Dendritic Cells from HIV Controllers Have Low Susceptibility to HIV-1 Infection In Vitro but High Capacity to Capture HIV-1 Particles

ANRS CO21 CODEX cohortInternational audienceHIV controllers (HICs), rare HIV-1 infected individuals able to control viral replication without antiretroviral therapy, are characterized by an efficient polyfunctional and cytolytic HIV-specific CD8+ T cell response. The mechanisms underlying the induction and maintenance of such response in many HICs despite controlled viremia are not clear. Dendritic cells play a crucial role in the generation and reactivation of T cell responses but scarce information is available on those cells in HICs. We found that monocyte derived dendritic cells (MDDCs) from HICs are less permissive to HIV-1 infection than cells from healthy donors. In contrast MDDCs from HICs are particularly efficient at capturing HIV-1 particles when compared to cells from healthy donors or HIV-1 patients with suppressed viral load on antiretroviral treatment. MDDCs from HICs expressed on their surface high levels of syndecan-3, DC-SIGN and MMR, which could cooperate to facilitate HIV-1 capture. The combination of low susceptibility to HIV-1 infection but enhanced capacity to capture particles might allow MDDCs from HICs to preserve their function from the deleterious effect of infection while facilitating induction of HIV-specific CD8+ T cells by cross-presentation in a context of low viremia

PLoS One

Compared to the general population, HIV-infected patients are at higher risk of developing non-AIDS-defining cancers. Chronic HCV infection has also been associated with a higher risk than that of the general population of developing cancers other than hepatocarcinoma. Evaluation of the impact of HCV-related factors on non-AIDS-defining and non HCV-liver (NANL) related cancers among HIV/HCV co-infected patients are scarce. The aim of this study was to identify the impact of HIV/HCV clinical characteristics on NANL related cancers in a large cohort of HIV/HCV-coinfected patients followed from 2005 to 2017. Cox proportional hazards models with delayed entry were used to estimate factors associated with NANL related cancer. Among 1391 patients followed for a median of 5 years, 60 patients developed NANL related cancers, yielding an incidence rate of 8.9 per 1000 person-years (95% CI, [6.6-11.1]). By final multivariable analysis, after adjustment for sex, tobacco or alcohol consumption, baseline CD4 cell count and HCV sustained viral response (SVR), age and a longer duration since HIV diagnosis were independently associated with a higher risk of NANL related cancer (aHR for each additional year 1.10, 95% CI 1.06-1.14, p<0.0001 and 1.06, 95% CI 1.01-1.11, p = 0.02, respectively). Duration of HCV infection, cirrhosis, HCV viral load, genotype and SVR were not associated with the occurrence of NANL related cancer. Among HIV/HCV-coinfected patients, age and the duration of HIV infection were the only characteristics found to be associated with the occurrence of NANL related cancer. In contrast, no association was observed with any HCV-related variables

The French national prospective cohort of patients co-infected with HIV and HCV (ANRS CO13 HEPAVIH): Early findings, 2006-2010

<p>Abstract</p> <p>Background</p> <p>In France, it is estimated that 24% of HIV-infected patients are also infected with HCV. Longitudinal studies addressing clinical and public health questions related to HIV-HCV co-infection (HIV-HCV clinical progression and its determinants including genetic dimension, patients' experience with these two diseases and their treatments) are limited. The ANRS CO 13 HEPAVIH cohort was set up to explore these critical questions.</p> <p>To describe the cohort aims and organization, monitoring and data collection procedures, baseline characteristics, as well as follow-up findings to date.</p> <p>Methods</p> <p>Inclusion criteria in the cohort were: age > 18 years, HIV-1 infection, chronic hepatitis C virus (HCV) infection or sustained response to HCV treatment. A standardized medical questionnaire collecting socio-demographic, clinical, biological, therapeutic, histological, ultrasound and endoscopic data is administered at enrolment, then every six months for cirrhotic patients or yearly for non-cirrhotic patients. Also, a self-administered questionnaire documenting socio-behavioral data and adherence to HIV and/or HCV treatments is administered at enrolment and yearly thereafter.</p> <p>Results</p> <p>A total of 1,175 patients were included from January 2006 to December 2008. Their median age at enrolment was 45 years and 70.2% were male. The median CD4 cell count was 442 (IQR: 304-633) cells/μl and HIV RNA plasma viral load was undetectable in 68.8%. Most participants (71.6%) were on HAART. Among the 1,048 HIV-HCV chronically co-infected patients, HCV genotype 1 was predominant (56%) and cirrhosis was present in 25%. As of January, 2010, after a median follow-up of 16.7 months (IQR: 11.3-25.3), 13 new cases of decompensated cirrhosis, nine hepatocellular carcinomas and 20 HCV-related deaths were reported, resulting in a cumulative HCV-related severe event rate of 1.9/100 person-years (95% CI: 1.3-2.5). The rate of HCV-related severe events was higher in cirrhotic patients and those with a low CD4 cells count, but did not differ according to sex, age, alcohol consumption, CDC clinical stage or HCV status.</p> <p>Conclusion</p> <p>The ANRS CO 13 HEPAVIH is a nation-wide cohort using a large network of HIV treatment, infectious diseases and internal medicine clinics in France, and thus is highly representative of the French population living with these two viruses and in care.</p

