Hélène Fontaine

FIB-4: an inexpensive and accurate marker of fibrosis in HCV infection. comparison with liver biopsy and fibrotest.

To optimize the management of patients with chronic hepatitis C virus (HCV) infection, noninvasive tests to determine the degree of hepatic fibrosis have been developed. The aims of this study were (1) to validate a simple, inexpensive, noninvasive test called FIB‐4, which combines standard biochemical values (platelets, ALT, AST) and age, in a series of 847 liver biopsies performed in HCV‐monoinfected patients; and (2) to compare the results of 780 FIB‐4 and FibroTests performed the same day in a series of 592 HCV‐infected patients. The FIB‐4 index enabled the correct identification of patients with severe fibrosis (F3‐F4) and cirrhosis with an area under the receiver operating characteristic curve of 0.85 (95% CI 0.82‐0.89) and 0.91 (95% CI 0.86‐0.93), respectively. An FIB‐4 index <1.45 had a negative predictive value of 94.7% to exclude severe fibrosis with a sensitivity of 74.3%. An FIB‐4 index higher than 3.25 had a positive predictive value to confirm the existence of a significant fibrosis (F3‐F4) of 82.1% with a specificity of 98.2%. Using these ranges, 72.8% of the 847 liver biopsies were correctly classified. The FIB‐4 index was strongly correlated to the FibroTest results for a score <1.45 or >3.25 (κ = 0.561, P < 0.01). A FIB‐4 value <1.45 or >3.25 (64.6% of the cases) was concordant with FibroTest results in 92.1% and 76%, respectively. Conclusion: For values outside 1.45‐3.25, the FIB‐4 index is a simple, accurate, and inexpensive method for assessing liver fibrosis and proved to be concordant with FibroTest results. (HEPATOLOGY 2007.)

Triple therapy in treatment-experienced patients with HCV-cirrhosis in a multicentre cohort of the French Early Access Programme (ANRS CO20-CUPIC) – NCT01514890

BACKGROUND & AIMS In phase III trials, the safety profile of triple therapy (pegylated interferon/ribavirin with boceprevir or telaprevir) seems to be similar in HCV treatment-experienced cirrhotic and non-cirrhotic patients, but few cirrhotics were included. We report the week 16 safety and efficacy analysis in a cohort of compensated cirrhotics treated in the French Early Access Programme. METHODS 674 genotype 1 patients, prospectively included, received 48 weeks of triple therapy. The analysis is restricted to 497 patients reaching week 16. RESULTS A high incidence of serious adverse events (40.0%), and of death and severe complications (severe infection or hepatic decompensation) (6.4%), and a difficult management of anaemia (erythropoietin and transfusion use in 50.7% and 12.1%) were observed. Independent predictors of anaemia < 8 g/dl or blood transfusion were: female gender (OR 2.19, 95% CI 1.11-4.33, p=0.024), no lead-in phase (OR 2.25, 95% CI 1.15-4.39, p=0.018), age ≥ 65 years (OR 3.04, 95% CI 1.54-6.02, p=0.0014), haemoglobin level (≤ 12 g/dl for females, ≤ 13 g/dl for males) (OR 5.30, 95% CI 2.49-11.5, p=0.0001). Death or severe complications were related to platelets count ≤ 100,000/mm(3) (OR 3.11, 95% CI 1.30-7.41, p=0.0105) and albumin <35 g/dl (OR 6.33, 95% CI 2.66-15.07, p=0.0001), with a risk of 44.1% in patients with both. However, the on-treatment virological response was high. CONCLUSIONS The safety profile was poor and patients with platelet count ≤ 100,000/mm(3) and serum albumin <35 g/L should not be treated with the triple therapy.

Ultrasonographic surveillance of hepatocellular carcinoma in cirrhosis: A randomized trial comparing 3- and 6-month periodicities†‡

