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Will you use boceprevir in this patient? How will you determine whether he is responding to the drug, how long will you give him the medication, and how will you monitor him for side effects? How will you determine that treatment-related anemia is related to boceprevir and is not related to ribavirin? Which side effects of boceprevir will warrant the discontinuation of treatment? Will your approach vary with the genotype for the interleukin-28 (IL-28) polymorphism?..Continue Reading..
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Bile Acid Retention and Antiviral Response in Chronic HCV
How do bile acids potentially alter the effectiveness of antiviral drugs in the treatment of hepatitis C?
Journal of Viral Hepatitis, December 2011
Discussion Only
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In hepatitis C-infected patients, sustained response (SVR) to antiviral therapy with PEG-interferon and ribavirin depends on both viral and host characteristics.[4] Besides HCV genotype and baseline viral load as viral factors, several patient-based factors are related to reduced response rates including age, gender, ethnicity, coinfection with human immunodeficiency virus, liver cirrhosis, obesity and alcohol intake.[4] Baseline clinicochemical parameters and viral dynamics during therapy can help to predict the patients probability of response.[5] Previous observations in small and heterogenous HCV populations with different, inferior treatment regimens indicate that accumulation of bile acids, particularly in combination with elevated ferritin levels, may be a negative prognostic marker to predict sustained virus response.[8,9] Recently, in vitro studies demonstrated an activation of HCV replication by bile acids via a FXR-dependent mechanism.[6,7] Consequently, the present study investigated the effects of bile acid levels and a related gene polymorphism in a large and well-defined cohort of hepatitis C patients who were invariably treated with a standard PEG-interferon/ribavirin regimen. This work analysing a combination of two large cohorts presents several new findings: (i) A slight but significant difference in the frequency of the ABCB11 1331CC genotype in patients with CHC compared to healthy subjects may be a hint towards a potential causal role of increased hepatocellular bile acids as a host factor to develop HCV chronicity. (ii) Regarding standard PEG-interferon/ribavirin treatment, bile acid levels >8 μm affect the response to antiviral treatment only in genotype 2/3 patients, whereas elevated GGT levels selectively predict non-SVR in the genotype 1 subgroup. (iii) In contrast to in vitro studies, no effect of bile acid levels on HCV viral load can be observed in vivo.
In previous genetic studies, the common ABCB11 1331T>C polymorphism has been associated with increased susceptibility for cholestatic diseases including ICP and drug-induced cholestasis.[11,12,17,19] Recently, comprehensive analysis of ABCB11 missense mutations and single-nucleotide polymorphisms demonstrated aberrant pre-mRNA splicing and protein processing/function as a cause for significant deficiency of BSEP.[20] Particularly, the ABCB11 1331T>C polymorphism which is encountered in about half of the Caucasian population has been associated with reduced expression levels of the mature BSEP protein.[11,12,17,20] However, in this study, mean bile acid levels in patients with CHC carrying the 1331CC genotype were only marginally elevated. This finding reflects the fact that bile acid retention is mostly caused by the coincidence of acquired factors such as hepatic inflammation in addition to genetic predisposition.
In line with observations from other cohorts,[8,9] patients with CHC experiencing SVR had significantly lower bile acid concentrations than those with non-SVR. Owing to the large number of patients in our study, significant differences in therapy response according to bile acid levels could be detected for a combined HCV genotype 2/3 subgroup and with marginal statistical significance also for genotype 1 patients (Fig. 1). To investigate the discriminatory power of bile acid reference values for the prediction of treatment outcome, bile acid levels were categorized in normal (≤8 μm) vs elevated (>8 μm) with significant differences in SVR for HCV genotype 2 and 3 patients (P = 0.002) and marginal significance for genotype 1 (P = 0.058) (Fig. 2). ROC analysis indicates a fairly good sensitivity and specificity for bile acid levels of >8 μm to predict sustained virus response (AUC = 0.80) in these patients. Multivariate analysis demonstrates a significant increase in SVR for HCV-patients with normal bile acid levels irrespective of the HCV genotype (OR 1.66 for all HCV genotypes; OR 2.54 for HCV-2/3) while an association between SVR and presence of the ABCB11 1331C allele was only detectable in the subgroup of HCV genotype 2 and 3 infected patients (OR 2.94) but not for genotype 1 (Fig. 4; Table 2). The influence of bile acids and the ABCB11 genotype on SVR appears to be independent from the IL28B rs12979860 genotype because the former significantly affects SVR only HCV genotypes 2 and 3 while the latter exclusively influences genotype 1.[22] All results of the combined genotype 2/3 group could be confirmed in a subgroup analysis for HCV genotype 3 patients alone, whereas this analysis was impossible for HCV genotype 2 because of the limited number of nonresponders (n = 4) in this subgroup.
