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Hepatitis C Virus Infection and Increased Risk of Cerebrovascular
Disease - pdf attached
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Download the PDF Here
WHEN TO BEGIN HCV THERAPY: from Jules: don't delay HCV therapy. this is only 1 of numerous diseases people who are HCV-infected can develop, so the notion that HCV therapy can be delayed is increasingly risky, the longer you wait to treat HCV the greater the risk for developing other diseases. Therefore, earlier HCV therapy is crucial to consider, of course there are other considerations in deciding when to begin therapy, and the suggestion not to delay therapy does not mean one has to start immediately but the idea is not to delay therapy too long and this becomes increasingly important with the advent of oral drugs and more potent therapy. Next year we will have the 1st 2 oral HCV protease inhibitors expected to be approved by the FDA, but they will at least for now be used in combination with peginterferon plus ribavirin. Soon we will have other orally administered HCV drugs, within a couple of additional years, and we will have as in HIV multi-drug combination therapy composed of 2 or more oral HCV drugs plus peginterferon/ribavirin. The combination of 2 oral HCV drugs plus peginterferon/ribavirin will certainly increase cure rates a lot more than therapy with only 1 oral HCV drug plus peginterferon/ribavirin, and this becomes more important for patients who have trouble mounting a good response to peginteferon/ribavirin. So for these patients it may serve them better to wait for when they can use a 2 oral drug regimen plus peginterferon/ribavirin or a regimen with 3 or more oral HCV drugs with or without peginterferon/ribaviron. For patients with advanced HCV disease they may not be able to wait for better regimens with 2 or more oral HCV drugs, this is a decision to discuss with a knowledgeable clinician/doctor. But researchers are exploring oral drug combination therapy without peginterferon/ribavirin with 2-4 oral HCV drugs. We will have some answers soon on whether we can eliminate peginterferon and ribavirin from therapy but we don't know yet. At the AASLD annual big USA liver meeting, which starts Friday, we will have new study results from 2 studies examining 2 oral HCV drugs in combination without peginterferon/ribavirin. Still by next year we will not yet have an answer to this question. In any case within a few years there will be many more good options and strategies for HCV treatment underscoring that there is not a good reason to delay therapy for too long.
Hepatitis C Virus Infection and Increased Risk of Cerebrovascular Disease - pdf attached
Stroke Jnl of the American Heart Association, Oct 2010
"In conclusion, HCV infection is associated with an increased risk of cerebrovascular mortality, particularly for those with elevated serum HCV RNA levels.....In our study, the increasing risk of cerebrovascular death across the biological gradient of serum HCV RNA levels was found and this dose-response relationship further supports the causal association......Elevated serum HCV RNA levels were associated with an increasing the risk of cerebrovascular death with a dose-response relationship (P<0.001; Table 4). The multivariate-adjusted HR (95% CI) of cerebrovascular death was 1.40 (0.62 to 3.16), 2.36 (1.42 to 3.93), and 2.82 (1.25 to 6.37), respectively, for anti-HCV-seropositives with undetectable, low, and high serum HCV RNA levels compared with anti-HCV-seronegatives.....Elevated serum HCV RNA level was associated with an increased risk of cerebrovascular death, suggesting that individuals with an active HCV infection may trigger a stronger inflammation response by host-virus interaction leading to atherothrombosis......infectious agents may play as a stimulus for atherothrombosis.7,27,28 Infection affects atherothrombosis by triggering a cascade of immune responses and inflammatory stimuli either locally within vascular tissue or systemically through inflammatory mediators.29 It has been found that HCV infection is associated with an increased risk of cryoglobulinemia,30 which is thought to participate in the formation of immune complexes precipitating in vessel walls then leads to vasculitis.31"
Mei-Hsuan Lee MSc, PhD; Hwai-I Yang PhD; Chih-Hao Wang MD, PhD; Chin-Lan Jen MSc; Shiou-Hwei Yeh PhD; Chun-Jen Liu MD, PhD; San-Lin You PhD; Wei J. Chen MD, ScD; and Chien-Jen Chen ScD*
From the Graduate Institute of Epidemiology (M.-H.L., W.J.C., C.-J.C.), College of Public Health, National Taiwan University, Taipei, Taiwan; the Genomics Research Center (M.-H.L., H.-IY., C.-L.J., S.-L.Y., C.-J.C.), Academia Sinica, Taipei, Taiwan; the Department of Cardiology (C.-H.W.), Cardinal Tien Hospital, College of Medicine, Fu-Jen Catholic University, Taipei, Taiwan; the Department of Microbiology (S.-H.Y.), National Taiwan University, Taipei, Taiwan; and the Department of Internal Medicine (C.-J.L.), National Taiwan University Hospital, Taipei, Taiwan.
