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HIV/Aging/Viral Infections: HCV Leading Cause of Death in HIV?
  from Jules: When HCV/HIV coinfection was identified as a major problem in HIV, which was a number of years ago, around 2000, coinfection with HCV & HIV was widely considered a leading cause of death, perhaps the leading cause of death in HIV, and outside of AIDS itself HCV was in some studies found to be the leading cause of death. It is important to realize the full impact of HCV among HIV+ individuals, not to do so minimizes how important it is to advocate for coinfected patients, they are at great risk for death & liver disease without the quickest development & access to new IFN-free therapies, yet coinfection studies are conducted later in the development stage of the new oral DAA IFN-free therapies, where we expect 2-4 drug oral IFN-free regimens will cure as much as 100% of patients. This study immediately below finds that among women with HIV HCV were 3-times greater at risk for AIDS & AIDS deaths which suggests that for some individuals who died of AIDS conditions HCV could have played a crucial role but their deaths would not have been officially contributed to HCV thereby hiding the real contribution of HCV to in fact being the leading cause of death in HIV. Clearly it takes having closely followed the science of HCV in HIV during the early years 1998-2002 & through subsequent years to observe these partially obscured trends. Some studies over the years found AIDS was the leading cause of death in HIV and after that HCV and more recently other comorbidities have joined the list, like heart disease. Kaplan et al found immune activation in WIHS was a cause of heart disease among women in WIHS, although I don't think he looked at it, HCV likely played a role in contributing to overall immune activation. As people with HIV have increasingly aged with over 20-25% of HIV+ now being over 50 yrs old & this percent is increasing quickly, the onset of aging related diseases like heart, bone & kidney diseases have joined the space of that which is causing premature death in HIV; and add to that the fact that many with HCV/HIV coinfection have died already because they couldn't be treated successfully or because they remained undiagnosed, then the numbers today dying due to HCV among HIV+ is I think likely to be reduced thus recent studies may not be able to identify the full impact of HCV in HIV regarding how much coinfection causes higher rates of deaths or the highest rates of death.
In olds HOPS Study:
Compared with patients in the HIV-only group, HIV-HCV coinfected patients were more likely to have AIDS, renal disease, cardiovascular disease, cirrhosis, and elevated transaminase levels......Only 19 (7.1%) of the 267 HIV-HCV coinfected patients were prescribed IFN- and/or ribavirin.
In an early meta-analysis by Cami Graham in 2001 in CID:
Influence of human immunodeficiency virus infection on the course of hepatitis C virus infection: a meta-analysis. Clin Infect Dis 2001; 33:5629 "A recent study found that HCV was the leading non-AIDS cause of death in coinfected persons, and another study found that 50% of deaths in a cohort of patients with HIV in 1998 were the result of end-stage liver disease [19, 20]......In summary, analysis of these data shows that the risk of severe liver disease is significantly increased in patients who are coinfected with HIV and HCV, compared with those patients who have HCV monoinfection. This risk is modified by the duration of HCV infection, because the progression to decompensated liver disease or cirrhosis occurs earlier in HIV-coinfected patients.....This meta-analysis estimates the overall RR (relative risk) of decompensated liver disease or histological cirrhosis to be 2.92 (95% CI, 1.705.01) by use of adjusted data. This value is comparable to the OR of 2.9 (95% CI, 1.36.2) for persons with chronic liver disease due to concomitant HCV and excessive alcohol intake, compared with those persons who have HCV alone.....The combined adjusted RR for histological cirrhosis was 2.07 (95% CI, 1.403.07) [13, 16, 18, 23], whereas that of decompensated liver disease was 6.14 (95% CI, 2.8613.20; figure 2) [12, 13, 15, 26]."