Comparing patients with chronic HCV infection and healthy individuals discloses a slight but still significant difference in the frequency of the ABCB11 1331CC genotype within these groups. This finding fuels the speculation that increased bile acid levels may play a causal role for a susceptibility to develop chronic HCV infection because of an impaired endogenous interferon response during the acute phase of infection. These findings are also in line with an established negative effect of bile acids on interferon signalling and the induction of proteins involved in the antiviral activity in cell culture studies.[26] The assumption that bile acids rather influence the interferon response than the viral replication itself is also supported by the absent correlation of viral RNA load and bile acid levels in this study (Figure S3).
Although differences in response to interferon therapy between HCV genotypes have been described extensively,[1,3,4] only very few data on distinctions with regard to viral biology in vivo exist. The strong association of bile acids with interferon response in patients with HCV genotype 2 and 3 but only weaker in genotype 1 clearly highlights the complexity of host–virus interaction, and obvious differences between HCV genotype 1 and genotype 2/3 biology both warranting more genotype-directed study in the future.
In this context, the fact that elevated GGT has been identified as a predictor for negative therapy outcome only in HCV genotype 1 patients is remarkable, because no such association can be observed for genotype 2 and 3 (Fig. 3). Our data are in line with a recent study identifying low GGT levels as predictor for SVR in patients with HCV genotypes 1, 4 and 6 infection in contrast to those with genotypes 2 and 3[5] and highlight again biological differences within different genotypes. One reason for non-SVR in HCV genotype 1–infected patients with increased GGT levels may consist in the fact that increased serum GGT concentration is associated with nonalcoholic steatosis but interestingly not with cholestasis in patients with CHC.[27] Such a link is further supported by the recent DITTO trial.[21,28] Interestingly, steatosis negatively affected the final outcome of treatment mainly in patients infected with HCV genotype non-3 in this study. From our data, it is attractive to speculate that particularly HCV genotype 3 response is modulated by cholestasis with bile acid retention, whereas HCV genotype 1 response is negatively altered by steatosis and associated conditions such as redox stress.
In summary, we show that bile acids may play a role as a host factor affecting response to antiviral therapy in HCV genotype 2/3, whereas only weak association was found for HCV genotype 1 patients. In contrast to the results of previous in vitro studies, no effect of bile acid levels on viral load could be observed.
(Beijing Time) Xinhua English
HEFEI, Dec. 3 (Xinhua) -- More than 200 villagers, many of them children, have been found infected with hepatitis C virus (HCV) in east and central China over the past two weeks, with the reuse of old needles by a rural clinic suspected as the cause.
From Nov. 17 to Dec. 1, 105 people from the Dancheng township of Woyang county in the eastern province of Anhui tested positive for the disease, a spokesman with the Woyang Health Bureau said Saturday.
But no serious cases have been reported, he said.
Earlier, 104 people in the neighboring Maqiao township of Yongcheng city in central province of Henan had also tested positive for the virus, and six of them had been confirmed as HCV patients.
Investigators are focusing on a doctor at a privately-run village clinic in Maqiao. Wu Wenyi, 60, is suspected of causing the infection by reusing old needles.
Local residents said Wu, a village doctor for four decades, seldom changed needles, and is known as the "miracle doctor" for his ability to alleviate patients' fever and diarrhea through injections and a few tablets.
HCV is mainly transmitted through contact with infected blood. It can also spread through sex, and from mother to baby during delivery. The infection may lead to liver cancer.
Research Yields Insights About HIV-Related Headaches
Newswise — OXFORD, Miss. – A University of Mississippi study of headaches among HIV patients is being hailed as a critical step to improving treatment and reducing unnecessary medical costs among sufferers.
The paper, "Headache among Patients with HIV Disease: Prevalence, Characteristics, and Associations," is being published in a forthcoming issue of the journal Headache and is already available online at http://onlinelibrary.wiley.com/doi/10.1111/j.1526-4610.2011.02025.x/abstract.
