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HIV/HCV Coinfection -Psych/Social Issues, Screening for HCC, Pathogenesis of Accelerated Fibrogenesis, excerpts from meeting
  Pdf of report attached here for download
Excerpts from:
Meeting Report
Human immunodeficiency virus and liver disease forum 2012
Kenneth E. Sherman,1 David Thomas,2 and Raymond T. Chung3
published in Jan 2014 but meeting was held: The 4th Biennial Forum on HIV and Liver Disease was held in Jackson, Wyoming, in September 2012 I excerpted this because they appear to remain relevant despite some of report appears dated, pdf attached
Psychiatric and Social Issues in Liver Disease Care (Conway, Treisman, McCance-Katz)
Although we see significant advances in our understanding of the pathophysiology of liver disease in those with HIV infection and major strides in the development of new medications to treat hepatitis C, significant issues related to poverty, health care access, concomitant psychiatric disorders, and substance abuse remain as barriers to improved health. Indeed, many of these issues are intrinsically related to each other.[53] In substance-abuse cohorts, traditional medical models that depend upon diagnosis linkage to treatment with subsequent improvement in prognosis may not apply. Veterans with psychiatric disorders are less likely to be offered HCV treatment.[54] Among injection drug users (IDUs) with HCV, treatment uptake rates ranging from 1.1% to 4% have been reported.[55, 56] Reasons for this are clearly multifactoral, but include bias by providers against treatment of IDUs,[57] lack of health care funding for disease management and treatment of the uninsured, and an overall lack of providers able to provide care. System models that seem effective include use of multidisciplinary academic or community-based partnerships that incorporate physicians with training in addiction and hepatology, as well as nurses, outreach workers, and research coordinators. Reinfection with HCV remains an issue for many patients, with ongoing risk behaviors leading caregivers to withhold treatment. Rates of reinfection with HCV reported in the literature vary, but rates as high as 5.27 cases/100 person-years have been reported in incarcerated subjects[58] and 5.4 cases/100 person-years in active IDUs in the community.[59] There is some evidence that engagement in liver care and treatment reduces risk behaviors, and there may be an immunologic component of protection against reinfection as well.[60]
Management of individual patients with substance abuse remains a significant barrier to HCV treatment, despite evidence that such treatment improves SVR rates among IDUs treated for HCV infection and improves the likelihood of receiving HIV care as well.[61] Psychiatric diagnoses are common among those with HIV- and liver-related coinfections. At Johns Hopkins, 54% of patients presenting for medical evaluation had an Axis 1 psychiatric diagnosis, including major depression (20%), adjustment disorder (18%), cognitive impairment (18%), and substance abuse (74%). The presence of untreated mental disorders has a significant effect on the probability of overall survival.[62]
Screening for HCC (Thio, McGovern, Peters, Goodman, Stock)
Persons with chronic viral hepatitis are at increased risk of HCC, and that risk may be even higher in those who are HIV coinfected.[29, 30] In serial nationwide surveys in France, the proportion of liver-related deaths attributed to HCC rose from 15% in 2000 to 25% in 2005 and the percent resulting from HCV rose from 10% to 25%.[31]
There is a complex association between HIV infection and cancer. HIV infection clearly promotes some cancers, typically those caused by another virus. For example, Kaposi's sarcoma is caused by human herpes virus 8 and almost exclusively occurs in HIV-infected persons in the United States. Likewise, the risk of Epstein-Barr virus associated non-Hodgkin's lymphoma and human papilloma virus-associated cervical cancer are markedly increased in HIV-infected persons.[32] In other instances, associations between HIV and cancers might be confounded by more exposure to tobacco in HIV-infected persons than the HIV-uninfected control group.[33] With HCC, it is not clear whether HIV infection itself promotes cancer or just accelerates liver fibrosis in persons with chronic viral hepatitis and that greater liver fibrosis increases the risk of HCC. If the latter is true, then the recommendations for HCC surveillance for HIV-infected persons would be indexed to liver disease stage and would be essentially the same as for HIV-uninfected persons. Further research into this issue is clearly indicated.
