- Despite the advent of directly acting antiviral agents (DAAs) for curing the hepatitis C virus (HCV), patients who are coinfected with HIV still have a greater mortality risk, early onset of hepatocellular carcinoma (HCC) and more aggressive HCC
- This review discusses the pathogenesis of HCV/HIV-related liver disease, how HIV infection affects fibrogenesis and why HCV clearance may be insufficient to prevent further liver damage and progression to HCC
- Sustained virological response to DAAs or interferon-based therapy does not ameliorate all immune activation and profibrotic mediators
- HIV infection itself can promote liver damage
- Continued follow-up is warranted for HCV-cured patients, particularly those with established fibrosis, and should include assessment for fibrosis progression as well as HCC surveillance
Human immunodeficiency virus (HIV)-infected individuals who are coinfected with the hepatitis C virus (HCV) are at increased risk of liver-related mortality. HIV infection enhances transmission of HCV and accelerates progression of HCV-related liver disease.
Now that directly acting antiviral agents (DAAs) are the standard of care, HCV/HIV coinfected patients achieve rates of sustained virologic response (SVR) or cure of HCV similar to those of HCV-monoinfected patients, and measures of fibrosis also improve.
However, coinfected patients still have a greater mortality risk, earlier onset of hepatocellular carcinoma (HCC) and more aggressive HCC. This suggests DAAs do not completely resolve inflammatory and profibrogenic stimuli. In addition, it's becomingly increasingly evident that HIV infection itself can promote liver damage.
In The Journal of Infectious Diseases, Raymond Chung, MD, vice chief of the Gastrointestinal Division and director of the Hepatology and Liver Center at Massachusetts General Hospital, and colleagues recently reviewed the pathogenesis of HCV/HIV-related liver disease, how HIV infection affects fibrogenesis and, as summarized here, why HCV clearance is insufficient to prevent further liver damage and progression to HCC.
Effects of SVR on Liver Disease
There is mixed evidence on how DAA-induced SVR affects the following mechanisms of accelerated liver disease in HCV/HIV coinfected patients:
- Altered cytokine profile: The effects of SVR are unclear. One study detected persistently elevated serum levels of the proinflammatory cytokines interleukin-6 (IL-6) and tumor necrosis factor (TNF) in patients treated with pegylated interferon-alfa and ribavirin. Along the same lines, an in vitro study showed no effect of SVR on levels of tumor growth factor–beta, which is profibrogenic and immunosuppressive. On the other hand, another study showed that DAAs reduce circulating levels of proinflammatory chemokines
- Immune system dysfunction: SVR has no effect
- Microbial translocation and gut dysbiosis: SVR has no effect in reducing this
- Profibrotic macrophage activation: SVR probably has a positive effect. Patients treated with pegylated interferon-alfa and ribavirin showed reduced levels of soluble CD163, which is associated with inflammation and fibrosis. In a different study, DAAs were also associated with reduced levels of soluble CD163, although the improvement was not statistically significant
- Steatosis: SVR has a positive effect. It has been linked to improved insulin resistance and measures of diabetes in patients with HCV. DAAs have been found to normalize lipid homeostasis and, in a separate study, to reduce steatosis
Effects of SVR on Development of HCC
HCV monoinfected patients are at residual risk of HCC even after DAA therapy, partly because of the persistently altered cytokine milieu. Furthermore, HCV infection induces an epigenetic signature associated with HCC development that is also unaltered by current therapy.
Guidance for Clinicians
Liver function improves with DAAs, but even so, the incidence of HCC among HCV/HIV coinfected patients continues to rise. In the absence of approved antifibrotic drugs, continued follow-up is warranted for HCV-cured patients, particularly those with established fibrosis, and should include assessment for fibrosis progression as well as HCC surveillance.
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