P. Ingiliz

Chapter 4 Biomarkers Of Liver Fibrosis

1. Abstract Liver biopsy, due to its limitations and risks, is an imperfect gold standard for assessing the severity of the most frequent chronic liver diseases. This chapter summarized the advantages and the limits of the available biomarkers of liver fibrosis. Among a total of 2237 references, a total of 14 validated biomarkers have been identified between 1991 and 2007. Nine were not patented and five were patented. FibroTest™ (FT) was the most studied test with 33 different populations including 6549 patients and 925 controls. The mean diagnostic value for the diagnosis of advanced fibrosis assessed using standardized area under the receiver operating characteristics (ROC) curves was 0.84 [95% confidence interval (CI), 0.83–0.86], without significant difference between the causes of liver disease, hepatitis C, hepatitis B, alcoholic or nonalcoholic fatty liver disease. High‐risk profiles of false negative/ positive of FT are present in 3% of populations, mainly Gilbert syndrome, hemolysis, and acute inflammation. FT has higher accuracy than aspartate aminotransferase/platelets ratio index (APRI), the most used nonpatented test. No significant difference has been observed between the five patented tests. A quality score has been assessed in order to compare the quality of fibrosis biomarkers. Neither biomarkers nor biopsy are sufficient alone to take definitive decision in a given patient and all the clinical and biological data must be taken into account. Due to the evidence‐based data, health authorities in some countries have already approved validated biomarkers as first‐line procedure for the staging of liver fibrosis. This overview of evidence‐based data suggests that biomarkers could be used as an alternative to liver biopsy for the assessment of fibrosis stage in the four more common chronic liver diseases: C virus (HCV), hepatitis B virus (HBV), hepatitis nonalcoholic fatty liver disease (NAFLD), and alcoholic liver disease (ALD). Neither biomarkers nor biopsy are sufficient alone to take definitive decision in a given patient and all the clinical and biological data must be taken into account.

HCV reinfection incidence and spontaneous clearance rates in HIV-positive men who have sex with men in Western Europe

BACKGROUND & AIMS Moderate cure rates of acute hepatitis C virus (HCV) infections with pegylated interferon and ribavirin have been described in the last decade in men who have sex with men (MSM), who are also coinfected with the human immunodeficiency virus (HIV). However, a subsequent high incidence of HCV reinfections has been reported regionally in men who both clear the infection spontaneously or who respond to treatment. METHODS Retrospective analysis of reinfections in HIV infected MSM in eight centers from Austria, France, Germany, and the UK within the NEAT network between May 2002 and June 2014. RESULTS Of 606 individuals who cleared HCV spontaneously or were successfully treated, 149 (24.6%) presented with a subsequent HCV reinfection. Thirty out of 70 (43%) who cleared again or were successfully treated, presented with a second reinfection, 5 with a third, and one with a fourth reinfection. The reinfection incidence was 7.3/100 person-years (95% CI 6.2-8.6). We found a trend for lower incidence among individuals who had spontaneously cleared their incident infection than among individuals who were treated (Hazard ratio 0.62, 95% CI 0.38-1.02, p=0.06). Spontaneous clearance of reinfection was associated with ALT levels >1000IU/ml and spontaneous clearance of a prior infection. CONCLUSIONS HCV reinfection is an issue of major concern in HIV-positive MSM. Prevention strategies are needed for high risk groups to reduce morbidity and treatment costs. HIV-positive MSM with a prior HCV infection should be tested every 3 to 6months for reinfection. Those who had achieved a reinfection should be tested every 3months. LAY SUMMARY We evaluated the occurrence of HCV reinfection in HIV-positive men who have sex with men. We found an alarming incidence of 7.3/100 person-years. Prevention measures need to address this specific subgroup of patients at high risk for HCV.

Assessment of liver fibrosis: noninvasive means.

Liver biopsy, owing to its limitations and risks, is an imperfect gold standard for assessing the severity of the most frequent chronic liver diseases chronic hepatitis C (HCV), B (HBV) non alcoholic (NAFLD) and alcoholic (ALD) fatty liver diseases. This review summarizes the advantages and the limits of the available biomarkers of liver fibrosis. Among a total of 2,237 references, a total of 14 validated serum biomarkers have been identified between 1991 and 2008. Nine were not patented and five were patented. Two alternatives to liver biopsy were the most evaluated FibroTest and Fibroscan. For FibroTest, there was a total of 38 different populations including 7,985 subjects with both FibroTest and biopsy (4,600 HCV, 1,580 HBV, 267 NAFLD, 524 ALD, and 1014 mixed). For Fibroscan, there was a total of 11 published studies including 2,260 subjects (1,466 HCV, 95 cholestatic liver disease, and 699 mixed). For FibroTest, the mean diagnostic value for the diagnosis of advanced fibrosis assessed using standardized area under the ROC curves was 0.84 (95% confidence interval 0.83-0.86), without a significant difference between the causes of liver disease, hepatitis C, hepatitis B, and alcoholic or non alcoholic fatty liver disease. High-risk profiles of false negative/false positive of FibroTest, mainly Gilbert syndrome, hemolysis and acute inflammation, are present in 3% of the populations. In case of discordance between biopsy and FibroTest, half of the failures can be due to biopsy; the prognostic value of FibroTest is at least similar to that of biopsy in HCV, HBV and ALD. In conclusion this overview of evidence-based data suggests that biomarkers could be used as an alternative to liver biopsy for the first line assessment of fibrosis stage in the four most common chronic liver diseases, namely HCV, HBV, NAFLD and ALD. Neither biomarkers nor biopsy alone is sufficient for taking a definite decision in a given patient; all the clinical and biological data must be taken into account. There is no evidence based data justifying biopsy as a first line estimate of liver fibrosis. Health authorities in some countries have already approved validated biomarkers as the first line procedure for the staging of liver fibrosis.

