Atherosclerotic Cardiovascular Events in Patients Infected With Human Immunodeficiency Virus and Hepatitis C Virus.

BACKGROUND: An increased risk of cardiovascular disease (CVD) was reported in patients coinfected with human immunodeficiency virus (HIV) and hepatitis C virus (HCV), without identifying factors associated with atherosclerotic CVD (ASCVD) events. METHODS: HIV-HCV coinfected patients were enrolled in the Agence Nationale de Recherches sur le Sida et les hépatites virales (ANRS) CO13 HEPAVIH nationwide cohort. Primary outcome was total ASCVD events. Secondary outcomes were coronary and/or cerebral ASCVD events, and peripheral artery disease (PAD) ASCVD events. Incidences were estimated using the Aalen-Johansen method. Factors associated with ASCVD were identified using cause-specific Cox proportional hazards models. RESULTS: At baseline, median age of the study population (N = 1213) was 45.4 (interquartile range [IQR] 42.1-49.0) years and 70.3% were men. After a median follow-up of 5.1 (IQR 3.9-7.0) years, the incidence was 6.98 (95% confidence interval [CI], 5.19-9.38) per 1000 person-years for total ASCVD events, 4.01 (2.78-6.00) for coronary and/or cerebral events, and 3.17 (2.05-4.92) for PAD ASCVD events. Aging (hazard ratio [HR] 1.06; 95% CI, 1.01-1.12), prior CVD (HR 8.48; 95% CI, 3.14-22.91), high total cholesterol (HR 1.43; 95% CI, 1.11-1.83), high-density lipoprotein cholesterol (HR 0.22; 95% CI, 0.08-0.63), statin use (HR 3.31; 95% CI, 1.31-8.38), and high alcohol intake (HR 3.18; 95% CI, 1.35-7.52) were independently associated with total ASCVD events, whereas undetectable baseline viral load (HR 0.41, 95% CI, 0.18-0.96) was associated with coronary and/or cerebral events. CONCLUSIONS: HIV-HCV coinfected patients experienced a high incidence of ASCVD events. Some traditional cardiovascular risk factors were the main determinants of ASCVD. Controlling cholesterol abnormalities and maintaining undetectable HIV RNA are essential to control cardiovascular risk.

Risk of severe clinical events after sustained virological response following direct-acting antiviral therapy in HIV and hepatitis C virus coinfected participants.

OBJECTIVES: Sustained virological response (SVR) decreases the risk of hepatitis C virus (HCV)-related events. Nevertheless, a substantial risk of events persists. We estimated incidences and identified factors associated with severe clinical events after SVR following treatment with a direct-acting antiviral (DAA) in HIV/HCV-coinfected patients. METHODS: Participants from the ANRS CO13 HEPAVIH were included if they reached SVR. Incidence rates of overall mortality, liver-related events, AIDS-defining events, ischaemic events and non-liver non-AIDS-defining cancers (NLNA) were estimated. Factors associated with the risk of those events were identified using Poisson models adjusted on age at SVR and sex. RESULTS: In all, 775 participants were included. Incidence rates (95% confidence interval) of liver-related events, overall mortality, AIDS-defining events, ischaemic events and NLNA cancers per 1000 person-years were 5.9 (3.3-10.3), 22.2 (16.8-29.5), 0.6 (0.1-4.5), 7.3 (4.4-12.2) and 13.7 (9.4-20.0), respectively. For all events, incidence rates were higher in cirrhotic than in non-cirrhotic participants. Cirrhosis, liver stiffness and CD4 count were associated with liver-related events. Factors associated with overall mortality were age, cirrhosis, liver stiffness and gamma-glutamyl transferase (GGT). For ischaemic events and NLNA cancers, associated factors were total cholesterol and CD4 count, respectively. CONCLUSIONS: After SVR following a DAA treatment, liver-related and AIDS-defining events were observed less frequently than NLNA cancers. Severity of liver disease was associated with the risk of liver-related events and of overall mortality but not with ischaemic events and NLNA cancers. Factors reflecting HIV infection were associated with NLNA cancers and liver-related events.

Addition of boceprevir to PEG-interferon/ribavirin in HIV-HCV-Genotype-1-coinfected, treatment-experienced patients: efficacy, safety, and pharmacokinetics data from the ANRS HC27 study.