Background and Purpose-The association between hepatitis C virus (HCV) infection and cerebrovascular disease remains controversial. This study aimed to assess the risk of lethal cerebrovascular diseases associated with chronic HCV infection.
Methods-In this community-based prospective cohort study, 23 665 residents (aged 30 to 65 years) were enrolled in 1991 to 1992. They were personally interviewed using structured questionnaires and provided blood samples for various serological and biochemical tests at study entry. Serum HCV RNA level and HCV genotype were tested for participants seropositive for antibodies against HCV (anti-HCV). Deaths from cerebrovascular disease during follow-up were ascertained by computerized linkage with National Death Certification profiles from 1991 to 2008 (International Classification of Diseases, 9th Revision 430 to 438). Multivariate-adjusted hazard ratio with 95% CI was estimated for each risk predictor.
Results-There were 255 cerebrovascular deaths during 382 011 person-years of follow-up. The cumulative risk of cerebrovascular deaths was 1.0% and 2.7% for seronegatives and seropositives of anti-HCV, respectively (P<0.001). The hazard ratio (95% CI) of cerebrovascular death was 2.18 (1.50 to 3.16) for anti-HCV seropositives after adjustment for several conventional risk factors of cerebrovascular disease. Compared with participants seronegative for anti-HCV as the referent, the multivariate-adjusted hazard ratio (95% CI) was 1.40 (0.62 to 3.16), 2.36 (1.42 to 3.93), and 2.82 (1.25 to 6.37), respectively, for anti-HCV-seropositive participants with undetectable, low, and high serum levels of HCV RNA (P<0.001 for trend). However, no significant association was observed between HCV genotype and cerebrovascular death.
Conclusions-Chronic HCV infection is an independent risk predictor of cerebrovascular deaths showing a biological gradient of cerebrovascular mortality with increasing serum HCV RNA level.
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There are 170 million people affected with chronic hepa- titis C virus (HCV) infection, which may cause liver cirrhosis and hepatocellular carcinoma, worldwide.1 In addi- tion to hepatic complications, chronic HCV infection has been suggested to cause extrahepatic disorders.2 Antiviral therapy has successfully decreased the rate of fibrosis pro- gression in patients with chronic HCV infection,3 and a large community-based study in Australia found declined standard- ized mortality ratios for liver-related deaths in HCV-infected patients from 1995 to 2002.4
Cerebrovascular disease is the second leading cause of death worldwide. It is becoming a great health burden in most industrialized countries in future decades.5 Conventional risk factors for cerebrovascular disease include cigarette smoking, alcohol consumption, obesity, hyperlip-
6 idemia, hypertension, and diabetes. These risk factors cannot completely explain the occurrence of the disease, and new risk factors including infectious agents have been documented.7,8
Chronic HCV infection has been found to increase the risk of ultrasonographically defined carotid intima-media thickness and/or plaque,9 -11 which are predictors for cerebrovascular disease.12 However, these cross-sectional studies could not verify the causal temporality between HCV infection and cerebrovascular disease. Serum HCV RNA level is a biomarker of active HCV replication, and HCV genotype determines the severity of liver diseases associated with HCV infection.13 To further elucidate the relationship between HCV infection and cerebrovascular deaths, we conducted this population-based, long-term prospective study to (1) estimate mortality rates of cerebrovascular diseases in participants with and without HCV infection; (2) assess the independent effect of HCV infection on cerebrovascular deaths after adjustment for conventional risk factors; and (3) evaluate the importance of serum HCV RNA level and HCV genotype in the risk prediction of cerebrovascular death.