Renal outcomes after up to eight years of tenofovir exposure in HIV–HBV-coinfected patients

International audienceBackground: Renal toxicity is a common side effect during tenofovir (TDF)-use in HIV-infected, but not necessarily HBV-infected, patients. Nevertheless, little is known regarding TDF-use on renal impairment during HIV–HBV coinfection. We aimed to evaluate the progression and determinants of renal impairment in coinfected patients undergoing TDF.Methods: A total of 175 coinfected patients initiating TDF-containing antiretroviral therapy were prospectively followed. Estimated glomerular filtration rates (eGFR) were calculated at baseline and every 6–12 months. Determinants of eGRF change from baseline (ΔeGFR) were evaluated using mixed-effect linear regression and progression towards renal impairment using proportional-hazards regression.Results: At baseline, average eGFR was 96.7 ml/min per 1.73m2 (95% CI 93.8, 99.6). During a median 58.3 months (IQR 33.7–92.1) of treatment, eGFR decreased a monthly average of -0.14 ml/min per 1.73m2 (95% CI -0.16, -0.12). Significantly faster ΔeGFR was associated with baseline eGFR>90 (P=0.002), male gender (P=0.04), previous AIDS-defining illness at baseline (P=0.03), baseline liver cirrhosis (P=0.03) and concomitant protease inhibitor use (P=0.005). Between respective baseline and end of follow-up visits, the proportion of patients with renal impairment increased: normal function, 65.7% to 53.1%; mild impairment, 32.6% to 40.0%; moderate impairment, 1.7% to 6.9%. Higher age (P=0.01) and previous AIDS-defining illness (P=0.02) at baseline were independent risk-factors for developing impairment, while undetectable HBV DNA on-treatment was protective (P=0.006). Five (2.9%) patients permanently discontinued TDF after a renal event.Conclusions: Severe HIV-related and HBV-related morbidity negatively affects renal function in coinfected patients undergoing long-term TDF. Although most patients only developed mild/moderate impairment, close renal monitoring is warranted for this particular population

Development of anti-hepatitis B surface (HBs) antibodies after HBs antigen loss in HIV-hepatitis B virus co-infected patients

International audienceBackgroundHepatitis B surface antigen (HBsAg)-seroconversion, or loss of HBsAg and acquisition of anti-hepatitis B surface (HBs) antibodies, defines functional cure of chronic hepatitis B virus (HBV) infection. After HBsAg-loss, little is known regarding the development of anti-HBs antibodies and even less so in individuals co-infected with HIV.ObjectivesTo determine anti-HBs antibody kinetics after HBsAg-loss and explore determinants of HBsAg-seroconversion in HIV-HBV co-infected patients.Study designPatients enrolled in the French HIV-HBV cohort were included if they had >1 study visit after HBsAg-loss. Individual patient kinetics of anti-HBs antibody levels were modeled over time using mixed-effect non-linear regression, whereby maximum specific growth rate and maximal level of antibody production were estimated from a Gompertz growth equation.ResultsFourteen (4.6%) of 308 co-infected patients followed in the cohort exhibited HBsAg-loss, all of whom were undergoing antiretroviral therapy. Nine (64.3%) of these patients achieved HBsAg-seroconversion during a median 3.0 years (IQR = 1.1–5.1) after HBsAg-loss. Across individuals with HBsAg-seroconversion, the fastest rates of antibody growth ranged between 0.57–1.93 year−1 (population maximum growth rate = 1.02) and antibody production plateaued between 2.09–3.66 log10 mIU/mL at the end of follow-up (population maximal antibody levels = 2.66). Patients with HBsAg-seroconversion had substantial decreases in HBV DNA viral loads (P = 0.03) and proportion with elevated ALT levels (P = 0.02) and HBeAg-positive serology (P = 0.08). No such differences were observed in those without HBsAg-seroconversion.ConclusionsMost co-infected patients with HBsAg-seroconversion produced and maintained stable antibody levels, yet kinetics of anti-HBs production were much slower compared to those observed post-vaccination or after clearance of acute HBV-infection

