Individuals with histories of drug use account for the majority of new hepatitis C infections in Western countries. This population is at risk for liver fibrosis, and a number of disease progression cofactors highlight the relevance of medical assessment. Evaluating liver fibrosis via non-invasive tests early in the course of drug addiction may increase the proportion of patients who are eligible for treatment. This study of young adults with chronic hepatitis C shows that the factors associated with higher FIB-4 scores clearly differed between the HCV-monoinfected and HCV/HIV-coinfected individuals.
The main contribution of the study is related to the fact that unhealthy alcohol use had a differential effect on FIB-4 values if patients have hepatitis C alone or HCV/HIV coinfection. Unhealthy alcohol drinking has been regarded as a major contributor to the progression of liver disease in the setting of chronic hepatitis C 
and, a synergistic effect between HCV and alcohol has been proposed 
. However, even though alcohol use is among the cofactors related with liver fibrosis in coinfection in studies with liver biopsy 
, the present and other studies that have used non- invasive methods to estimate fibrosis 
, does not detect an additional effect of alcohol drinking on the FIB-4 of HCV/HIV-coinfected patients.
In coinfected patients with unhealthy alcohol consumption, the FIB-4 does not reflect the negative impact of alcohol intake on liver fibrosis. Therefore, clinicians may not be able to assess the impact of ethanol nor can advise the patient on the risk of disease progression. On the contrary, unhealthy alcohol use is reflected in the FIB-4 of the monoinfected patients thus making possible preventive interventions to reduce harm.
Unhealthy alcohol use in the HCV-monoinfected patients and HIV-related immunodeficiency in the HCV/HIV-coinfected patients are the most important cofactors associated with fibrosis progression in the respective populations. In addition, we found that drug use duration and serum albumin were correlated with the FIB-4 scores of both the monoinfected and coinfected patients, whereas unhealthy alcohol use, GGT and total cholesterol were associated with higher FIB-4 scores only in the monoinfected patients. The effect of HIV-related immunodeficiency in the coinfected patients was strong (an increase of 3.5% in the FIB-4 score for every 100 CD4 cells/µL decrease). Furthermore, we did not observe differing FIB-4 values between the HCV-monoinfected and coinfected individuals with CD4 cell counts above 900 cells/µL. This observation suggests that FIB-4 elevation is associated with immunoactivation and the resulting decrease of CD4 cell counts in HCV/HIV-coinfected drug users.
The relationship between HIV-related immunodeficiency and liver fibrosis progression has been described in coinfected patients 
; in fact, treating HIV/AIDS with HAART has been shown to reverse the effect of HIV-related immunodeficiency in patients with chronic hepatitis C 
In this study, decreased serum albumin and increased total bilirubin were associated with elevated FIB-4 scores. This finding may facilitate identifying a subpopulation of patients at increased risk for cirrhosis. It is well known that albumin and bilirubin are key components of the Child-Turcotte-Pugh score that clinicians use to assess decompensated liver cirrhosis.
In individuals with history of injection drug use, the duration of injection use is a surrogate for the duration of HCV infection 
. As expected, the duration of drug addiction in this study was related to increased FIB-4 scores.
It has been reported that HCV infection itself lowers both low-density lipoprotein (LDL) and total cholesterol and that patients treated for chronic hepatitis C had larger increases in LDL and total cholesterol from baseline 
. Interestingly, the current study did not find a significant association between cholesterol levels and FIB-4 scores among the HCV/HIV-coinfected patients.
This study has a number of limitations that should be mentioned. First, the alcohol intake assessment was limited to one categorical variable (>50 g/day, ≤50 g/day in the 6-month period before admission), and there was no information on the history and complications of alcohol consumption. In previous studies, however, recent alcohol consumption has been treated as a dichotomous variable using a threshold of 40–50 grams of ethanol per day or using the definition of heavy alcohol intake provided by the US National Institute on Alcohol Abuse and Alcoholism (NIAAA) 
. Second, we used a single measurement of laboratory parameters to calculate the FIB-4 scores which precluded examining the evolution of fibrosis over time. Furthermore, nearly half of the patients had normal aminotransferases values, as has been previously described for IDUs 
; despite the lack of correlation between liver enzyme alterations and liver damage, it is possible that FIB-4 scores are affected by normal liver enzymes 
. Third, the HAART status of the HIV-positive patients was represented by a qualitative covariate, which hindered an analysis of the effect of antiretroviral treatment on FIB-4.
In summary, this study shows that unhealthy alcohol use strongly influence FIB-4 in HCV- monoinfected patients, whereas in the context of HCV/HIV coinfection, HIV-related immune depression exerts a major negative role on FIB-4 results, with no significant worsening by alcohol intake.