Results
There were 22358 participants seronegative for anti- HCV and 1307 seropositive for anti-HCV in this study (Figure 1). Baseline characteristics of study participants stratified by serostatus of anti-HCV are compared in Table 1. Anti-HCV seropositives had higher proportions of females, older ages, low educational level, no alcohol consumption, high body mass index, low serum triglycer- ides level, diabetes, and hypertension history than sero-negatives (P<0.05).
All participants were followed for a median of 16.9 years. There were 255 cerebrovascular deaths occurred during 382 001 person-years of follow-up, giving a cerebrovascular mortality rate of 66.8 per 100 000 person-years. The cumulative risk of cerebrovascular deaths was 1.0% for anti-HCV seronegatives and 2.7% for anti-HCV seropositives (Figure 2, <0.001). As shown in Table 2, increased cerebrovascular mortality rates were found for anti-HCV seropositives. The crude HR (95% CI) of cerebrovascular death was 2.61 (1.80 to 3.78) for seropositivity of anti-HCV. In multivariate model, the risk of cerebrovascular death for anti-HCV sero- positives was 2.18 (1.50 to 3.16) compared with anti-HCV seronegatives (Table 3).
Among 1307 anti-HCV seropositives, 1154 had retrievable serum samples for the test of HCV RNA. Among 785 participants with detectable HCV RNA levels, 587 and 198 participants had low and high serum HCV RNA levels, respectively. Elevated serum HCV RNA levels were associated with an increasing the risk of cerebrovascular death with a dose-response relationship (P<0.001; Table 4). The multivariate-adjusted HR (95% CI) of cerebrovascular death was 1.40 (0.62 to 3.16), 2.36 (1.42 to 3.93), and 2.82 (1.25 to 6.37), respectively, for anti-HCV-seropositives with undetectable, low, and high serum HCV RNA levels compared with anti-HCV-seronegatives. The multivariate-adjusted HR (95% CI) of cerebrovascular death was 1.92 (0.98 to 3.75) and 3.48 (1.94 to 6.23) for anti-HCV- seropositive participants infected with genotype 1 and nongenotype 1 HCV, respectively, in another analysis. The risk of cerebrovascular death was 1.89 (0.79 to 4.53) for those infected with HCV nongenotype 1 compared with genotype 1 as the reference group.
By excluding 4129 (17.4%) participants seropositive for HBsAg, the associations between HCV infection and cerebrovascular death remained statistically significant. The multivariate-adjusted HR for anti-HCV seropositives was 2.14 (1.43 to 3.21) compared with seronegatives. The multivariate HR (95% CI) was 1.64 (0.73 to 3.71), 2.01 (1.12 to 3.61), and 2.78 (1.14 to 6.78), respectively, for anti-HCV seropositives with undetectable, low, and high serum HCV RNA level compared with anti-HCV sero- negatives (<0.001 for trend).
Discussion
Previous clinical studies found that HCV-infected transplant recipients had an increased risk of accelerated coronary stenosis.21,22 Similar to our findings, a large-scale study in Australia found an excess mortality from circulatory dis- eases in a population with HCV infection showing a standardized mortality ratio of 1.3 (1.2 to 1.5) compared with the general population in Australia.4 In another study of 10 259 anti-HCV seropositive and other 10 259 matched anti-HCV seronegative blood donors in the United States, the HR of death from stroke was 2.20 (0.84 to 5.79) for HCV infection.23 The blood donor study essentially sup- ported our findings with similar HR, but it was limited by the low statistical power to detect a significant association because of the small number (n=19) of cerebrovascular deaths in younger and generally healthier blood donors. Both studies may potentially be confounded by the inad- equate adjustment of risk factors, including lifestyle hab- its, serum lipid profiles, and history of diseases.