For persons without HIV, HCC screening is considered cost-effective when the risk of HCC exceeds 1.5% per year for HCV and 0.2% per year for HBV.[34]In general, HCC surveillance is recommended for HCV-infected persons only when there is bridging fibrosis or cirrhosis. For persons with chronic hepatitis B, the recommendations are more complex and include age, gender, HBV DNA level, disease stage, tobacco use, family history, and other factors. The risk of HCC increases with age, and it is likely that this risk is distinct from disease stage. HIV-infected persons have liver disease at fibrosis stages comparable to persons 10 years older.[35] However, it is not known whether HCC risk is also effectively advanced by a decade. There are emerging data suggesting that HCC surveillance can reduce HCC-related mortality.[36] The method typically recommended is ultrasound (US) testing every 6 months.[34] Some authorities also recommend using alpha- fetoprotein (AFP) testing and getting baseline testing with magnetic resonance imaging or bi- or triphasic computed tomography. There is at least one report suggesting that every-4-month testing was superior to every-6-month testing in a high-HCC-incidence setting. There are a paucity of data to apply these principles to HIV-infected persons. Some studies suggest that HCC is more aggressive in HIV-infected persons, and that would diminish the value of current surveillance methods.[29, 30] In addition, limited access to liver transplants would also reduce the benefits of detection of HCC for those for whom transplantation is the optimal treatment. On the other hand, the higher risk of HCC might make surveillance more cost-effective. At least one authoritative guideline recommends HCC screening for HIV-infected persons, effectively as in persons without HIV (see Table 2).[37]
Pathogenesis of Accelerated Fibrogenesis in HCV/HIV Coinfection (Chung, Thomas, Kottilil)
Natural history studies have shown that HIV coinfection promotes accelerated HCV hepatic fibrosis progression, even with excellent HIV control under ART. Moreover, in those who have progressed to cirrhosis, higher rates of liver failure and death are observed, compared with patients with HCV monoinfection.[21] The mechanisms underlying accelerated hepatic fibrosis are being increasingly understood. Though immunopathogenesis as a result of virus-specific infiltrating T cells is a key driver of liver injury, it is unlikely that the dys-regulated T-cell response in HIV coinfection can alone suffice to explain the accelerated natural history. Rather, a series of perturbations brought about by HIV infection in the liver microenvironment appears to contribute to the observed phenotype.[22]
Remarkably, HIV alters the natural history of HCV-related liver disease through at least five important mechanisms independently of its effects on T cells: (1) HIV signals, through chemokine (C-X-C motif) receptor 4 and chemokine (C-C motif) receptor 5, coreceptors on hepatocytes to up-regulate HCV replication in a transforming growth factor beta 1 (TGF-ß1)-dependent manner[23]; (2) HIV augments HCV-related increases in TGF-ß1 from hepatocytes, thereby enhancing fibrogenesis[23]; (3) HCV and HIV independently induce TGF-ß1 through the generation of reactive oxygen species (ROS), which, in turn, induces p38 mitogen-activated protein kinase, c-Jun N-terminal kinase, and extracellular signal-regulated kinase, and converge on nuclear factor kappa B[24, 25]; (4) HCV and HIV independently induce hepatocyte apoptosis, providing another means by which these infections contribute to hepatic fibrosis progression[26]; and (5) HIV is associated with a gut CD4 depletion enteropathy, promoting microbial translocation and induction of fibrogenesis through engagement of Toll-like receptor 4 on hepatocytes and stellate cells.[27, 28] Collectively, these findings provide evidence that HIV itself, independent of its effects on cellular immunity and despite its lack of tropism for hepatocytes, accelerates HCV-related liver disease progression. Besides addressing the HCV side of the equation with direct-acting antiviral agents, the central role of ROS and apoptosis in driving fibrogenesis provides novel, attractive antifibrotic targets. The advent of improved, humanized mouse models that support both HIV and HCV infections will enhance our understanding of the multiple mechanisms promoting liver disease progression in HIV-infected persons.
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