Summary and Introduction
The most reliable predictor of a sustained virological response in patients with persistently normal ALT has not been identified. We analysed 17 patients with genotype 1 chronic HCV who underwent therapy with pegylated interferon alfa 2b and ribavirin for 48 weeks. Two patients discontinued therapy within 28 days because of side effects and the remaining 15 patients were analysed in detail. An analysis of on treatment virological response using area under the receiver operating characteristic analyses showed that a 2 log drop in HCV RNA at day 28 was the best predictor of a sustained virological response and a failure to reduce viral load by 2 logs correctly identified patients with a low (<15%) probability of achieving a sustained virological response. Introduction of this early discontinuation rule in patients with normal ALT would allow nearly half of the patients to discontinue futile therapy at an early stage.
Hepatitis C virus (HCV) represents an important public health issue and an economic burden. Alanine aminotransferase (ALT) is commonly used as a marker of hepatic inflammation and damage in HCV infection. Fluctuating ALT levels characterize chronic hepatitis C, but in 30–40% of infected HCV patients, ALT values are persistently normal.
Controversy persists concerning virological, epidemiological and histological characteristics of HCV patients with persistently normal ALT levels, while the natural history of disease in patients with normal serum ALT remains unsettled. Available data suggest that patients with persistently normal ALT levels are more likely to be women, generally having milder disease and a relatively favourable prognosis. This suspected favourable prognosis was supported in our study of over 200 patients with chronic HCV infection; patients with normal ALT had half the rate of fibrosis progression of those with elevated ALT. However, up to 5–10% of patients with normal ALT levels have bridging fibrosis or cirrhosis, suggesting that a relatively favourable prognosis is not universal. Moreover, about 30–50% of patients showed abnormal ALT levels over extended follow-up.
Pegylated interferon (PEG IFN) with ribavirin is the established therapy for HCV patients with elevated ALT levels. A large international randomized study in patients with persistently normal ALT levels showed that PEG IFN-α2a plus ribavirin had similar efficacy, tolerance and safety as that in patients with elevated ALT levels. The evolving standard of care suggests that patients with persistently normal ALT should be evaluated for treatment based on considerations similar to those for patients with abnormal ALT. Nevertheless, when considering discrete or moderate liver injury, early criteria highly predictive of viral eradication are crucial to avoid unnecessary prolongation of treatment in patients with low sustained virological response (SVR) probability.
One early predictive criterion of SVR was identified from previous studies focusing on HCV RNA kinetics. Upon antiviral treatment, HCV RNA kinetics comport a triphasic decline referred to as the ε, δ and Mδ phases. These three phases correspond, respectively, to blocking of viral production, pre-treatment-infected-cell loss and infected-cell loss during treatment. Patients with chronic hepatitis C and persistently normal ALT disclosed similar viral kinetics as those with elevated ALT levels during antiviral therapy. In patients with elevated ALT, a 2-log HCV RNA drop at week 12, the so-called 'early virological response', is a simple and reliable tool for early prediction of SVR. More recently, it has been shown that undetectable HCV RNA at week 4 (so-called 'rapid virological response') identified HVC-1 patients highly responsive to PEG IFN plus ribavirin, with SVR ranging from 80 to 90%. However, the rapid virological response is highly specific but not sensitive, as it identifies only 20% of patients who will attain SVR. Thus, this criterion cannot be used in clinical practice to decide treatment discontinuation. Unfortunately, investigators did not focus on patients with persistently normal ALT to describe early criteria predictive of SVR.
Up until now, there has been a paucity of studies using a statistical approach and specifically devoted to finding the most valid virological criteria (both highly sensitive and highly specific) predictive of SVR in patients with normal ALT. One optimal approach lies in comparison of the area under the receiver operating characteristic (AUROC) curves according to different time points. The aim of the present work was to study HCV-1 patients with normal ALT, treated with peg-interferon-α2b and ribavirin, for identification of: (1) the earliest and most optimal time at which the decline in viral load becomes the best predictor of SVR; and (2) the best cut-off of viral load reduction predictive of SVR.