There have been negative findings that failed to show the association between HCV infection and cardiovascular-carotid atherosclerosis after controlling risk factors.25 In a follow-up study on atherosclerotic lesion through ultrasound scanning, chronic active hepatitis B/C was not associated with carotid plaques.26 Unfortunately, the diagnostic of serostatus in that study was ill-defined.26 The discrepancy in the findings of these previous studies and our study might have resulted from different characteristics of the study population and different prevalence of HCV infection. Moreover, it is probable that HCV infection may only play a role during particular stages of the natural history of atheroscle- rosis. In this study, there were 53 deaths from all vascular diseases among anti-HCV seropositives. Among them, 32 died from cerebrovascular diseases and 12 from ischemic heart diseases. There was no significant association between HCV infection and ischemic heart diseases showing an age- and sex-adjusted HR (95% CI) of 1.19 (0.66 to 2.14). However, the number of deaths from ischemic heart diseases among anti-HCV seropositives was too small to draw a confident conclusion for ischemic heart diseases.
The frequency and intensity of infection might be associated with the progression of atherosclerosis. A 2.5-year follow-up study on several serological markers of infectious agents showed that individuals who had been exposed to an increased number of infectious pathogens had an elevated risk of atherosclerosis.27 Individuals seropositive for HCV core protein, 1 of the seromarkers of HCV replication, had 5.6 times risk of developing carotid plaque.11 In our study, the increasing risk of cerebrovascular death across the biological gradient of serum HCV RNA levels was found and this dose-response relationship further supports the causal association.
Infectious agents may play as a stimulus for atherothrombosis.7,27,28 Infection affects atherothrombosis by triggering a cascade of immune responses and inflammatory stimuli either locally within vascular tissue or systemically through inflammatory mediators.29 It has been found that HCV infection is associated with an increased risk of cryoglobulinemia,30 which is thought to participate in the formation of immune complexes precipitating in vessel walls then leads to vasculitis.31 Elevated serum HCV RNA level was associated with an increased risk of cerebrovascular death, suggesting that individuals with an active HCV infection may trigger a stronger inflammation response by host-virus interaction leading to atherothrombosis. Whether patients with persistent HCV infection had increased circulating levels of inflammation markers such as C-reactive protein or endothelial progenitor cells may provide insights on the mechanisms of HCV infection and cerebrovascular disease.32,33
This study was limited to small number of cerebrovascular deaths (32 in anti-HCV seropositives); thus, the impacts of HCV infection on subtypes of stroke could not be evaluated adequately. Moreover, by using mortality data, whether HCV infection increased the incidence of cerebrovascular events or amplified the risk of cerebrovascular recurrence was not easily determined. Third, HCV infection was found to be a risk factor for the development of Type 2 diabetes.34 It is possible that HCV infection induces the onset of diabetes and then the occurrence of cerebrovascular disease. Unfortu- nately, the incidence of diabetes of our study participants was not followed and it was impossible to evaluate whether diabetes played an intermediate role. In this study, history of hypertension was based on self-report, which might thus be underestimated. Because there has never been a report on the association between hypertension and HCV infection, it is believed that the misclassification of self-reported hyperten- sion status was nondifferential between anti-HCV seroposi- tives and seronegatives. Therefore, the residual confounding effect of hypertension is considered limited. Finally, a HCV- infected patient with severe cerebrovascular disease was found to experience both progressive functional recovery and no recurrent stroke events during antiviral therapy.35 There were very few people had interferon treatment in our study population; thus, it was hard to evaluate whether HCV eradication had impacts on cerebrovascular mortality.
Our study has implications for clinical practice and future researches. Patients infected with HCV need to be consulted by their clinicians about their increased risk for cerebrovas- cular mortality in addition to hepatic complications. Patients should be encouraged to modify their health behaviors to reduce potential risk for cerebrovascular disease. Chronic HCV infection was related to neurocognitive impairment, which cannot be attributed to coexistent depression or hepatic encephalopathy.36 The recent detection of HCV genetic sequences in brain tissue raised the possibility of HCV infection of the central nervous system.37 However, further studies are required to confirm pathological mechanisms. If future additional studies confirm the role of HCV infection and the development of cerebrovascular disease, it may be possible to prevent cerebrovascular disease by using specific antiviral strategies.
In conclusion, HCV infection is associated with an increased risk of cerebrovascular mortality, particularly for those with elevated serum HCV RNA levels.
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