Activation of CD8 T Cells Predicts Progression of HIV Infection in Women Coinfected with Hepatitis C Virus, The Journal of Infectious Diseases March 15 2010 http://www.natap.org/2010/HIV/022410_02.htm
"HCV-positive viremic women had a statistically significantly higher percentage of activated CD8 T cells (p<.001).......our study demonstrates that HIV-coinfected HCV-positive viremic women are at increased risk for AIDS-defining conditions compared with HCV-negative women, possibly because of high levels of activation of T cells, especially CD8 T cells, which indicates increased immune dysregulation in this population of women......HCV-positive viremic women may benefit from treatment of HIV and HCV infection to prevent significant immunologic changes and improve long-term outcome.......HCV viremic women were more likely to report wasting syndrome, bacterial pneumonia, and encephalopathy......"HCV coinfection was associated with increased CD8 activation. Finally, our most important finding was the statistically significant association between the level of activated CD8 T cells and incident AIDS among HCV-positive viremic women. HCV-positive viremic women with >43% activated CD8 T cells had an almost 3-fold increased risk of AIDS-defining conditions and/or AIDS-related deaths compared with HCV-positive viremic women with <26% activated CD8 T cells. This was not found for HCV-negative women"........Ongoing antigen-driven activation of CD8 T cells ultimately leads to CD8 T cell exhaustion and replicative senescence, which lead to inability to fight opportunistic pathogens....... factors that drive immune activation may increase the available targets for further viral replication. Finally, HCV infection may impair T cell maturation more globally to a more immature primed activated phenotype and also may impair responses to Toll-like receptors, suggesting that both the innate and adaptive arms are affected [24, 39]"
Early Immune Senescence in HIV Disease, Current HIV/AIDS Reports, Seema Desai1 and Alan Landay1 http://www.natap.org/2010/HIV/021510_01.htm
Aging, Persistent Viral Infections, and Immunosenescence: Can Exercise ''Make Space''? http://www.natap.org/2011/HIV/070411_01.htm
"Aging and persistent viral infections (particularly latent CMV infection) are major contributors to immunosenescence and the associated IRP (immune risk profile)......It is now well established that latent viral infections, particularly CMV, are associated with a greater frequency of highly differentiated and senescent T cells in the periphery........After primary infection, many viruses are capable of evading the immune system to persist in the host. In some instances, these infections become chronic (i.e., human immunodeficiency virus, hepatitis C), during which there is a lack of immune containment, allowing the virus to continuously replicate and generate ubiquitous viral antigens.......A hallmark of aging and persistent CMV infection is the accumulation of terminally differentiated senescent T cells.......latent herpesvirus infections ..... are..... indicative of biological age and immunosenescence......persistent CMV infection induces senescence in CD8+ T lymphocytes........it is has been shown, both epidemiologically and experimentally, that individuals who engage in habitual physical exercise of a moderate intensity exhibit a lower frequency of immune biomarkers associated with the IRP........Many latent infections, however, have the potential to be reactivated (i.e., caused by stress), which allows for increased viral replication to occur and more viral particles to be present systemically
The HCV and HIV Coinfected Patient: What Have We Learned About Pathophysiology?
Current Gastroenterology Reports 2002
"Recent studies suggest that, in the era of potent anti-retroviral therapy, the number of deaths caused by liver disease in HIV-1-infected individuals has been increasing. In a cohort of approximately 4000 individuals, liver disease was the primary cause of non-AIDS death [8]. In a recently published study that retrospectively examined the causes of death between 1991 and 1998 in HIV-1-seroposi-tive individuals, end-stage liver disease was found to be the leading cause among those who were hospitalized [9]. The majority of these individuals were HCV positive."
HCV in HIV Coinfection and in IVDUs
The average progression rate in coinfected patients was faster than in monoinfected patients: 0.2 fibrosis unit/year compared to 0.125 in HCV mono-infected patients (p=0.001).
The estimated time from infection to established cirrhosis in coinfected patients was 20 years compared to 32 years in HCV mono-infected persons. The rate of HCV progression in 6 patients who had paired liver biopsies was 0.29 fibrosis unit/year, with an estimated time to cirrhosis of 13.8 years. In addition, co-infected patients had significantly higher inflammatory grade (p=0.006) despite lower alcohol consumption.
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