine. The school's main teaching focus is graduate education in areas ranging from public health to health policy. The school's research and teaching examines local, national and global health challenges and spans seven themes. For more information, visit http://www.spph.ubc.ca/.

Vancouver Coastal Health Research Institute is the research body of Vancouver Coastal Health, which includes BC's largest academic and teaching health sciences centres: Vancouver General Hospital, UBC Hospital, and GF Strong Rehabilitation Centre. The institute is academically affiliated with UBC Faculty of Medicine, and is one of Canada's top funded research centres, with $102 million in total research funding for 2008/2009. http://www.vchri.ca/.

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Experts recommend more Hepatitis C testing

Updated: 2010-08-05 20:21:34 CST

Despite advancements in treatment options for hepatitis C, many experts say that expanding the availability of testing for the disease will play a critical role in lowering the rates of infection in the coming years.

Several drug companies have recently made breakthroughs testing new drugs that may control Hepatitis C infections to a greater extent. Some even believe a cure for the chronic disease is on the horizon.

This has led some to suggest that funding for programs aimed at making hepatitis C testing more available could be better used to pay for the new drugs. However, Andrew Muir, the director of gastroenterology and hepatology research at Duke University, says that this is the wrong path to take.

"This approach is wrong and contrary to the direction in which we should and must move our healthcare system," he said. "Our healthcare system misses most infected individuals, who only learn that they have hepatitis C once they have progressed to liver cancer, cirrhosis, or liver failure. At that juncture, treatment options are limited and success rates are lower."

He said that providing more Hepatitis C testing could work in concert with new drugs to identify infected individuals and help treat them more effectively.

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Older adults get HIV diagnosis later, die sooner

By Frederik Joelving

NEW YORK
Fri Aug 6, 2010 8:28am IST

NEW YORK (Reuters Health) - People over 50 with HIV are more likely to be diagnosed with late-stage disease than younger adults, according to a British study.

They are also more than twice as likely to die within a year of their HIV test as are younger people, even if they are diagnosed late.

"We have a group of people who don't get tested because they don't think they are at risk," said Dr. Valerie Delpech, of the U.K. Health Protection Agency Center for Infections in London, who worked on the study.

She said the number of HIV-infected Britons has tripled over the past decade, reaching more than 55,000 in 2007. While older adults account for only about one in six of these cases, the number of new diagnoses is growing faster among those aged 50 and older.

"The numbers are still small," said Delpech, whose findings appear in the journal AIDS; she estimated fewer than one in 1,000 Britons were infected with HIV. But "everyone can be at risk, and we need to think about that," Delpech said.

From 2000 to 2007, the number of newly diagnosed people over 50 jumped from 299 to 710. Compared with their younger peers, older people with HIV were more likely to be gay, white men.

"It wasn't all gay men," Delpech stressed. "In fact, there were a large proportion of heterosexual men and women."

Almost half of them were diagnosed at advanced stages of the disease. Fourteen percent of these people had died a year later, compared to only one percent of those tested promptly.

"What this means is that screening is particularly important in people over 50," said Dr. Anupam B. Jena of Massachusetts General Hospital in Boston, who was not involved in the study.

"The take home point from this paper is that it always makes sense to be screening younger people for HIV, but that maybe the balance should shift a little bit toward older people," he said.

In an earlier study of sexually transmitted diseases, Jena found that 60-year-old men taking the erectile dysfunction drug Viagra had twice the rate of STDs of their non-medicated peers. (See Reuters Health story of July 6, 2010.)

While the reasons were unclear, he said more divorces and better health might have conspired to boost sexual prowess and activity among graying heads.

He said the new study made it clear for the first time that the growing number of HIV-positive seniors wasn't just due to people living longer with newer, more effective medicines. In fact, the researchers were able to show that about half of those diagnosed after their 50th birthday had also been infected at age 50 or older.

Delpech said everybody should consider getting tested if they are gay, have been abroad and had sex with locals, or have started a new relationship. If diagnosed promptly at age 30, she said people could easily live to 75 at this point.

"It's not all bad news," she added. "If you are diagnosed early there are highly effective medicines."

SOURCE: link.reuters.com/ger53n AIDS, online July 7, 2010.

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Serum visfatin was correlated with disease severity and metabolic syndrome in chronic hepatitis C infection

Journal of Gastroenterology and Hepatology
Published Online: 30 Jul 2010
Journal compilation © 2010 Blackwell Publishing Asia Pty Ltd and Journal of Gastroenterology and Hepatology Foundation

Jee-Fu Huang 1-3 ; Chung-Feng Huang 2,3 ; Ming-Lung Yu 3,4 ; Chia-Yen Dai 3,4 ; Ching-I Huang 2,3 ; Ming-Lun Yeh 2,3 ; Meng-Hsuan Hsieh 5 ; Jeng-Fu Yang 6 ; Ming-Yen Hsieh 3 ; Zu-Yau Lin 3,4 ; Shinn-Chern Chen 3,4 ; Wan-Long Chuang 3,4

1 Department of Internal Medicine, Kaohsiung Municipal Hsiao-Kang Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.
2 Graduate Institute of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
3 Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.
4 Faculty of Internal Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
5 Department of Occupational and Environmental Medicine, Kaohsiung Municipal Hsiao-Kang Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.
6 Department of Preventive Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.

