HCV and HIV co-infection: mechanisms and management

Abstract

HCV and HIV co-infection is associated with accelerated hepatic fibrosis progression and higher rates of liver decompensation and death compared to HCV monoinfection, and liver disease is a leading cause of non-AIDS-related mortality among HIV-infected patients. New insights have revealed multiple mechanisms by which HCV and HIV lead to accelerated disease progression, specifically that HIV infection increases HCV replication, augments HCV-induced hepatic inflammation, increases hepatocyte apoptosis, increases microbial translocation from the gut and leads to an impairment of HCV-specific immune responses. Treatment of HIV with antiretroviral therapy and treatment of HCV have independently been shown to delay the progression of fibrosis and reduce complications from end-stage liver disease among co-infected patients. However, rates of sustained virologic response with PEG-IFN and ribavirin have been significantly inferior among co-infected patients compared with HCV-monoinfected patients, and treatment uptake has remained low given the limited efficacy and tolerability of current HCV regimens. With multiple direct-acting antiviral agents in development to treat HCV, a unique opportunity exists to redefine the treatment paradigm for co-infected patients, which incorporates data on fibrosis stage as well as potential drug interactions with antiretroviral therapy.

Figure 1. Driving factors underlying liver disease pathogenesis in HCV/HIV co-infection

Driving factors underlying liver disease pathogenesis in HCV–HIV co-infection. HIV infection leads to an impaired immune response against HCV, increased HCV replication, hepatic inflammation and apoptosis, increased microbial translocation from the gastrointestinal tract and increased fibrosis.

Figure 2. Interactions between HCV and HIV in hepatocytes and hepatic stellate cells that contribute to hepatic fibrogenesis

In the liver, HIV has indirect effects on HSCs and hepatocytes. HIV might be able to infect HSCs, but can indirectly lead to increased production of ROS. This increased level of ROS, in turn, leads to increased production of MCP and TIMP-1, two highly profibrotic proteins, along with COL1A1, a component of the extracellular matrix. In hepatocytes, exposure to HIV also increases ROS, TIMP-1 and COL1A1 production, but also increases TGF-β1 production, which drives fibrosis and increases HCV replication. In both HSCs and hepatocytes these effects can be abrogated by inhibition of the transcription factor NFκB. Finally, hepatic apoptosis is induced by HIV exposure through upregulation of TRAIL binding to DRs, leading to cell death. Abbreviations: CCR5, C-C chemokine receptor type 5; COL1A1, type 1 collagen; CXCR4, C-X-C chemokine receptor type 4; DR, death receptor; HSC, hepatic stellate cell; MCP-1, monocyte chemoattractant protein 1; ROS, reactive oxygen species; TGF-β1, transforming growth factor beta-1; TIMP-1, tissue inhibitor of metalloproteinases; TRAIL, TNF-related apoptosis-inducing ligand.

Figure 3. Algorithm to assess fibrosis in patients co-infected with HCV and HIV