HCV/ HIVCo-infection: Time To Re-evaluate the Role of HIV in the Liver?

Jason T. Blackard; K. E. Sherman

Disclosures

J Viral Hepat. 2008;15(5):323-330. 

In This Article

Summary and Natural History of HCV/HIV Co-infection

Summary

Because of major advances in the treatment of HIV/AIDS, HIV-positive persons now live longer, healthier lives; however, hepatitis C virus (HCV) is increasingly recognized as a major cause of morbidity and mortality in this population. Among HCV-infected persons, HIV co-infection is associated with increased HCV RNA levels, increased hepatic inflammation and fibrosis, and more rapid progression to cirrhosis and end-stage liver disease. Compounding this problem are reduced HCV treatment response rates among HCV/HIV co-infected persons. Moreover, antiretroviral therapy used to suppress HIV replication is often associated with a paradoxical increase in HCV RNA levels, as well as hepatotoxicity. Despite the adverse clinical consequences of HCV/HIV co-infection, the mechanisms by which these two viruses interact at the cellular level remain largely unexplored. This review focuses on the evidence demonstrating direct infection of hepatocytes by HIV, as well as the indirect mechanisms by which HIV may regulate HCV replication at the cellular level. A comprehensive understanding of virus–virus and virus–cell interactions is critical to the development of novel treatment strategies to combat HCV/HIV co-infection.

Natural History of HCV/HIV Co-infection

Over 170 million people worldwide are infected with hepatitis C virus (HCV), an enveloped, single-stranded RNA virus. Infection with HCV is a major cause of chronic liver disease, with 60–80% of patients developing chronic hepatitis and up to 20% of chronically infected persons developing cirrhosis within 20years of infection.[1] HCV infection is also a major cause of hepatocellular carcinoma and the major reason for liver transplantation in the US. There is no effective vaccine for the prevention of HCV infection and current treatment regimens achieve sustained virological response in only 50% of treated individuals.[2]

Because of shared routes of transmission, co-infection with HCV is increasingly recognized as a major cause of morbidity and mortality among HIV-positive persons.[3] In the US, 150000 to 300000 persons are infected with HIV and HCV, representing 15–30% of all HIV-infected persons and 5–10% of all HCV-infected persons.[4,5]

The effects of HCV infection on HIV disease are not well understood but have been addressed in a small number of studies. Daar etal. reported that increased HCV RNA levels were associated with clinical progression to AIDS in haemophiliacs even after controlling for CD4 cell count and HIV RNA level.[6] In the Swiss HIV Cohort Study, HCV seropositivity was associated with progression to a new AIDS-defining illness or to death.[7] HCV seropositivity was also associated with a reduced CD4 cell recovery during antiretroviral therapy (ART). While these results have been generally supported by other clinical investigations,[8–12] not all cohorts have found an association between HCV co-infection and HIV disease progression.[13] While the mechanisms by which HCV may impact HIV disease progression have not been elucidated, they may include intolerance to ART in the presence of HCV and/or HCV-induced immune activation that leads to HIV disease progression. Moreover, extrahepatic replication of HCV does occur;[14] therefore, HCV could significantly impair CD4 cell proliferation and function and consequently impact HIV disease progression.

In contrast, it is well established that HIV significantly alters the clinical course of HCV disease. Co-infection with HIV results in enhanced HCV replication as HCV RNA levels are significantly elevated in HCV/HIV co-infected persons compared with HCV mono-infected persons[15,16] and HIV seroconversion is associated with sustained increases in HCV viral load.[17] Paradoxically, ART initiation is frequently associated with sustained increases in HCV viral load, as well as hepatotoxicity.[18–23] The clinical course of HCV infection is also accelerated in HCV/HIV co-infected persons as they experience more advanced liver fibrosis and cirrhosis, as well as higher rates of progressive liver disease and death than do HCV mono-infected persons.[3,24–32] Importantly, HIV therapy appears to slow the progression of hepatic disease in co-infected persons (reviewed in [33]). Further compounding the clinical management of HCV disease, HIV co-infection is associated with decreased response rates to HCV treatment compared with HCV mono-infection.[34–36] Thus, HIV co-infection clearly has a negative impact on HCV pathogenesis.

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