https://orcid.org/0000-0003-4211-456X
To the Editor—Gardner et al [1] reported the course over time of 3 noninvasive markers of fibrosis (enhanced liver fibrosis [ELF], aspartate aminotransferase to platelet ratio index [APRI], and Fibrosis-4 [FIB-4]) in 116 women with human immunodeficiency virus/hepatitis C virus (HIV/HCV) treated with direct-acting antiviral (DAA) drugs for their HCV infection. The authors analyzed 2 time points posttherapy, at indeterminate dates situated within 1 year and 1–2 years. They found that fibrosis regression occurred within the first year posttreatment, but not in the following period (1–2 years after DAA). They concluded that the flattening in the slopes during the 1–2-year period after HCV cure suggests that continued monitoring and interventions to mitigate fibrosis progression remains essential. Our study, published on 9 March 2022 [2], is relevant to their findings and helps to clarify uncertainties in their data.
In our study, we prospectively and comprehensively analyzed a large cohort of 374 patients with HCV (110 women, 214 HIV/HCV coinfected). In this population, we evaluated 4 noninvasive markers of fibrosis (transient elastography [TE], APRI, Forns, and FIB-4), as well as diverse metalloproteinase single-nucleotide polymorphisms, and a large number of covariates determined at the following time points: baseline, 1, 3, 6, 12, and 24 months after the onset of DAA treatment. This fixed time schedule allowed us to analyze the changes over time more precisely.
Our results show that there was a decline in TE during the 2-year follow-up. Regarding the other 3 markers, our results were clear and reliable: there was a marked improvement in the 3 markers within the first month after the onset of therapy, followed by a flattening of the curves during the remaining follow-up.
Figure 1 displays the course over time of APRI and FIB-4, the 2 markers evaluated by Gardner et al [1] (the course of Forns, not shown, was very similar). As AST and AST are components of these 2 markers, we also displayed their values over time.
Course over time of mean aspartate aminotransferase to platelet ratio index (APRI) and Fibrosis-4 (FIB-4) indexes, as well as aspartate aminotransferase (AST) and alanine aminotransferase (ALT). Error bars show 95% confidence intervals.
Figure 1 shows clearly the initial, rapid improvement in APRI and FIB-4 to reach a plateau after the first month, similarly to that observed in the curves of AST and ALT, which averaged completely normal levels as early as the first month. This very early improvement in these tests seems to be the consequence of a rapid recovery in the inflammation [3–9], followed by further stabilization. Therefore, these indexes are clearly not useful for the evaluation of fibrosis following treatment.
On the other hand, we also found in our study that there was no difference in the measurements of these fibrosis markers at each time point, or during the 2-year follow-up, between individuals with HCV monoinfection and HIV/HCV coinfection. Therefore, the same limitations apply irrespective of the HIV serostatus.
Kronfli et al [9] also observed a relatively early decrease in APRI and FIB-4 after treatment to remain stable later, but the first time point used in their study (3 months) was appreciably longer than ours (1 month), and the values we observed at the third month were very similar to those already reached at the first month. Furthermore, another study reported that the improvement in these markers occurs as early as 2 weeks after the onset of therapy [5].
We did not evaluate the ELF index, but in a subset of 61 patients we also measured several metalloproteinases and their tissue inhibitors, including TIMP-1, which is a component of the ELF index, and observed a continuous and steady decrease in plasma levels during the 2 years of follow-up. Other authors have also stressed the possible role of TIMP-1 as a marker of liver fibrosis [3].
Gardner et al [1] question the value of ELF to evaluate the posttreatment course of fibrosis, as there was a flattening in the slope during the 1–2 year period. However, our results suggest that at least TIMP-1, one of its components, would be adequate for this purpose, as TIMP-1 levels continued decreasing during that period.
In summary, APRI, FIB-4, and Forns indexes are not valid for the assessment of liver fibrosis after treatment, because they are tightly dependent on the AST and ALT values, and these enzymes decrease rapidly after therapy to remain stable later, even when liver fibrosis continues improving.
The wide range of time used by Gardner et al [1] for the first posttherapy evaluation (1 year) precluded identification that the changes observed in APRI and FIB-4 indexes occur early during the first month, then stabilize. On the contrary, TIMP-1 decreased steadily in our study during the 2-year follow-up.
Notes
Disclaimer. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Financial support. This work was supported by the Ministry of Health of Spain, Fondo de Investigaciones Sanitarias (grant numbert FISS-17-PI/16/01999); and ViiVHealthcare Spain research grant (both given to V.A.).
References
Author notes
Potential conflicts of interest. All authors: No reported conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.
