Our results, in agreement with other studies, confirmed that LF is more severe in HIV/HCV co-infected patients than in HCV or HIV mono-infected patients[5,23,24
]. In addition, ALF was significantly associated with a lower CD4+cell count in co-infected patients. There is convincing evidence that co-infection with HIV worsens the prognosis of HCV-related liver disease. It has been reported that in patients co-infected with HIV and HCV the risk of progressing to cirrhosis and liver failure is higher than in those infected with only HCV[25,26
], especially in individuals with CD4 < 200 cells/μL and alcohol consumption[2
In our study, 20% of HIV/HCV co-infected patients were under virologically unsuccessful HAART and in 50% CD4+ levels were below 400 cells/mm3
suggesting, in agreement with former findings, that the less successful the response to HAART, the less marked is its clinical benefit. In fact, immune recovery under HAART has been associated with longer overall survival, slower progression of HCV-related liver damage in HIV co-infected patients and with lengthier survival times before death attributable to liver disease[27
]. In the same way, Pineda et al[27
] demonstrated that liver decompensation emerged earlier in patients who maintained an undetectable HIV viral load for a shorter period during follow-up. Nevertheless, the association between ALF and lower CD4 cell count suggests that the response to HAART, measured using CD4 cell gain and HIV viral load decline, determines the evolution of liver disease and that virologically and immunologically successful HAART may slow progression of LF in HIV/HCV co-infected patients.
On the other hand, antiretroviral-related liver toxicity could have further contributed to liver damage in our HIV population[7
]. Mitochondrial toxicity of nucleoside analogues and glucose or lipid abnormalities, particularly common when using some protease inhibitors, may produce or enhance LF progression in HIV-seropositive patients. The correlation between use of antiretroviral drugs and LF in patients with HIV/HCV co-infection has been evaluated in different studies but with contradictory results[21,28-30
Macías et al[21
] reported that HAART regimens, including nevirapine, were associated with an increased degree of LF, while the use of protease inhibitor-based HAART was associated with less severe fibrosis and a slower progression of fibrosis in HIV/HCV co-infected patients. In contrast, Berenguer et al[28
] found that exposure to NNRTI was associated with a reduction in LF progression. In addition, Halfon et al[29
] showed that exposure to NNRTI was an independent factor in LF while Blanco et al[30
] highlighted that exposure to dideoxynucleosides was an independent factor associated with ALF.
In our study, no correlation was found between HAART exposure, duration of HAART exposure or cumulative exposure to any class of antiretroviral drugs and LF. In addition, we analyzed the correlation between duration of exposure to dideoxynucleosides (in particular didanosine, stavudine, zidovudine) and LF but also in this case no correlation was observed, suggesting that these drugs could not play any role in the progression of LF.
ALF was significantly higher in HIV/HCV co-infected patients than in HCV mono-infected patients when the subset of co-infected patients with undetectable HCV-RNA were excluded from the analysis. Overall, HIV/HCV co-infected patients with undetectable HCV-RNA had either no or only mild fibrosis (F0-F1) compared to the remaining co-infected patients, suggesting that the presence of HCV is important in conditioning the progression of LF and that anti-HCV therapy is mandatory in HIV/HCV co-infected patients in order to eradicate the virus. In fact, other authors have reported that achieving HCV clearance may reduce liver-related complications and mortality[31,32
] and probably permits at least a partial regression of LF[33
]. However, in HIV-positive patients liver cirrhosis may also occur without chronic viral hepatitis, and possible causes of hepatic steatosis in patients with HIV may be due to HIV itself, pathological alcohol use, diabetes mellitus, obesity or antiretroviral medications[34
Evaluation of LF using the 2 biochemical scores (APRI and FIB-4) was not in full agreement with LS measurement. In fact, these 2 biochemical tests were in agreement with TE values only for high-grade LF, but not in low and moderate LF, suggesting that at least in these cases liver biopsy could be necessary to assess the precise degree of LF. In this respect, we are aware that the lack of liver biopsy, as a reference tool of LF, is a limitation of our study.
More consideration, perhaps, should be given to transaminase levels. In fact, the HCV mono-infected group had the highest levels of transaminases, which may have influenced LS values by increasing them. This result could further support our observation that co-infected patients are at highest risk of LF because of their high AST levels and the immune suppression associated with a low CD4 cell count.
Finally, also in our area, HCV genotype 3 was confirmed to be more associated with HIV-positive patients, because of their habits as drug abusers[35
In conclusion, in our population, HIV/HCV co-infected patients had more ALF than HCV and HIV mono-infected patients. This result was not correlated with long-term exposure to HAART but with a lower CD4 cell count, suggesting that immunologically successful HAART may protect from progression of liver damage in HIV/HCV co-infected patients. In addition, the detection of unsuspected ALF in HIV mono-infected patients confirms that FibroScan® is very useful in this population. HCV infection, with its different pattern of cytolysis, may condition LS values, but viral eradication is mandatory to reduce fibrosis progression. Finally, the use of these non-invasive parameters of LF should be considered with caution. In fact, from our data it emerges that both TE and the biochemical scores may be suitable only for high grades of LF. In contrast, for mild/moderate degrees of fibrosis, they could not replace liver biopsy in the correct evaluation of LF.