Hepatitis C virus (HCV) infection causes liver fibrosis that worsens as patients age, potentially progressing to cirrhosis and culminating in liver failure. A NIDA-funded study shows that concurrent infection with human immunodeficiency virus (HIV) is likely to hasten the onset of these clinical turning points.
Dr. Gregory Kirk and colleagues at the Johns Hopkins University (JHU), Baltimore, assessed liver fibrosis serially in more than 1,100 current and former injection drug users who were infected with HCV. After allowing for other factors that speed fibrosis, the JHU team estimated that patients with HIV–HCV coinfection progressed to successive degrees of severity 9 years sooner than those infected with HCV alone.
Further findings from the study suggest that suppressing HIV with antiretroviral medications may slow HCV-related liver fibrosis. Moreover, the findings accord with a hypothesis that HIV infection accelerates the general aging process—in which case suppressing HIV may moderate the progression of other chronic diseases as well.
HIV and Fibrosis
Dr. Kirk and his team tapped the ALIVE (AIDS Linked to the IntraVenous Experience) cohort for volunteers for their study. ALIVE members are adult residents of Baltimore with histories of injection drug use. Recruited in several waves since 1988, they have cooperated in several research projects. The 1,176 participants in the fibrosis study were primarily African American (85%), with a median age of 49 years. All were infected with HCV, and 1 in 3 were also infected with HIV.
The researchers used the FibroScan technique to noninvasively assess fibrosis in each participant at baseline and every 6 months thereafter. FibroScan uses an instrument similar to an ultrasound to perform elastography and measure the liver’s elasticity, a surrogate marker of fibrosis. The elasticity or stiffness of the liver is measured in kilopascals (kPa), with values of less than 9.3 kPa being suggestive of a person having no clinically significant fibrosis and levels equal to or above 12.3 being indicative of cirrhosis. Altogether, the researchers obtained a total of 5,634 liver scans over 5 years.
One in 5 HIV-coinfected participants had liver stiffness at baseline that was classified as cirrhosis, whereas only 1 in 9 of those infected only with HCV had cirrhosis. Based on the data from all the scans, the researchers calculated that HIV coinfection increased liver stiffness, on average, by 1.17 to 2.02 kPa. This increase was roughly equal to what the patients without HIV coinfection accumulated due to aging over roughly 9.2 years (see Figure).
Among the participants with HIV coinfection, both higher HIV viral burdens and lower CD4 cell counts were associated with more extensive HCV-related fibrosis. These findings suggest that antiretroviral therapy—which suppresses viral burden and raises CD4 count—might retard fibrosis. The JHU researchers recommend that future studies examine this hypothesis.
In addition to age and HIV coinfection, several other factors exacerbated HCV-related fibrosis. In order of the estimated size of their respective impacts, these included higher HCV viral burden, hepatitis B coinfection, daily alcohol use, and an elevated body mass index. The researchers point out that medical interventions and behavioral changes can modify each of these factors.
Figure. HIV Increases Liver Fibrosis in Patients with HCV Infection A plot based on 5,634 elastography readings shows that HIV coinfection compounds HCV-related liver fibrosis. All other factors being equal, the plot predicts that patients with HIV coinfection will cross the threshold (9.3 kiloPascals, horizontal broken line) that signifies clinically significant fibrosis 9.2 years sooner than those with HCV alone.
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The y-axis of the graph in this figure shows scores for liver fibrosis in kilopascals (kPa) measured with a FibroScan machine, and the x-axis shows an individual’s age in years. The broken red line indicates the FibroScan values at different ages predicted from a regression analysis for a representative study participant (black overweight male who has no regular alcohol use, is hepatitis B virus surface antigen–negative, and has high HCV viral load) when infected with both HIV and HCV; the solid blue line indicates the FibroScan values at different ages predicted for the representative participant when infected only with HCV. The broken horizontal line indicates the threshold (of 9.3 kPa) above which liver fibrosis is considered clinically significant. As shown by the vertical red and blue arrows and the connecting curly bracket denoting the time points at which fibrosis scores in individuals from the two study populations crossed the threshold of clinical significance, individuals infected with both HIV and HCV had fibrosis scores similar to those in individuals infected only with HCV and who are almost a decade older.
HIV and Aging
“Antiretroviral therapy has extended life expectancy with HIV, so that now many infected individuals live into their 50s and are developing chronic diseases of older age,” says Dr. Kirk. Some studies have suggested that HIV hastens the development of age-related health conditions, including declining immune function, cardiovascular disease, and some cancers. The JHU results are consistent with this hypothesis and indicate that individuals with HCV and histories of injection drug use may develop end-stage liver disease as much as 9 years earlier when HIV is present.
Although the mechanisms by which HIV may accelerate HCV-related liver disease and other age-related diseases are not known, Dr. Kirk speculates that inflammation may play a role. “HIV infection increases chronic inflammation, and levels of inflammation stay high even with antiretroviral therapy,” he says. “And most age-related diseases have a component of chronic inflammation.”
Dr. Jag Khalsa of NIDA’s Medical Consequences of Drug Abuse and Co-occurring Infections Branch emphasizes that HIV–HCV coinfection is common, and especially prevalent among individuals with histories of injection drug use. For this reason, and because the number of deaths from HCV-related illnesses now surpasses that from HIV infection, Dr. Khalsa says, “Investigations of the effect of HIV on HCV infection are of great significance to public health.”
This study was supported by NIH grants DA016078, DA04334, and DA12568.
Source:
Kirk G.D. et al. HIV, age, and the severity of hepatitis C virus–related liver disease: a cohort study. Annals of Internal Medicine 158(9):658–666, 2013. Full Text