Liver disease has now surpassed AIDS-defining illnesses as a major cause of morbidity and mortality in several HIV-positive cohorts [12
]. Thus, there is a growing need to assess liver disease in this population. Nonetheless, liver biopsies are generally not indicated in patients with HIV/AIDS, because biopsies rarely provide information that influences HIV therapy, and they are not recommended for routine evaluation of abnormal hepatic function test results in the absence of viral hepatitis. Thus, it has been somewhat difficult to directly assess the effects of HIV infection on the liver. HIV infection is associated with a number of hepatic and biliary tract disorders, hepatomegaly, hepatic steatosis, and elevated serum liver enzyme levels [14
]. Even HIV-positive patients with no evidence of viral hepatitis co-infection exhibit mild-to-moderate increases in liver enzyme levels [18
]. These findings are not unexpected, given that several lines of evidence suggest that HIV may directly interact with multiple liver cell types in vivo (reviewed in [20
]). For instance, HIV RNA and proviral DNA have been detected in liver biopsy specimens from persons with HIV infection [21
], and subsequent studies have demonstrated HIV p24 protein and HIV RNA in Kupffer cells, inflammatory mononuclear cells, sinusoidal cells, and hepatocytes [21
]. Moreover, expression of HIV entry receptors has been demonstrated in hepatocytes [26
]. We [31
] and others [27
] have demonstrated HIV infection of hepatocyte-derived cell lines, as well as primary hepatocytes in vitro. However, the precise mechanisms by which HIV infects and replicates within hepatocytes have not been elucidated. Thus, the effects of soluble HIV proteins and HIV infection on hepatocyte cell function and HCV replication are clearly areas of research that merit additional investigation.
In the current study, plasma HIV RNA level was associated with increased FIB-4 in HIV–mono-infected women in the absence of ART or alcohol use. This finding is supported by additional studies in which HIV load was positively associated with severe fibrosis or increased ALT and/or AST levels [19
]. This suggests a possible effect of HIV load on liver enzyme elevations and/or hepatic fibrosis, although additional longitudinal and in vitro studies are necessary to establish causality. Additionally, Kovari et al [37
] recently reported that chronic ALT elevations in HIV-infected persons without HBV or HCV co-infection were associated with HIV RNA levels >100,000 copies/mL. There are limited data to suggest that HIV suppression may be associated with decreased rates of hepatic fibrosis, supporting our hypothesis that HIV infection is an independent predictor of liver scarring. For example, Brau et al [38
] reported that HIV suppression was associated with less fibrosis in HIV/HCV–co-infected individuals, compared with those individuals without viral suppression. Moreover, use of another noninvasive marker technique, transient elastography, also suggests a strong relationship between the rate of fibrotic progression and ART-associated HIV control [39
]. At a cellular level, such findings may be explained, in part, by the interaction of HIV envelope proteins with hepatic stellate cells and stimulation of collagen production [40
Additional variables associated with FIB-4 in HIV–mono-infected and HIV/HCV–co-infected women included albumin level, CD4+ cell count, and receipt of ART. It is not surprising that albumin levels were negatively associated with FIB-4, given that albumin level is an important indicator of liver dysfunction, and albumin synthesis correlates with the severity of liver disease [41
]. Additionally, others have reported that higher CD4+ cell counts and/or HIV suppression were associated with lower ALT/AST levels or noninvasive markers of liver damage [10
], although these associations have not been observed in all studies [43
]. In HIV treatment–naive patients, a positive correlation between AST (or ALT) levels and HIV load has been reported [19
]. Similarly, in HIV positive patients without HBV or HCV infection, chronic elevated ALT levels were associated with high HIV RNA levels [37
Interestingly, factors such as chronic HBV infection and alcohol use, which are known to promote liver disease, were not associated with increased FIB-4 scores in any subgroup analyzed. For HBV, this finding likely reflects the low prevalence of HBsAg positivity in this cohort, as well as different cut-off values for predicting severe fibrosis and cirrhosis in patients with chronic HBV infection [44
], compared with those with HCV infection. For alcohol, it is possible that lifetime alcohol use is a more accurate predictor of liver disease than recent use. Moreover, whereas alcohol and HCV may have a synergistic effect on liver disease, the effect of alcohol may less pronounced in persons with HIV/HCV co-infection, as reported recently [45
]. However, a more detailed assessment of alcohol consumption over time in the HER Study may provide additional data on the complex interactions between alcohol, viral hepatitis, HIV infection, and liver disease in women.
Our study design has several distinct advantages over previous analyses. First, the observational nature of the HER Study cohort permits the direct comparison of noninvasive indices of liver fibrosis in HIV–mono-infected, HCV–mono-infected, HIV/HCV–co-infected, and uninfected women from the same cohort with similar risk factors. Moreover, women represent an understudied population with respect to HIV infection, as well as liver disease. Second, at the onset of the HER Study, only 30% of the HIV-positive women were receiving ART, and none were receiving HAART; thus, the contribution of ART to FIB-4 values could be assessed. Third, because of the historical nature of the cohort, prior treatment with interferon-based regimens for HCV infection was quite rare and was therefore highly unlikely to impact liver fibrosis in any appreciable manner. Nonetheless, limitations to our study design should also be noted, including its cross-sectional nature and the use of HCV antibody detection to denote HCV infection, because HCV RNA levels were not assessed at all time points and were therefore not evaluated. It should also be emphasized that the HER Study was conducted at the beginning of the HAART era; thus, the majority of study visits occurred among women who were either ART naive or receiving less than optimally suppressive ART regimens [7
]. Newer ART regimens have become simpler, more potent, and better tolerated, and data have emerged suggesting increased survival with the earlier initiation of treatment [46
]. Importantly, the findings in the current study may suggest an additional benefit of earlier suppression of HIV replication (ie, prevention of HIV-mediated hepatic fibrosis).
Collectively, these data suggest that advanced HIV disease is associated with more-advanced liver disease. Thus, the FIB-4 index may be widely applicable for the screening of liver fibrosis in HIV-infected populations. Longitudinal studies to determine whether highly effective HIV regimens result in decreased FIB-4 values and reduced hepatic fibrosis in vivo are clearly warranted.