Hepatitis B Virus Genotype G and Liver Fibrosis Progression in Chronic Hepatitis B and Human Immunodeficiency Virus Coinfection: MALAGNINO \textscet Al.

Introduction Infection with hepatitis B virus (HBV) genotype G has been associated with increased liver fibrosis levels compared with other genotypes in cross-sectional studies, yet its role in fibrosis evolution remains to be established. Methods In this prospective cohort study, 158 human immunodeficiency virus (HIV)-HBV coinfected patients had available HBV genotyping at baseline. Liver fibrosis was assessed at baseline and every 6 to 12 months by the FibroTest (BioPredictive, Paris, France). Risk factors for fibrosis regression (F3-F4 to F0-F1-F2) and progression (F0-F1-F2 to F3-F4) between baseline and end of follow-up were evaluated. Results Most patients were male (88.6%) with a median age of 39 years. HBV genotype A was more prevalent compared with other HBV genotypes (62.7% vs D = 10.8%, E = 10.8%, and G = 15.8%). Patients were followed up for a median of 83 months (IQR = 37-97). In the 43 (27.2%) patients with F3-F4 baseline liver fibrosis, 7 (16.2%) regressed to F0-F1-F2 fibrosis at the last follow-up visit. In the 115 (72.8%) with F0-F1-F2 fibrosis at baseline, 19 (16.5%) progressed to F3-F4 fibrosis at last visit. In multivariable analysis, fibrosis progression was independently associated with older age (P &lt;0.005), baseline CD4+ cell count less than 350/mm(3) (P &lt;0.01), longer antiretroviral therapy duration (P &lt;0.03), and HBV genotype G infection (vs non-G, P &lt;0.01). When examining averages over time, the rate of FibroTest increase was faster in genotype G vs non-G-infected patients with baseline F0-F1-F2 fibrosis (P for interaction = 0.002). Conclusion In HIV-HBV coinfected patients, HBV genotype G is an independent risk factor for liver fibrosis progression as determined by noninvasive markers. HBV genotype G-infected patients with low initial liver fibrosis levels may require more careful monitoring

Profiles of liver fibrosis evolution during long-term tenofovir treatment in HIV-positive patients coinfected with hepatitis B Running title: Liver fibrosis evolution in HIV/HBV coinfection

International audienceBackground & AimsData on liver fibrosis evolution and its involvement in liver-related morbidity are scarce in individuals with human immunodeficiency virus (HIV) and hepatitis B virus (HBV) co-infection during treatment. We identified profiles of liver fibrosis evolution in coinfected patients undergoing tenofovir (TDF).MethodsWe included 169 HIV-HBV-coinfected patients on TDF-based antiretroviral therapy. Virological and clinical data were obtained at TDF-initiation and every 6-12 months. From data on non-invasive liver fibrosis assessments collected yearly (FibroTest®), we established clusters of individuals with similar liver fibrosis evolution using group-based trajectory models.ResultsFour profiles of liver fibrosis evolution were established from a median follow-up of 7.6 years (IQR = 3.1-13.1): low fibrosis with no progression (29.6%, profile A), low fibrosis with progression (22.5%, profile B), moderate fibrosis with high fluctuation (39.6%, profile C), and cirrhosis with no regression (8.3%, profile D). When compared to profile A, baseline HBeAg-positive status was associated with profiles B (P = .007) and C (P = .004), older age with profiles C (P < .001) and D (P = .001), exposure to second-generation protease inhibitors with profile C (P = .004), and CD4+ <500/mm3 at the last visit with profiles C (P = .02) and D (P = .002). Incident liver-related events occurred in profiles other than A (B, n = 1/38; C, n = 6/67; D, n = 3/14) and all five cases of hepatocellular carcinoma occurred in profiles C (n = 2) and D (n = 3).ConclusionsTDF-treated HIV-HBV coinfected individuals do not seem to benefit from comparable levels of liver fibrosis regression as in HBV mono-infection. Liver-related morbidity occurs mainly in those with fluctuating or consistently high fibrosis levels