Correspondence to Wan-Long Chuang M.D., Ph.D.,
Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, 100 Tzyou Road, Kaohsiung City 807, Taiwan.
Tel: +886-7-3208282
Fax: +886-7-312-3955
Email:jf71218@gmail.com; waloch@cc.kmu.edu.tw

Financial and conflict of interest: none

CONTRIBUTIONS OF AUTHORS:

Conception and design: Jee-Fu Huang, Chia-Yen Dai, Ming-Lung Yu, Wan-Long Chuang, Chung-Feng Huang
Acquisition of data: Jee-Fu Huang, Chia-Yen Dai, Ming-Yen Hsieh, Chung-Feng Huang, Ching-I Huang, Ming-Lun Yeh, Zu-Yau Lin, Shinn-Chern Chen
Data analysis and interpretation: Jee-Fu Huang, Chung-Feng Huang, Chia-Yen Dai, Wan-Long Chuang, Ming-Lung Yu
Manuscript drafting and critical revising: Jee-Fu Huang, Chia-Yen Dai, Ming-Lung Yu, Wan-Long Chuang

This is an Accepted Article that has been peer-reviewed and approved for publication in the Journal of Gastroenterology and Hepatology, but has yet to undergo copy-editing and proof correction. Please cite this article as an "Accepted Article"; doi: 10.1111/j.1440-1746.2010.06438.x

KEYWORDS
hepatitis C virus • visfatin • histological activity index • fibrosis

ABSTRACT

Background & Aim: Cytokines activation is a common feature in chronic hepatitis C (CHC) infection. Visfatin, as a recently-recognized adipocytokine, may correlate with metabolic abnormalities. We aimed to elucidate the characteristics of visfatin in CHC patients.

Methods: This retrospective study included 102 treatment-naïve CHC patients and 97 sex-/age-matched healthy adults. Serum visfatin levels were examined by an ELISA test. The correlation between visfatin and hepatitis C virus (HCV) infection in terms of virological, metabolic, and histopathological profiles was analyzed. The impact of visfatin on the treatment response to pegylated interferon plus ribavirin (PEGIFN/RBV) therapy was also assessed.

Results: The visfatin level was correlated significantly with fibrosis scores (r = 0.23, P = 0.02) in CHC patients. A significant higher visfatin level was observed in CHC patients with histological activity index scores of mild and more (P = 0.01) and advanced fibrosis (P = 0.04). The mean visfatin level (0.81 ± 0.28 log ng/mL) of 26 CHC patients with metabolic syndrome was significantly lower than their counterparts (0.95 ± 0.30 log ng/mL) (P = 0.03). There was no significant correlation between visfatin and HCV genotypes, viral load, and treatment response to PEGIFN/RBV therapy. Multiple logistic regression analyses demonstrated that MS was the leading negative variable (OR = 0.09, 95% CI = 0.02–0.46, P = 0.004) associated with high visfatin level, followed by advanced fibrosis (OR = 2.88, 95% CI = 1.06–6.78, P = 0.03).

Conclusions: Serum visfatin was correlated with disease severity and metabolic syndrome in CHC patients.

Received date: 23-Jan-2010
Accepted date: 8-Jul-2010

DIGITAL OBJECT IDENTIFIER (DOI)
10.1111/j.1440-1746.2010.06438.x About DOI
 
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Scientists Identify Proteins That Ensure Iron Balance

Article Date: 06 Aug 2010 - 0:00 PDT

Most organisms need iron to survive, but too much iron is toxic, and can cause fatal organ failure. The same is true inside cells, where iron balance must also be maintained. In a study published in Cell Metabolism, scientists at the European Molecular Biology Laboratory (EMBL) in Heidelberg, Germany, have discovered that a group of proteins named IRPs ensure that this iron balance is kept and as such are essential for cell survival. More specifically, they found that IRPs are required for the functioning of mitochondria, the cell's energy factories.

Mitochondria need iron in order to function, but they also convert iron into other chemical forms used throughout the cell: iron sulphur clusters and haem - one of the building blocks of haemoglobin. Thanks to new mouse models they engineered, the EMBL scientists have been able to selectively shut down IRP function in specific cell types such as hepatocytes, liver cells that carry out multiple vital metabolic functions.

"Mice whose liver cells can't produce IRPs die of liver failure a few days after birth," says Bruno Galy, Staff Scientist in Matthias Hentze's group at EMBL, who spearheaded the work: "The mitochondria in those cells have structural defects and don't function properly, because they don't have enough iron."

Galy and colleagues found that in cells that cannot produce IRPs, the mechanisms for iron export and storage go into over-drive, while iron import is drastically reduced. This combination of factors leads to an iron shortage in the cell. As a consequence, the mitochondria don't receive enough iron, so they can't function properly, and can't make enough haem and iron sulphur clusters available to the cell machinery that depends on them. In short, the role of IRPs is to ensure that there is enough iron available in the cell to sustain mitochondrial iron needs.

"We have indications that this is probably a general process by which most cells control their iron content and secure mitochondrial iron sufficiency" Hentze concludes.

This mechanism for regulating iron balance could be particularly important in cells with very high mitochondrial iron needs, such as red blood cell precursors that manufacture copious amounts of haem for oxygen transport. However, this may well be a double-edged sword. Indeed, there are situations in which mitochondria get iron but are not able to make use of it. The cell interprets this as a sign of mitochondrial iron insufficiency and responds by activating IRPs, which ultimately results in detrimental iron overloading of mitochondria. This may underlie the pathology of several diseases including inherited sideroblastic anaemias - in which cells are unable to incorporate iron into haemoglobin - or the neurodegenerative disorder Friedreich's ataxia, which the EMBL scientists are currently investigating.

Source:
Lena Raditsch
European Molecular Biology Laboratory

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