Detection of small hepatocellular carcinoma (HCC) eligible for curative treatment is increased by surveillance, but its optimal periodicity is still debated. Thus, this randomized trial compared two ultrasonographic (US) periodicities: 3 months versus 6 months. A multicenter randomized trial was conducted in France and Belgium (43 sites). Patients with histologically proven compensated cirrhosis were randomized into two groups: US every 6 months (Gr6M) or 3 months (Gr3M). For each focal lesion detected, diagnostic procedures were performed according to European Association for the Study of the Liver guidelines. Cumulative incidence of events was estimated, then compared using Grays test. The prevalence of HCC ≤30 mm in diameter was the main endpoint. A sample size of 1,200 patients was required. A total of 1,278 patients were randomized (Gr3M, n = 640; Gr6M, n = 638; alcohol 39.2%, hepatitis C virus 44.1%, hepatitis B virus 12.5%). At least one focal lesion was detected in 358 patients (28%) but HCC was confirmed in only 123 (9.6%) (uninodular 58.5%, ≤30 mm in diameter 74%). Focal‐lesion incidence was not different between Gr3M and Gr6M groups (2‐year estimates, 20.4% versus 13.2%, P = 0.067) but incidence of lesions ≤10 mm was increased (41% in Gr3M versus 28% in Gr6M, P = 0.002). No difference in either HCC incidence (P = 0.13) or in prevalence of tumors ≤30 mm in diameter (79% versus 70%, P = 0.30) was observed between the randomized groups. Conclusion: US surveillance, performed every 3 months, detects more small focal lesions than US every 6 months, but does not improve detection of small HCC, probably because of limitations in recall procedures. (HEPATOLOGY 2011;)

Nodular regenerative hyperplasia is a new cause of chronic liver disease in HIV-infected patients.

Objective:To describe and explain the syndrome of HIV-associated cryptogenic liver disease in eight consecutive patients suffering from portal hypertension. Methods:The study was undertaken at a liver disease centre in Paris and involved eight of 97 consecutive HIV-infected patients presenting abnormal liver function tests and/or symptomatic portal hypertension of unknown origin. Serology, pathology, and liver function tests were performed. Results:A clear nodular architecture corresponding to nodular regenerative hyperplasia was observed in seven patients and suggested in one, based on the presence of sinusoidal dilatation in a clinical context of portal hypertension, without overt liver disease. Conclusions:Nodular regenerative hyperplasia appears to be a new cause of portal hypertension in HIV-infected patients. This syndrome can be of critical importance as patients can be exposed to the significant complications of portal hypertension and to refractory ascites which may require liver transplantation.

Predictive factors for development of cirrhosis in parenterally acquired chronic hepatitis C: a comparison between immunocompetent and immunocompromised patients

BACKGROUND/AIMS The aim of this study was to evaluate the impact of the host immune status and of virological and environmental parameters on the development of cirrhosis during chronic hepatitis C virus infection. METHODS Liver histology (cirrhosis or not, Knodell score) was evaluated according to age, sex, route and age of contamination, alcohol consumption and immune status in a large series of 553 HBsAg-negative patients (whose duration of hepatitis C virus infection could be precisely evaluated) divided into three groups: group 1 consisted of 462 immunocompetent subjects (46.1% intravenous drug users, 53.9% transfused), infected for a mean of 12.5+/-6.7 years, including 16.6% of alcohol abusers (>80 g/day); groups 2a and 2b consisted of 91 immunocompromised patients, 52 human immunodeficiency virus-coinfected patients corresponding to group 2a and 39 kidney recipients undergoing immunosuppressive therapy for group 2b, having been infected by hepatitis C virus for a mean of 12.6+/-5.3 and 11.5+/-5.3 years, respectively. RESULTS Group 1: cirrhosis was present in 11.0% of group 1 patients and in 23.6% of immunocompetent patients with a duration of hepatitis C virus infection of 20 years or more. Forty-three percent of patients with cirrhosis and with hepatitis C virus infection for more than 20 years were alcohol abusers. The time taken to develop cirrhosis was 14+/-7 years in patients infected before the age of 40 years as compared to 8+/-5 years in those infected after 40 years (p<0.001). Groups 2a and 2b: cirrhosis was present in 19.8% of immunocompromised patients, a significantly higher rate than in immunocompetent patients (p<0.01). Alcohol abuse did not increase the risk of cirrhosis in this group. All patients but one were infected by hepatitis C virus before the age of 40 and the calculated time elapsed until the occurrence of cirrhosis was 12.4+/-5.5 years. In groups 1, 2a and 2b, there was no relation between histological severity, hepatitis C virus genotype and viral load. Four variables were independently associated with the occurrence of cirrhosis in the multivariate analysis: age over 40 at time of contamination (RR=9.3 in age range 40 to 59 and 91.2 in > or =60 years); long duration (> or =20 years) of hepatitis C virus infection (RR=15.4); alcohol consumption over 80 g/d (RR=2.9); and human immunodeficiency virus-coinfection (RR=2.6). CONCLUSIONS Our study on a large series of well-characterized patients provides an accurate evaluation of the risk of cirrhosis in parenterally-contaminated immunocompetent hepatitis C virus-infected patients, with an overall figure of 11%. It also demonstrates the impact of the host immune status on the risk of severe histological lesions during chronic hepatitis C virus infection. It finally establishes the importance of age at the time of viral infection in the occurrence of cirrhosis, as well as the importance of alcohol consumption. Thus, at least following parenteral infection, both host-related and environmental cofactors play a major role in the severity of the liver lesions associated with hepatitis C virus infection.

