In this investigation, persons coinfected with HIV and HCV had liver fibrosis measures equal to those of persons with only HCV who were nearly 1 decade older. These data are consistent with the hypothesis that both HIV infection and older age promote HCV-related liver disease progression and may reflect common mechanisms.
Older age is consistently associated with greater progression of HCV-related liver disease (10
). For example, in a large cross-sectional study of persons with HCV, Poynard and colleagues (16
) reported that the rate of fibrosis progression (biopsy stage divided by estimated years of infection) increased progressively with age and was 67% greater in those older than 50 years than in those aged 41 to 50 years. Age was strongly linked to liver fibrosis even after adjustment for duration of HCV infection. HIV infection is also consistently associated with progression of HCV-related liver fibrosis (19
). In a study of 1816 anti-HCV–positive persons with hemophilia, the risk for end-stage liver disease was increased 8.1-fold in those who also had HIV (21
HIV infection and age also increase the risk for other conditions, including cardiovascular disease, cancer, dementia, and various forms of lung disease (1
). The reported ages at which these diseases manifest have been younger for persons with HIV than for those without HIV. For example, Shiels and colleagues (3
) reported that the ages when most types of cancer were diagnosed were approximately 20 years younger among persons with AIDS. However, they and others have also pointed out that some (or, in some instances, all) of this apparent reduction in the age of onset of cancer could be explained by the younger age distribution of persons with HIV compared with the general population (3
). In addition to a younger age distribution, risk factors for cancer and other chronic non-AIDS conditions (for example, cigarette smoking, alcohol use, and viral hepatitis) are highly prevalent among populations with HIV. Thus, it is critical to identify control populations that are similar in all respects other than the HIV infection to make inferences about the effects of HIV.
It is noteworthy that in the present study, persons with and without HIV were recruited and followed identically in a study designed to assess the effect of HIV on various conditions. Liver disease outcome and exposures were evaluated prospectively and directly using a method that includes the full spectrum of disease, rather than by using death certificates or billing codes. Instead of using general population-based controls, we recruited and studied persons with and without HIV by using the same protocols and carefully monitored potential confounders. Even after adjustment for HCV RNA level, chronic HBV status, sex, race, BMI, and alcohol use, persons with HIV had liver fibrosis as advanced as those without HIV who were nearly 1 decade older.
The mechanisms through which HIV and aging affect liver fibrosis progression are poorly understood. Accumulating evidence points toward a role for telomere dysfunction or cellular senescence in several age-related phenotypes, especially in mice (24
). In humans, telomere shortening in various cell types has been reported with cirrhosis (26
), HCV (27
), and HIV (28
). Although these data support the hypothesis that shortened hepatocyte telomeres (whether due to age, HCV, HIV, or a combination of these) may contribute to hepatocyte senescence and reduced regenerative capacity, there is no convincing unifying evidence.
In this study, we detected a dose–response relationship between HCV RNA level and contemporaneous liver fibrosis. Although the connection between blood HCV RNA level and the likelihood of response to interferon and ribavirin treatment is well-recognized, most previous studies failed to detect a strong correlation between HCV RNA level and liver fibrosis (10
). However, some other studies have also suggested an increased risk for end-stage liver disease or death in persons with greater HCV RNA levels (33
). Whether the strong association detected in the present study is related to the wider linear range of newer HCV RNA real-time assays compared with former viral load tests, the large number of persons studied, or the use of liver stiffness to assess liver fibrosis is not evident.
In addition to age and HCV RNA level, liver fibrosis among persons with HIV was associated with having lower nadir or current CD4 count and greater HIV RNA levels. These findings may suggest that ART would reduce the risk for liver fibrosis progression among persons coinfected with HIV and HCV. In a study from 1 center, the risk for liver-related deaths seemed to be lower during the highly active ART era than in earlier periods or that of persons not taking ART (35
). However, in the present study, we did not detect an association among persons coinfected with HIV and HCV between liver fibrosis and ART use. Long-term, prospective follow-up is ongoing to clarify the longitudinal relationships among age, ART use, HIV disease markers, and liver fibrosis.
Besides treatment directed against HIV or HCV infections, other risk factors for liver fibrosis (for example, overweight or obesity and alcohol use) were identified that may be potentially modifiable. Although widely recognized that weight loss and reduced alcohol consumption should be encouraged among persons with chronic HCV infection (36
), implementation in practice is often limited. With aging of the populations with HCV and HIV infections, increasing emphasis should be placed on determining the most effective strategies for reducing modifiable risk factors and incorporating newer antivirals into HCV management of complex, older patients.
The measurement of fibrosis is a challenge in all studies of liver disease. The gold standard is the clinical expression of end-stage liver disease (10
). However, studies of the clinical expression of liver disease fail to capture important intermediate transitions because they are not clinically evident. We have also assessed the degree of liver fibrosis in this cohort by examination of liver tissue obtained by biopsy (33
). However, too few persons could be studied regularly by liver biopsy to assess risk factors with high precision. Thus, an indirect measurement of liver fibrosis, liver stiffness measured by elastography using FibroScan, which was first developed in Europe and subsequently validated in our cohort, was used to provide insights about the associations of age, HCV RNA levels, and race that we previously failed to detect (12
). Nonetheless, it is important to acknowledge that liver stiffness is only a proxy for liver fibrosis.
Liver fibrosis occurs over decades in most persons with HCV. Thus, the exposures that we assessed at or near the time of the liver stiffness measurement may not be representative of the previous exposures responsible for the development of fibrosis detected later, as illustrated perhaps by the lack of association of liver fibrosis with ART use. Greater measured fibrosis at each age among persons with HIV but with similarly increasing slopes of fibrosis with age by HIV status may suggest that the difference between persons with and without HIV occurred before our fibrosis assessment. In addition, the relatively flat slope of the elastography–age relationship may result in imprecision in our estimate of how much older a person without HIV would be compared with someone with HIV who had equal liver fibrosis (for example, small changes in FibroScan score can translate into substantial changes in age). Likewise, too few persons in this study had successful treatment of HCV infection to assess the effect of anti-HCV treatment on fibrosis progression. It is also noteworthy that duration of HCV infection is not known for most persons; however, in this cohort, time from first drug use correlates strongly (38
). Age is also strongly correlated with both measures, such that we can model only 1 of these variables at a time. Thus, if HCV infection occurred at earlier ages in persons with HIV, it may seem that HIV causes liver fibrosis at younger ages. Of importance, the estimated duration of HCV infection in our population does not differ substantially by HIV status (median, 28.6 vs. 28.9 years for persons with and without HIV, respectively).
In summary, persons who are coinfected with HIV and HCV have liver fibrosis stages similar to persons infected with HCV alone who are nearly 1 decade older. Additional work is needed to understand the biological basis for this observation and investigate whether effective treatment of HIV and HCV infections reduce future liver fibrosis progression.