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Regression of liver fibrosis in hepatitis C virus/HIV-co-infected patients after treatment with pegylated interferon plus ribavirin

Soriano, Vincenta; Labarga, Pabloa; Ruiz-Sancho, Andrésa; Garcia-Samaniego, Javierb; Barreiro, Pabloa

doi: 10.1097/01.aids.0000247583.38943.95
Epidemiology and Social: Editorial Comment

From the aDepartment of Infectious Diseases

bHepatology Unit, Hospital Carlos III, Madrid, Spain.

Correspondence to Vincent Soriano, Department of Infectious Diseases, Hospital Carlos III, Calle Sinesio Delgado 10, 28029 Madrid, Spain. Tel: +34 91 4532500; fax: +34 91 7336614; e-mail:

Chronic hepatitis C virus (HCV) infection affects one third of HIV-infected patients worldwide, but it is overepresented in the subset of individuals infected parenterally, such as intravenous drug users and haemophiliacs [1]. Progression to end-stage liver disease occurs faster in HCV/HIV-co-infected compared with HCV-monoinfected individuals. Overall, liver cirrhosis is seen in nearly half of dually infected patients after 25 years of chronic HCV infection [2–4]. As the average age of HIV-positive individuals in most western countries is currently approximately 45 years, and most co-infected patients were exposed to HCV for the first time before the age of 20 years, a large and growing number of them have already or will soon develop end-stage liver disease. This explains why clinical complications of cirrhosis and portal hypertension, such as ascites, hepatic encephalopathy, variceal bleeding and even hepatocellular carcinoma, have become a major cause of hospital admission and death among HCV/HIV-co-infected patients in western countries in recent years [5–7].

The combination of pegylated interferon plus ribavirin is the recommended treatment for chronic hepatitis C. Although response is overall achieved by 55–60% of HCV-monoinfected [8,9] and only 28–40% of HCV/HIV-co-infected patients [10,11], it should be highlighted that success translates into the cure or eradication of HCV. This goal is not achievable in HIV infection. The demonstration of negative serum HCV RNA 6 months after the completion of a course of anti-HCV therapy, which is known as sustained virological response (SVR), is strongly associated with the permanent clearance of HCV. This has been proved in a recent analysis of 492 HCV-monoinfected patients who had achieved SVR with previous anti-HCV therapy and were re-assessed 5 years later [12]. In that study, only five individuals relapsed, all within the first year. The Kaplan–Meier estimate for continued SVR over 5 years was 99%. A similar analysis conducted in HCV/HIV-co-infected patients reproduced these findings; none of 77 co-infected subjects who achieved SVR with interferon-based therapies showed virological relapse over the next 5 years of follow-up [13]. This observation was particularly noteworthy because a worsening of HIV-related immunodeficiency occurred in some of the patients.

Given that liver histology rather than plasma viraemia is the most important prognostic factor in patients with chronic hepatitis C [14], it remains important to clarify to what extent virological clearance is associated with histological improvement. Ultimately this benefit should translate into the absence of clinical manifestations, such as decompensated liver disease or hepatocellular carcinoma. Interferon-based therapies may improve liver damage in chronic hepatitis C by two mechanisms. First, by eliminating HCV, which is the trigger of the inflammatory processes driving hepatic lesions. Second, through its intrinsic anti-inflammatory effects, suppressing the release of profibrogenic cytokines such as transforming growth factor 1 beta, hyaluronic acid and procollagen III [15]. The latest effect of interferon explains the histological benefit noticed in many treated patients despite not achieving SVR, and has provided the rationale for exploring whether maintenance therapy with low doses of pegylated interferon can ameliorate liver disease deterioration when HCV eradication is not feasible [16]. Several large trials in HCV-monoinfected (EPIC3, HALT-C, Co-PILOT) and more recently in HIV-co-infected (SLAM-C and ENDURE) virological non-responders are currently under way to prove this hypothesis.

In this issue of the journal, Lissen et al. [17] report the results of a substudy of the APRICOT trial [10], in which the histological response to anti-HCV treatment was assessed in 401 HCV/HIV-co-infected patients with paired liver biopsies at baseline and after an average of 6 months after the completion of treatment. The histological benefit was significantly greater in patients receiving pegylated interferon plus ribavirin than in those receiving pegylated interferon monotherapy or standard interferon plus ribavirin.

These results from the APRICOT study are good news, and expand to HIV-infected patients what is seen in HCV-monoinfected individuals. Moreover, they confirm preliminary evidence from the ACTG 5071 trial, a smaller study in HCV/HIV-co-infected patients in which 35% of non-responders showed histological improvement shortly after ending therapy [18]. The study by Lissen et al. [17] is the largest study conducted so far in dually infected patients, and provides reassuring evidence of a beneficial histological effect of anti-HCV therapy in this population. Two main caveats, however, might temper the optimistic interpretation of the results made by the authors. First, the second liver biopsy was performed too close to the end of therapy (6 months on average). Studies in which second liver biopsies have been performed much later after the completion of therapy have not proved a significant histological benefit in patients who were not cured [12,19]. This observation underlines the fact that histological improvements while on therapy or shortly thereafter mainly reflect the antifibrotic effect on interferon [15,16], and therefore it tends to vanish thereafter in patients who did not clear HCV. A second aspect of interest is that histological worsening was seen in 20% of APRICOT patients treated with interferon plus ribavirin, 27% of those exposed to pegylated interferon alone, and in 13% of those treated with pegylated interferon plus ribavirin. Moreover, worsening was recognized in 10% of patients cured of HCV. This is somewhat unexpected, and might reflect the limitations of liver biopsy in terms of reliability [20,21], as well as the short lag of time between the first and second liver biopsies in the study.

With the advent of new non-invasive methods to assess hepatic fibrosis, the long-term pathological monitoring of patients with chronic hepatitis C exposed to interferon-based therapies is now feasible and permits investigation of the potential reversibility of liver fibrosis. In APRICOT, a large proportion of patients refused to undergo a second liver biopsy. Using transient elastometry, a new non-invasive tool that accurately measures liver fibrosis [22,23], at least three recent studies have demonstrated that long-term follow-up of patients with SVR is associated with a reduction in liver fibrosis staging [24–26]. Uniformly, they showed different degrees of regression of hepatic fibrosis in responders, but invariably fibrosis progression in non-responders or relapsers to interferon-based therapies. Moreover, the longer the time after ending HCV therapy, the less the severity of liver fibrosis among SVR [26]. However, the degree of histological benefit in responders was not uniform nor universal, and complete normalization was seen only rarely, even after many years of follow-up. This is consistent with the notion that hepatic fibrosis mainly constituted by collagen 3 deposits is subject to dynamic processes of production and removal, whereas the storage of collagen 1 represents a fixed material in most instances. At this time it is difficult to ascertain which collagen predominates in a given patient's liver. Altogether, even with the limitations mentioned, these findings support the theory that liver fibrosis, including cirrhosis, can be reversible although not universally, and may only be recognized after many years in patients who have cleared HCV infection with interferon-based therapies.

Sponsorship: This work was partly supported by grants from Fundación Investigación y Educación en SIDA (IES), Agencia Lain Entralgo, Red de Investigación en SIDA (RIS) and the VIRGIL Network.

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cirrhosis; hepatitis C; HIV; interferon; liver; ribavirin

© 2006 Lippincott Williams & Wilkins, Inc.