Hepatitis B Surface Antigen Concentrations in Patients with HIV/HBV Co-Infection

HBsAg clearance is associated with clinical cure of chronic hepatitis B virus (HBV) infection. Quantification of HBsAg may help to predict HBsAg clearance during the natural course of HBV infection and during antiviral therapy. Most studies investigating quantitative HBsAg were performed in HBV mono-infected patients. However, the immune status is considered to be important for HBsAg decline and subsequent HBsAg loss. HIV co-infection unfavorably influences the course of chronic hepatitis B. In this cross-sectional study we investigated quantitative HBsAg in 173 HBV/HIV co-infected patients from 6 centers and evaluated the importance of immunodeficiency and antiretroviral therapy. We also compared 46 untreated HIV/HBV infected patients with 46 well-matched HBV mono-infected patients. HBsAg levels correlated with CD4 T-cell count and were higher in patients with more advanced HIV CDC stage. Patients on combination antiretroviral therapy (cART) including nucleos(t)ide analogues active against HBV demonstrated significant lower HBsAg levels compared to untreated patients. Importantly, HBsAg levels were significantly lower in patients who had a stronger increase between nadir CD4 and current CD4 T-cell count during cART. Untreated HIV/HBV patients demonstrated higher HBsAg levels than HBV mono-infected patients despite similar HBV DNA levels. In conclusion, HBsAg decline is dependent on an effective immune status. Restoration of CD4 T-cells during treatment with cART including nucleos(t)ide analogues seems to be important for HBsAg decrease and subsequent HBsAg loss.

HIV-HCV co-infection facing HCV protease inhibitor licensing: implications for clinicians.

With the licensing of the first hepatitis C (HCV) protease inhibitors (PI), telaprevir (TVR) and boceprevir (BOC), cure rates for chronic HCV infection will substantially improve. Human immunodeficiency virus‐ chronic hepatitis C (HIV‐HCV) co‐infected patients are in urgent need for these new drugs, because they are facing both severe liver disease and lower response rates than HCV monoinfected patients. The currently available efficacy data are however, limited to two phase II trials. Fortunately, TVR and BOC appear to be able to improve cure rates in co‐infected patients. A major challenge for clinicians will be the management of drug–drug interactions of antiretroviral drugs and new PI. As HCV PI are also metabolized by the cytochrome P450 3A4 system interactions are probable as well with non‐nucleoside reverse transcriptase inhibitors as with HIV PI. To our knowledge, TVR can only be safely used with one protease inhibitor, boosted atazanavir, and also with efavirenz (EFV), although this combination requires TVR dose adjustments. Boceprevir should not be combined with HIV PI and should not be combined with EFV. The approval of TVR and BOC will create new chances of cure also for HIV‐HCV co‐infected patients. However, the decision who to treat or not has to be taken carefully on the basis of fibrosis stage and previous treatment outcomes. In addition, HIV therapy needs to be optimized according to the available drug–drug interaction data.

Variation in IFNL4 genotype and response to interferon-based therapy of hepatitis C in HIV-positive patients with acute and chronic hepatitis C.

The IFNL4 ss469415590 polymorphism has recently be shown to better predict treatment response in chronic hepatitis than the IL28B rs12979860 variant. However, no data exist in patients with HIV/hepatitis C virus (HCV) coinfection. Analysing 206 HCV(+)/HIV(+) and 162 HCV(+)/HIV(−) patients, we found that compared with IL28B rs12979860, IFNL4 ss469415590 was strongly associated with response to interferon/ribavirin therapy in HCV(+)/HIV(−) individuals but not in HIV(+)/HCV(+) patients. Thus, effects of the IFNL4 variant may differ in HIV(+) and HIV(−) patients.

High efficacy of sofosbuvir/velpatasvir and impact of baseline resistance-associated substitutions in hepatitis C genotype 3 infection

Twelve weeks of the pangenotypic direct‐acting antiviral (DAA) combination sofosbuvir/velpatasvir (SOF/VEL) was highly efficient in patients with hepatitis C virus (HCV) genotype 3 (GT3) infection in the ASTRAL‐3 approval study. However, presence of resistance‐associated substitutions (RASs) in the HCV nonstructural protein 5A (NS5A) was associated with lower treatment response.

Liver injury in HIV monoinfected patients: should we turn a blind eye to it?

With the advent of combined antiretroviral therapies, liver diseases have emerged as a key issue in the management of HIV infection. In addition to hepatitis co-infection, a large spectrum of liver diseases can affect the prognosis of HIV infection. Acute or progressive hepatic injuries require an accurate diagnosis for a better clinical management. Here, we provide an overview of the main liver diseases associated with HIV infection, which are not covered by the widely documented field of viral hepatitis co-infection.

Clinical and virological heterogeneity of hepatitis delta in different regions world-wide: The Hepatitis Delta International Network (HDIN)

Chronic hepatitis D (delta) is a major global health burden. Clinical and virological characteristics of patients with hepatitis D virus (HDV) infection and treatment approaches in different regions world‐wide are poorly defined.

Acute hepatitis C virus (HCV) infection in the setting of HIV coinfection: a single-centre 10-year follow-up

Acute hepatitis C virus (HCV) infection has emerged as a major cause of morbidity in the HIV‐infected population. Most guidelines recommend early treatment with pegylated interferon and ribavirin due to higher cure rates. The impact of acute HCV and its treatment on the outcome of the HIV‐infected population is unknown. With new treatment options for HCV, early treatment of acute HCV has to be questioned. Here, we report a long‐term analysis on patients with acute HCV.