This study showed that FIB-4 and APRI were strongly associated with all-cause mortality in HCV/HIV-co-infected women. Both fibrosis markers utilize standard laboratory values that are simple and regularly performed in clinical care of patients with HIV or HCV and include AST, ALT and platelets. Assessment of the degree of hepatic fibrosis carries important prognostic information and has therapeutic implications with respect to timing of HCV treatment and monitoring for evidence of complications of portal hypertension. If women have no liver fibrosis, they may elect to await newer all oral HCV therapies, but if they have severe fibrosis (fibrosis stage 3–4) they should undergo current treatment for HCV.
Although liver biopsy is considered by clinicians to be the most useful method to determine the amount of hepatic fibrosis and inflammation, it is an imperfect test, providing a small piece of liver with nonuniform histologic findings. Smaller tissue samples generally underestimate fibrosis [14
]. In WIHS, only 20% of HCV/HIV-co-infected women have undergone liver biopsy and fewer (1.8%) have received therapy for HCV. WIHS is not a treatment study, but an observational cohort. However, women are encouraged to seek treatment for HCV by WIHS investigators and we have provided educational programs, so that participants can learn about their HCV, liver disease and possible therapies.
In light of these limitations of liver biopsy, there has been interest and progress made in the development of noninvasive markers of hepatic fibrosis. One of these indices, FIB-4, was developed and validated in a cohort of patients co-infected with HCV/HIV [9
]. This study found that FIB-4 had an accuracy of 0.77 for differentiating between Ishak fibrosis stage 0–3 and Ishak fibrosis stage 4–6 among patients co-infected with HCV/HIV [18
]. APRI has been demonstrated to predict significant fibrosis and cirrhosis, with accuracies of 0.80 and 0.89, respectively, in patients with HCV infection alone [8
] and somewhat decreased accuracy (0.71–0.73 for cirrhosis) in the co-infected populations [19
]. The serological noninvasive methods of fibrosis assessment can be performed on small volume blood samples and can be automated and repeated frequently and retrospectively. Other markers of mortality risk include the model for end-stage liver disease [22
] and Child–Pugh–Turcotte scores [23
]. In patients with known cirrhosis (F4) and decompensated liver disease, they have been used to assess mortality risk for surgery and need for liver transplantation. They are not used in patients without cirrhosis in contrast to APRI and FIB-4, which assess the amount of liver fibrosis from none (F0) to cirrhosis (F4).
Death certificates have certain limitations and those ‘nonliver deaths’ in HCV/HIV-co-infected women may have had significant contribution from liver disease: for example, the contribution of hepatic disease may not have been noted in septic deaths, renal deaths and multisystem organ failure [12
]. In addition, not all abnormalities leading to changes in ALT, AST and platelets can be assumed to be due to hepatic fibrosis progression per se
, as hematologic disorders and medication effects, likely more common in HIV, may cause changes. As noted above, WIHS is an observational study without patient visits, so we do not have data for APRI or FIB-4 in hospitalized women or women who missed visits. Of interest, there were higher rates of death in women with severe fibrosis scores, suggesting that liver fibrosis played a role even in women deemed to have died from HIV. Indeed, our results demonstrate a significant association between increased levels of APRI and FIB-4 and the risk of death from any cause. Other studies have shown that HCV/HIV co-infection is associated with higher mortality than HIV alone [5
]. APRI and FIB-4 do not distinguish the cause of fibrosis. Patients with HCV have increased hepatotoxicity from HAART [24
], and those with cirrhosis have altered metabolism of drugs.
Our study is the first longitudinal study of noninvasive markers of fibrosis solely in women co-infected with HCV and HIV. The fibrosis markers were predictive of all-cause mortality, but were abnormal some years before death and were higher in women dying a liver-related death. This suggests that these noninvasive markers can be of practical value in all women co-infected with HIV and HCV to determine whether liver disease is progressing and, if so, to reinforce the need for therapy for HCV. These noninvasive markers have been shown to predict liver-related death in a smaller cohort of HIV-infected individuals, predominantly men [25
]. During the 5 years prior to death, our data showed higher overall fibrosis marker (APRI and FIB-4) levels, as well as more rapid increases in fibrosis marker levels in women who experienced a liver-related death compared with women who experienced a nonliver-related death. As the components of these indirect fibrosis tests are readily available as part of clinical care, they can be used to assess progression of liver fibrosis and even risk of mortality in co-infected women. This may lead patients and their providers to more strongly consider HCV therapy. Better, noninvasive methods for assessment of liver fibrosis are needed to provide timely selection of women whose liver disease is progressing and who are, therefore, in more urgent need of therapy for HCV.