The study, which is attracting broad interest in the medical and mental health communities, was conducted as part of a doctoral dissertation by UM psychology alumnus Kale Kirkland while working in the Headache Research and Treatment laboratory under Todd Smitherman, assistant professor of psychology. The study was conducted in conjunction with clinicians from the University of Alabama Health Center in Montgomery.
"This research is of interest to clinicians and physicians for several reasons," Smitherman said. "Recent research from the U.S. Centers for Disease Control and Prevention shows that, despite the availability of medications that effectively slow disease progression, most Americans with HIV do not have the disease under control. Our study shows that patients with poorly-controlled HIV/AIDS are most prone to suffer also from frequent, severe migraines at rates that far exceed those of the general population."
Specifically, the results of the study show that headache affects one of every two HIV/AIDS patients, but these are not your typical, run-of-the-mill tension headaches.
Approximately 27.5 percent of the patients studied met criteria for "chronic migraine," a rare headache condition in which a person has migraine symptoms – with or without other headaches – for 15 or more days per month. In comparison, only 2 percent of the general population is classified as having chronic migraines.
"This translates into a 13-fold increased risk of chronic migraine among patients with HIV disease," Smitherman said. "The strongest predictor of headache was the severity of HIV disease, such that patients with more advanced disease had more frequent, more severe and more disabling migraines."
This is the first study since the proliferation of highly active antiretroviral therapy, or HAART, medication to demonstrate that having HIV/AIDS portends a very high risk of headache, particularly migraines.
These data highlight how important it is for physicians to regularly monitor CD4 levels, an indicator of immune system functioning, among this population and to pay close attention to headache symptoms among patients with more advanced disease. They also emphasize the importance of adherence to medication regimens among HIV patients.
"The study used a structured diagnostic interview to assess headache symptoms consistent with diagnostic criteria from the International Classification of Headache Disorders among 200 clinic patients in Montgomery, Alabama with HIV or AIDS," Smitherman said. "Patients also completed measures of headache-related disability, and their medical records were reviewed for information about prescribed medications, CD4 cell count, date of HIV diagnosis, possible secondary causes of headache and other relevant medical history."
"We decided to conduct this study due to a lack of research in the area of headaches in the HIV population," Kirkland said. "In general, prior to our study, there was no 'typical' HIV headache.
"With the results from our study, we hope that infectious disease physicians will now be able to discuss with HIV patients what to expect in terms of headaches. This should also help prevent unnecessary medical costs, lessening the need to have expensive procedures – such as MRIs and spinal taps – ordered to rule out opportunistic infections."
HIV-related infections were determined not to be frequent causes of headache among patients in the study, but the authors caution that further studies that include neuroimaging procedures are needed to confirm these findings.
Because the study came from a psychological perspective, Smitherman and Kirkland said they hope to further educate mental health professionals on HIV, which should help improve treatment, given that HIV patients also have increased rates of depression and anxiety.
For more information about the UM Department of Psychology, visit http://www.olemiss.edu/depts/psychology/ or call 662-915-7383.
For more news from the University of Mississippi, go to http://zing.olemiss.edu/
Hope for Future, Fear of Failure on World AIDS Day
A curious emotional amalgam marked this year's World AIDS Day.
On one hand, there is increasing confidence that many of the tools needed to halt the devastating pandemic are either available or will soon be ready.
On the other, there is growing fear that the political and financial will to use those tools is failing.
"The science is beginning to tell us we can end the epidemic," said Mitchell Warren of the New York-based advocacy group AVAC. "Things are falling in to place."
But Warren and others told MedPage Today that global economic uncertainty could mean that the opportunity will be missed.
New 'Lite' Approach Could Save More Lives With Less Money
(The Independent, London, December 1, 2011)
"A radical approach to delivering antiretroviral drugs to people with HIV to halt the transmission of the virus is being implemented in...Africa, opening the way to treatment for least one million extra patients at no additional cost. The move...comes at a time when the global economic crisis is threatening progress against the pandemic. The project, known as 'Lab-Lite,' is being run in Uganda, Malawi and Zimbabwe and involves monitoring the roll-out of antiretroviral drugs to rural areas, where two-thirds of the population live, without the array of laboratory testing conventionally regarded as necessary. The [money saved can be used for]...purchasing more drugs and treating more patients…Routine laboratory testing every three or four months had been thought essential to monitor toxicity and side effects in people on antiretroviral drugs. But a study…in 2009, showed routine lab testing made little difference to survival after five years…One of the main barriers to people receiving treatment is that they live too far from the nearest hospital for testing. They often have to trek long distances to get drugs, so many drop out."
