Caroline Lascoux-Combe

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.

Major role of hepatitis B genotypes in liver fibrosis during coinfection with HIV.

Background:Little is know about the determinants of liver fibrosis progression and genomic variability in hepatitis B virus (HBV) in HIV/HBV-coinfected patients. Methods:A cross-sectional analysis examined common characteristics of HBV infection in an ongoing cohort study of 308 patients with both HIV-1-positive Western blot and plasma HBV surface antigen (HBsAg) seropositivity. Risk factors for liver fibrosis were studied in a subset of 104 patients for whom liver biopsy and complete HBV genomic analysis were available. Analysis was performed by exact multiple regression analysis. Results:Mean age of the study population was 40.3 years, with a ratio male to female of 5.3 and a mean duration of HIV infection of 9.3 years. In the subset of 104 patients, plasma HBV e antigen (HBeAg) in HBV-replicative patients could not be detected in 28.4% and lamivudine-resistant mutants were detected in 67.8%. HBV genotype A was the most frequent genotype (73/104) and 25 patients were infected by the usually rare genotype G. METAVIR fibrosis score was rated F2–F4 in 70 patients. After adjustment for the most common known determinants of liver fibrosis, HBV genotype G [odds ratio (OR), 12.60; 95% confidence interval (CI), 1.72–infinite; P < 0.009], efavirenz exposure (OR, 3.55; 95% CI, 1.14–12.14; P < 0.03), and the duration of HIV infection (3.86; 95% CI, 1.27–12.64; P < 0.01) were strongly associated with the risk of grade F2–F4 fibrosis. Conclusion:HBV genotype G is a determinant of liver fibrosis in HIV/HBV-coinfected patients and HBV genotyping should be considered as part of the management of patients with multiple risk factors for rapid progression of liver fibrosis.

Epidemiology, diagnosis and treatment of chronic hepatitis B in HIV-infected patients (EPIB 2005 STUDY).

Objective:To describe the characteristics of hepatitis B (HBV) infection in HIV-infected patients and the impact of anti-HBV treatments. Patients and methods:All the patients with past or present chronic HBV infection seen in October 2005 in 17 French hospitals were included. Data were retrospectively collected from their first visit in a time-dependent manner, through a detailed standardized questionnaire. Results:Among 477 HBV-infected patients, 261 (55%) were co-infected with HIV. The HBV–HIV co-infected patients underwent fewer serological, virological and histological evaluations. Initial positive HBe antigenemia (HBe Ag) was more frequent in these patients (57.9 versus 28.6%; P < 10−4), as was cirrhosis on the initial liver biopsy (17.9 versus 7.6%; P = 0.05). Throughout the mean 5-year follow-up, HBe Ag loss was less frequent (P = 0.04), as was HBe seroconversion (incidence rate 2.6 versus 10/100 patient-years; P < 10−3). HBe Ag loss was associated with fibrosis improvement (METAVIR score −0.5 ± 0.4 versus +0.2 ± 0.6 if persistent positive HBe Ag, P = 0.01). In co-infected patients on tenofovir, adefovir or interferon, HBe seroconversions were seen in patients on combined HBV treatment, the use of which is increasing (58% in 2005). Nevertheless, no significant difference in virological, immunological or biochemical evolution was observed between these different treatments. Conclusions:In HBV–HIV co-infected patients, the assessment of HBV infection still needs to be improved, the HBV wild-type remains predominant, and HBe Ag loss is rare and associated with a better histological evolution. There is insufficient evidence of the superiority of combined HBV treatment, and this still needs be demonstrated in long term studies.

Telaprevir for HIV/Hepatitis C Virus–Coinfected Patients Failing Treatment With Pegylated Interferon/Ribavirin (ANRS HC26 TelapreVIH): An Open-Label, Single-Arm, Phase 2 Trial