A Gene Expression Signature that Can Predict the Recurrence of Tamoxifen-Treated Primary Breast Cancer

Purpose: The identification of a molecular signature predicting the relapse of tamoxifen-treated primary breast cancers should help the therapeutic management of estrogen receptor–positive cancers. Experimental Design: A series of 132 primary tumors from patients who received adjuvant tamoxifen were analyzed for expression profiles at the whole-genome level by 70-mer oligonucleotide microarrays. A supervised analysis was done to identify an expression signature. Results: We defined a 36-gene signature that correctly classified 78% of patients with relapse and 80% of relapse-free patients (79% accuracy). Using 23 independent tumors, we confirmed the accuracy of the signature (78%) whose relevance was further shown by using published microarray data from 60 tamoxifen-treated patients (63% accuracy). Univariate analysis using the validation set of 83 tumors showed that the 36-gene classifier is more efficient in predicting disease-free survival than the traditional histopathologic prognostic factors and is as effective as the Nottingham Prognostic Index or the “Adjuvant!” software. Multivariate analysis showed that the molecular signature is the only independent prognostic factor. A comparison with several already published signatures demonstrated that the 36-gene signature is among the best to classify tumors from both training and validation sets. Kaplan-Meier analyses emphasized its prognostic power both on the whole cohort of patients and on a subgroup with an intermediate risk of recurrence as defined by the St. Gallen criteria. Conclusion: This study identifies a molecular signature specifying a subgroup of patients who do not gain benefits from tamoxifen treatment. These patients may therefore be eligible for alternative endocrine therapies and/or chemotherapy.

Hepatitis C virus in the semen of men coinfected with HIV-1: prevalence and origin.

Objective:To compare the prevalence of hepatitis C (HCV) RNA in semen from men infected with HCV and those coinfected with HIV-1/HCV and to study the origin of HCV shed in semen. Design:Two prospective studies (HC EP09 and BINECO) included 120 HCV-positive men, 82 coinfected with HIV-1; all had positive HCV RNA detection in blood. Methods:Paired blood and semen samples were collected for HCV RNA detection and quantification in seminal plasma and in blood serum; repeated semen samples were obtained for 45 men. HCV RNA was sought in spermatozoa and non-sperm cells. Phylogenetic analysis of the HVR-1 region of HCV compared the quasispecies in blood serum and seminal plasma of two men. Results:HCV RNA was more frequently found in the semen of men coinfected with HIV-1 (37.8%) than in those with only HCV infection (18.4%) (P = 0.033). HCV RNA detection in semen was intermittent and was positive in at least one semen sample of 42.8% of HIV-1/HCV-coinfected men who provided repeated samples. Men with HCV-positive semen had significantly higher HCV load in blood than men with HCV-negative semen (P = 0.038). Phylogenetic comparison of HCV quasispecies in blood and in semen showed no evidence of HCV replication in genital leukocytes; however, a phenetic structure was observed between compartments (P < 0.001). Conclusions:HCV particles in semen originate from passive passage from blood, with preferential transfer of some variants. Nearly half of HIV-1/HCV-coinfected men may intermittently harbour HCV in their semen. Recommendations of protected sex for HIV-infected individuals should be reinforced.

Safety and efficacy of interferon-ribavirin combination therapy in HCV-HIV coinfected subjects: an early report