FYI
on December 5th, 2011
The new issue of Stanford Medicine magazine, a special report on cancer, explains that while data and insights pour in as never before, the efforts to prevent, treat and cure cancer are faltering. The big threats? A dysfunctional cancer clinical-trial system, disastrous drug shortages and a health-care system unable to deliver cancer care at an affordable price.
By Tan Ee Lyn
HONG KONG Dec 6 (Reuters) - Merck & Co Inc said on Tuesday that it will establish a new Asian R&D headquarters in Beijing and commit $1.5 billion to research and development in China over the next five years.
In an interview with Reuters in late 2010, the company said it expected emerging markets to make up a bigger part of total revenue in coming years because of an explosion in chronic non-communicable diseases such as diabetes and hypertension.
It said seven countries -- Brazil, China, India, Mexico, Russia, South Korea and Turkey -- were especially important.
By the end of 2010, emerging markets were responsible for about 18 percent of overall global business and that figure was estimated to grow to 25 percent by 2013, the company said.
The United States is Merck's largest market, generating between 40 and 45 percent of revenue.
Healthy You
Report: Fish Oil Supplement Quality Spotty
By Michael Smith, North American Correspondent, MedPage Today
Published: December 06, 2011
Fish oil supplements can be a bit fishy in terms of quality, according to Consumer Reports magazine.
In lab tests of 15 major brands, the magazine said, "six fell a bit short on quality."
"In our recent tests, we found that some (supplements) were not as pure as one might think," the magazine's health editor, Ronni Sandroff, said in a statement.
But a spokesman for the Council for Responsible Nutrition, an industry group, said the magazine was putting a "negative spin" on what was really a positive report.
Fish oil supplements are a booming business, largely because of the health benefits associated with eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), omega-3 fatty acids that can reduce the risk of heart attacks and strokes.
Consumer Reports tested three lots each of the 15 brands to see if they contained the amount of EPA and DHA that they claimed and also to check on levels of lead, mercury, dioxins, or polychlorinated biphenyls.
The bottom line, the magazine said, is that "all had their labeled amount of EPA and DHA." As well, none of them had contaminant levels that exceed standards set by the U.S. Pharmacopeia (USP), a nongovernmental agency, or by the European Union.
In other words, the products "meet all of their applicable legal and regulatory requirements," said Duffy MacKay, ND, vice-president for scientific and regulatory affairs for the industry group.
The report is actually a positive assessment of the tested products, MacKay told MedPage Today.
The shortfalls the magazine noted include:
Four of the products had at least one sample with PCB levels that could require a warning label under a California consumer law
One product had "elevated levels of compounds that indicate spoilage"
Two samples of another supplement failed a test for pills with enteric coatings, suggesting the coatings might dissolve more quickly than intended, leaving a fishy aftertaste
Consumer Reports quoted the FDA as saying the agency has not taken action against any manufacturer for contaminants because it doesn't see a health risk.
MacKay said the California law cited by the magazine -- Proposition 65 -- is intended to let consumers know what is in products and has "nothing to do with health-related risk."
He noted that the law is "exclusive to California," where he said none of the tested products has been taken off shelves.
MacKay also said the magazine used a test for spoilage that is intended to detect a compound called anisidine, but used it on products that were lemon-flavored.
The addition of the lemon flavoring causes the test to yield a false positive, he said
Off The Cuff
U.K.: Hospital Patients 'More Likely to Die at Weekends'
(BBC News, November 28, 2011)
"Research company Dr Foster [found a]…10% spike in deaths compared with weekdays across 147 hospital trusts [in the England]. It said some deaths could have been avoided with better staffing and access to services such as diagnostics. The review also looked at performance overall, warning death rates appeared to be higher than they should be in more than a quarter of trusts. Dr Foster, which works closely with the Department of Health, said its findings needed to be investigated urgently. The data…looked at death rates using four measures -- deaths in hospital, deaths in hospital and within 30 days of discharge, deaths linked to low-risk conditions and deaths after surgery…it was acknowledged that some of the deaths were unavoidable as people who were at the end of life were more likely to be admitted to hospital at the weekend. This is because community services which they would have relied on if they had been close to death during the week would not be available…The report concluded weekend treatment was 'risky.'"
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