BACKGROUND Retreatment with pegylated interferon (peg-IFN) and ribavirin (RBV) results in poor sustained virological response (SVR) rates in human immunodeficiency virus (HIV)/hepatitis C virus (HCV)-coinfected patients. There are limited data regarding the use of telaprevir plus peg-IFN/RBV in this population. METHODS HIV type 1-infected patients who previously failed ≥12 weeks of peg-IFN/RBV for HCV genotype 1 coinfection were enrolled in a single-arm, phase 2 trial. Patients with cirrhosis and previous null response were excluded. Authorized antiretrovirals were tenofovir, emtricitabine, efavirenz, atazanavir, and raltegravir. All patients received peg-IFN alfa-2a (180 µg/week) plus RBV (1000-1200 mg/day) for 4 weeks, followed by telaprevir (750 mg or 1125 mg every 8 hours with efavirenz) plus peg-IFN/RBV for 12 weeks and peg-IFN/RBV for 32-56 weeks according to virological response at week 8. The primary endpoint was the SVR rate at 24 weeks after the end of treatment (SVR24). RESULTS Sixty-nine patients started treatment; SVR24 was achieved in 55 (80% [95% confidence interval, 68%-88%). SVR24 was not influenced by baseline fibrosis stage, IL28B genotype, antiretroviral regimen, HCV subtype, CD4 cell count, previous response to HCV treatment, HCV RNA level, or HCV RNA decline at week 4. HCV treatment was discontinued for adverse events (AEs) in 20% of patients, including cutaneous (4%), psychiatric (4%), hematological (6%), and other AEs (6%). Peg-IFN or RBV dose reduction was required in 23% and 43% of patients, respectively. Seventy percent of patients required erythropoietin, blood transfusions, or RBV dose reduction for anemia. Two patients died during the study. No HIV breakthrough was observed. CONCLUSIONS Despite a high discontinuation rate related to toxicity, a substantial proportion of treatment-experienced HIV-coinfected patients achieved SVR24 with a telaprevir-based regimen. Clinical Trials Registration. NCT01332955.

Longitudinal evaluation of viral interactions in treated HIV-hepatitis B co-infected patients with additional hepatitis C and D virus

Summary  Virological interactions of hepatitis B (HBV), hepatitis C (HCV) and hepatitis D (HDV) viruses in HIV‐infected patients have been poorly characterized especially under treatment influences. Undetection rates of hepatitis viruses were longitudinally analyzed in a 3‐year cohort of 308 HIV–HBV co‐infected patients and compared using Generalized Estimating Equation models adjusted for age, HIV‐RNA, CD4 cell‐count and antiviral treatment. Chronic hepatitis co‐infection in HIV‐infected patients (age years, SD) was: 265 HBV (40.7, 8.2); 19 HBV–HCV (39.7, 4.1); 12 HBV–HDV (35.2, 9.9); 12 HBV–HCV–HDV (39.2, 5.2). At inclusion, treatment with lamivudine/tenofovir was not significantly different between co‐infection groups. HBV suppression was significantly associated with HDV (aOR = 3.85, 95%CI 1.13–13.10, P = 0.03) and HCV tri‐infection (aOR = 2.65, 95%CI 1.03–6.81, P = 0.04), but marginally associated with HIV–HBV–HCV–HDV (aOR = 2.32, 95%CI 0.94–5.74, P = 0.07). In quad‐infection, lower HDV‐undetectability (vs HIV–HBV–HDV, P = 0.2) and higher HCV‐undetectability (vs HIV–HBV–HCV, P = 0.1) were demonstrated. The degree of HBV suppression varied between visits and co‐infection groups [range of aOR during follow‐up (vs HIV–HBV co‐infection): HIV–HBV–HCV = 2.23–5.67, HIV–HBV–HDV = 1.53–15.17]. In treated co‐infected patients, HDV expressed continuous suppression over HCV‐ and HBV‐replications. Peaks and rebounds from undetectable hepatitis B, C and/or D viremia warrant closer follow‐up in this patient population. HDV‐replication was uncontrolled even with antiviral treatment.

Role of a 48-week pegylated interferon therapy in hepatitis B e antigen positive HIV-co-infected patients on cART including tenofovir: EMVIPEG study

BACKGROUND & AIMS In hepatitis B e antigen (HBeAg) positive-HIV co-infected patients treated with combined antiretroviral therapy (cART), including tenofovir disoproxil fumarate (TDF), the rate of HBe seroconversion remains low. Whether adding pegylated interferon alfa (PegIFN) could increase the likelihood of HBeAg loss and HBe seroconversion has not been assessed. METHODS A 48-week PegIFN therapy was added to HBeAg positive-HIV co-infected patients on TDF and emtricitabine, or lamivudine for at least 6 months. The primary endpoint was HBV sustained response: HBe seroconversion with undetectable HBV DNA levels 24 weeks after completing PegIFN therapy (W72). RESULTS Fifty-one patients (49 men, median age 46 years, range: 32-65), were included. Median duration of HIV, HBV infections and TDF therapy was 10.3 (0.6-22), 9.8 (0.5-16), and 3.3 (0.5-6.8)years, respectively. Median baseline CD4 count was 506 (175-1316)/mm(3). HIV viral load was <50 copies/ml in 49 (96%) patients. Nine (18%) patients stopped PegIFN prematurely. Ten (20%) patients experienced HBeAg loss at W72 and four (8%) patients had a HBV sustained response. No HBs seroconversion was observed. Only patients with more than 350 CD4/mm(3) at baseline achieved HBe loss. HBeAg level >10 PEIU/ml at W12 or a quantitative HBsAg decline <0.5 log IU/ml at W24 had 100% and 84% negative predictive values for response, respectively. CONCLUSIONS 48-week PegIFN additional therapy to cART including TDF did not significantly increase the HBe seroconversion rate, despite an HBeAg loss in 20% of the patients. HBe and HBs kinetics may nevertheless be of help in tailoring and optimising this strategy.