BACKGROUND More severe liver disease together with a poor response rate to α interferon argue for the use of more potent anti-hepatitis C virus (HCV) therapies in human immunodeficiency virus (HIV)-HCV coinfected patients, but the efficacy and safety of interferon-ribavirin combination therapy in HIV infected subjects are unknown. AIM To retrospectively evaluate the efficacy and safety of anti-HCV combination therapy in 21 HCV-HIV coinfected patients receiving antiretroviral therapy, and to access the clinical relevance of in vitro inhibition of phosphorylation by ribavirin of potent inhibitors of HIV—that is, zidovudine, stavudine, and zalcitabine. PATIENTS Twenty one patients were treated with combined antiretroviral therapy including zidovudine (n=8) or stavudine (n=13) (in association with protease inhibitors in 12). All received ribavirin (1000 or 1200 mg/day) and α interferon (3 MU three times/week) for chronic hepatitis C infection. All patients had not responded (n=20) or relapsed (n=1) after a previous six month course of α interferon therapy. METHODS HIV viral load (Monitor test) and CD4 cells count were measured at the beginning and every three months during and after ribavirin plus α interferon therapy over a mean period of 11 (1) months. Clinical and biological adverse effects were recorded. RESULTS There was no significant variation in HIV viral load or CD4 cell counts after three or six months of ribavirin therapy compared with baseline values. Of the 21 subjects, three (14%) had an increase in HIV viral load of more than 0.5 log leading to discontinuation of ribavirin in one. Eleven of 21 (52.4%) had initial negative HCV viraemia at three (n=10) or six (n=1) months but only six were polymerase chain reaction negative at the end of therapy, leading to rates for primary response and breakthrough of 23.8% and 28.5%, respectively. Six months after completion of therapy, three patients relapsed (14.3%) and three (14.3%) had sustained virological response. Median haemoglobin concentration decreased significantly after three and six months of ribavirin therapy (p= 0.0002 and p=0.0003, respectively) leading to withdrawal of therapy in one patient. CONCLUSIONS These preliminary results show that: (1) despite in vitro interactions between ribavirin, zidovudine, and stavudine, significant variation in HIV replication does not usually occur in HCV-HIV coinfected patients receiving ribavirin and different antiretroviral regimens, including zidovudine and stavudine; (2) α interferon and ribavirin combination therapy induced primary and sustained virological responses in 28.5% and 14.3% of treated subjects (who were previous non-responders to interferon therapy), respectively; (3) anaemia is a frequent adverse event. Such results should be confirmed in larger prospective trials.

Efficacy and safety of adefovir dipivoxil in kidney recipients, hemodialysis patients, and patients with renal insufficiency.

Background. This study analyzes the biochemical, serological, and virological efficacy and the safety of adefovir dipivoxil in patients with renal disturbances. Methods. Twelve patients with lamivudine-resistant hepatitis B virus (HBV) chronic infection were treated for a median time of 15 (3–19) months. The daily dosage was 10 mg initially and then adjusted according to renal function. Results. Median (range) ALT values remained stable: 55 (13–117) and 37 (17–266) UI/L. After the 12th month, the median decline in serum HBV DNA was from 8.76 (6.3–9.7) to 2.97 (1.15–5.65) log10 Eq/ml (median decline of –5.5 log10). No virologic breakthrough was observed. One of the six HBeAg-positive patients lost HBe Ag but without HBe seroconversion; none had HBs Ag loss. There were no significant clinical and biochemical adverse effects. In the 11 nonhemodialysed patients, the creatinine clearance significantly improved from 70 (30–100) to 88 (38–125) ml/mn (P=0.01) and the mean serum creatinine levels increased only slightly from 114 (91–839) to 130 (81–561) &mgr;mol/ml (NS). Serum phosphorus remained stable. The urinary level of protein decreased from 0.16 (0.08–8.63) to 0.12 (0.01–0.74) g/day (NS). Conclusions. Adefovir dipivoxil is safe for the treatment of chronic hepatitis B in patients with varying degrees of renal dysfunction and lamivudine-resistant HBV and results in biochemical and virological efficacy similar to that reported in the general population.

HBV genotypic resistance to lamivudine in kidney recipients and hemodialyzed patients.

BACKGROUND Lamivudine is a potent inhibitor of human immunodeficiency virus reverse transcriptase and hepatitis B virus (HBV) DNA polymerase. Its overall efficiency is clearly hampered by relapse at discontinuation and by risk of genotypic resistance. We describe herein the first cases of HBV resistance to lamivudine in kidney recipients and hemodialyzed patients. METHODS We analyzed 26 HBV-infected kidney recipients and five hemodialyzed patients treated with lamivudine who became serum HBV DNA-negative (by Digene test). The biological and virological follow-up identified breakthrough as defined by the reappearance of serum HBV DNA. In two cases of breakthrough, HBV DNA was amplified and sequenced through the polymerase domain, including the YMDD motif, before the beginning of treatment and at time of breakthrough to determine genotypic mutations. RESULTS Ten breakthroughs (reappearance of serum HBV DNA) were observed after a median follow-up of 11 months in eight kidney recipients and two hemodialyzed patients after a median duration of treatment of 16.5 (from 4 to 31) months of treatment. Previous HBe/anti-HBe seroconversion was not observed in the patients who escaped. In two kidney recipients, the comparison of HBV-DNA sequences before the treatment and after the breakthrough identified in one case a mutation of the highly conserved YMDD motif (YVDD), whereas in the second case, no genotypic mutation was observed in the sequenced region. CONCLUSION We report the first cases of HBV genotypic resistance to lamivudine in kidney recipients and hemodialysis patients. Genotypic resistance is observed after 4-31 months of therapy. The YMDD mutation does not account for all cases of virological escape.