Persistent HBV replication and serological response during up to 15 years of tenofovir-based antiretroviral therapy in HIV/HBV-coinfected patients: a multicentre prospective cohort study

International audienceObjectivesTo determine the extent of hepatitis B virus (HBV) suppression and its association with seroclearance of hepatitis ‘e’ antigen (HBeAg) and hepatitis B surface antigen (HBsAg) in HIV/HBV-coinfected patients undergoing long-term tenofovir-based antiretroviral therapy (ART).MethodsWe prospectively followed 165 HIV/HBV-coinfected patients undergoing tenofovir-based ART. Serum HBV-DNA viral loads and HBeAg and HBsAg status were obtained at tenofovir initiation and every 6–12 months. We calculated the proportion achieving virological response (VR, <60 IU/mL) during follow-up. We also calculated rates of HBeAg- and HBsAg-seroclearance, which were compared between those who achieved versus never achieved VR during follow-up using an Exact binomial test.ResultsDuring a median 8.1 years (IQR = 4.0–13.2) of tenofovir treatment, 152 (92.1%) patients were able to achieve VR and 13 (7.9%) never achieved VR (median HBV-DNA at the end of follow-up = 608 IU/mL, range = 67–52 400 000). The prevalence of individuals with detectable HBV-DNA (≥60 IU/mL) decreased during tenofovir treatment: 15.1% (n = 14/93) at 5 years, 3.2% (n = 2/62) at 10 years and, 3.2% (n = 1/31) at 15 years. 44/96 HBeAg-positive patients (6.15/100 person-years) had HBeAg-seroclearance and 13/165 patients overall (0.87/100 person-years) had HBsAg-seroclearance. No difference in HBeAg-seroclearance was observed between those who achieved versus never achieved VR (7.4 versus 3.7/100 person-years, P = 0.33), while HBsAg-seroclearance was only observed in those with VR (1.0 versus 0/100 person-years, P = 0.49; respectively). Individuals with VR also had a higher frequency of undetectable HIV-RNA during treatment (P < 0.001).ConclusionsDuring long-term tenofovir-based ART for HIV/HBV coinfection, persistent HBV viraemia is apparent, but becomes less frequent over time. HBsAg-seroclearance only occurred in those with full HBV and relatively high HIV suppression

Burden of HIV disease and comorbidities on the chances of maintaining employment in the era of sustained combined antiretoviral therapies use.: HIV disease, comorbidityand employment

International audienceOBJECTIVES: Employment status is a major predictor of health status and living conditions, especially among HIV-infected people, a predominantly working-aged population. We aimed to quantify the risk of work cessation following HIV diagnosis in France in 2004-2010 and to measure the respective burden of HIV-related characteristics and of associated comorbidities on this risk. DESIGN: We used data from a multicenter cohort made of a diversified sample of recently diagnosed HIV-1-infected adults, antiretroviral treatment-naive at baseline in 2004-2008 (ANRS-COPANA cohort). Detailed information on living conditions and clinical and biological characteristics were collected prospectively. METHODS: The risk of work cessation among the 376 working-aged participants employed at baseline was estimated using the Kaplan-Meier method. Characteristics associated with the risk of work cessation were identified using multivariate Cox models. RESULTS: The cumulative probability of work cessation reached 14.1% after 2 years and 34.7% after 5 years. Diabetes, hypertension and, to a lesser extent, signs of depression were associated with increased risks of work cessation after accounting for socio-occupational characteristics [adjusted hazard ratios (95% confidence interval): 5.7 (1.7-18.8), 3.1 (1.5-6.4) and 1.6 (0.9-2.9), respectively]. In contrast, HIV disease severity and treatment and experience of HIV-related discrimination were not statistically associated with the risk of work cessation. CONCLUSION: The risk of work cessation during the course of HIV disease has remained substantial in the most recent period in France. Comorbidities, but not characteristics of HIV disease itself, substantially affect chances of maintaining employment. This provides insights into strategies for limiting the burden of HIV disease for individuals and society