Intensification with pegylated interferon during treatment with tenofovir in HIV–hepatitis B virus co‐infected patients

In hepatitis B “e” antigen (HBeAg) positive patients with hepatitis B virus (HBV) mono‐infection, intensification of nucleos(t)ide analogue treatment with pegylated interferon (PegIFN) could help induce higher HBeAg seroclearance rates. Our aim was to determine the long‐term effect of adding PegIFN to tenofovir (TDF)‐containing antiretroviral therapy on seroclearance in HBeAg‐positive patients co‐infected with the human immunodeficiency virus (HIV) and HBV. In this prospective matched cohort study, 46 patients with 1‐year PegIFN intensification during TDF‐containing antiretroviral therapy (TDF+PegIFN) were matched 1:1 to controls undergoing TDF without PegIFN (TDF) using a time‐dependent propensity score based on age, CD4+ count and liver cirrhosis status. Kinetics of HBeAg quantification (qHBeAg) and hepatitis B surface antigen quantification (qHBsAg) were estimated using mixed‐effect linear regression and time to HBeAg seroclearance or HBsAg seroclearance was modelled using proportional hazards regression. At baseline, previous TDF exposure was a median 39.8 months (IQR=21.4–59.4) and median qHBeAg and qHBsAg levels were 6.9 PEIU/mL and 3.72 log10IU/mL, respectively (P>.5 between groups). Median follow‐up was 33.4 months (IQR=19.0–36.3). During intensification, faster average declines of qHBeAg (−0.066 vs −0.027 PEIU/mL/month, P=.001) and qHBsAg (−0.049 vs −0.026 log10IU/mL/month, P=.09) were observed in patients undergoing TDF+PegIFN vs TDF, respectively. After intensification, qHBeAg and qHBsAg decline was no different between groups (P=.7 and P=.9, respectively). Overall, no differences were observed in HBeAg seroclearance (TDF+PegIFN=13.2 vs TDF=12.6/100 person·years, P=.5) or HBsAg seroclearance rates (TDF+PegIFN=1.8 vs TDF=1.3/100 person·years, P=.7). In conclusion, PegIFN intensification in HBeAg‐positive co‐infected patients did not lead to increased rates of HBeAg or HBsAg clearance, despite faster declines of antigen levels while on PegIFN.

Nonreactive Human Immunodeficiency Virus Type 1 Rapid Tests After Sustained Viral Suppression Following Antiretroviral Therapy Initiation During Primary Infection

We assessed the impact of early antiretroviral treatment (ART) on human immunodeficiency virus (HIV) antibody detection by rapid tests in 44 individuals after several years of successful ART. HIV self-tests and point-of-care tests were negative in 30% and 7%-9% of cases, respectively. These data reinforce the message that patients should never be retested after entering HIV care.

762 ADDITIONAL PEG-INTERFERON IN HBeAg-POSITIVE HIV CO-INFECTED PATIENTS ON cART INCLUDING TENOFOVIR: THE ANRS HB01 EMVIPEG STUDY

762 ADDITIONAL PEG-INTERFERON IN HBeAg-POSITIVE HIV CO-INFECTED PATIENTS ON cART INCLUDING TENOFOVIR: THE ANRS HB01 EMVIPEG STUDY P. Miailhes, M. Maynard-Muet, F. Lebosse, F. Carrat, C. Bouix, C. Lascoux-Combe, P. Sogni, S. Pol, P. Cacoub, F. Zoulim, L. Piroth. Hospices Civils de Lyon (HCL), Hopital de la Croix-Rousse, Inserm U 1052, Lyon, UMRS 707, Universite Paris 6, Inserm Sante Publique, APHP, Hopital Saint-Louis, Unite d’Hepatologie, Hopital Cochin, Inserm U 1016, Universite Paris Descartes, Service de Medecine Interne, Hopital Pitie-Salpetriere, Universite Pierre et Marie Curie, CNRS UMR 7087, Paris, Hopital du Bocage, CHU de Dijon, Universite de Bourgogne, Dijon, France E-mail: patrick.miailhes@chu-lyon.fr