BACKGROUND: Scarce data exist on the efficacy and safety of the PEGylated-interferon/ribavirin/boceprevir regimen in HIV/HCV-coinfected patients who failed to respond to PEGylated-interferon/ribavirin treatment. OBJECTIVES: To evaluate the efficacy and safety of this drug regimen and the impact of the addition of boceprevir(BOC) on atazanavir (ATV) or raltegravir (RAL) pharmacokinetic parameters in a subgroup of patients. METHODS: In this single-arm phase 2 trial, HIV-1/HCV-genotype-1-coinfected patients received PEGylated-interferonα2b (1.5 µg/kg/week)+ ribavirin (800-1400 mg/day) alone until W4 and with BOC(800 mgTID) until W48. Based on virologic response at W8, the three drugs were stopped or PEGylated-interferon/ribavirin was continued alone until W72. The primary endpoint was SVR at W24 off-therapy (SVR24). RESULTS: 64 patients were included. SVR24 was achieved in 53% of patients (CI90%: 43-63%) and in 90% of previous relapsers. In univariate analysis, SVR24 was associated with response to previous HCV treatment, HCV-1b subtype, HCV-RNA decline, ribavirin-Ctrough at W4, and HCV-RNA at W8 but not to fibrosis score, IL28B genotype, or boceprevir-Ctrough at W8. In multivariate analysis, SVR24 remained associated with response to previous HCV treatment [non-responders versus null responders: OR=5.0(1.3-20.0); relapsers vs. null responders: OR=28.8(4.9-169.5)]. HCV treatment was discontinued for adverse events in 17% of patients. A 51% decrease in ATV/r-AUC0-8 h (p<0.01) and a 57% increase in RAL-AUC0-8 h (p<0.01) were observed, although atazanavir/r or raltegravir did not affect BOC-AUC0-8 h significantly. The ATV mean Cthrough fell from 763.8 ng/mL (CI 95%: 230.3-1297.3) without BOC to 507.7 ng/mL (CI 95%: 164-851.4) with BOC. CONCLUSIONS: Boceprevir-based regimen demonstrated a high SVR24 rate in treatment-experienced HIV-HCV genotype-1-coinfected relapsers.

Hepatitis C treatment initiation in HIV-HCV coinfected patients.

BACKGROUND: There are few data regarding HCV treatment initiation among HIV/HCV coinfected patients. The objective of this study was to analyze the changing patterns of HCV coinfection and HCV treatment initiation over time in a large French cohort of HIV/HCV coinfected patients at the beginning of DAA's era and to analyze factors associated with treatment initiation. METHODS: All HIV/HCV coinfected patients enrolled during 2000-2012 were analyzed. HCV status was defined per calendar year as naïve, spontaneous cure, sustained virological response (SVR), failure or reinfection. HCV treatment initiation rate was determined per year. Trends over time were analyzed using Chi-2 test for trend and linear regression analysis. The effect of covariates on treatment initiation over time was analyzed using generalized estimating equations. RESULTS: Among 34,308 HIV-infected patients enrolled between 2000 and 2012, 5,562 were HCV coinfected. HCV prevalence declined from 38.4 to 15.1 %. HCV treatment initiation rate fluctuated from 5.6 to 7.4 %/year from 2000 to 2007, dropped to 5.6 % in 2011 and increased to 8.5 % in 2012 due to the use of first-generation DAAs (29.1 % of initiations in 2012). Cumulative HCV treatment initiation rate increased from 14.8 % in 2000 to 54.7 % in 2012. HCV cure rate increased from 12.4 to 45.2 %. Older age, male gender, male homosexuality, high CD4, undetectable HIV-RNA, CDC stage A-B, and severe fibrosis/cirrhosis were associated with a higher treatment initiation rate. The role of HCV genotype 1, CDC stage, fibrosis and recent HCV infection on treatment initiation rate changed over time. CONCLUSION: A high rate of HCV treatment initiation was observed at the beginning of DAAs era in HIV/HCV coinfected patients. Given the very high efficacy of new DAA-based regimens and if treatment initiation keeps increasing, HCV prevalence among HIV patients will drastically decrease during the forthcoming years.

Frailty and prefrailty phenotypes increase the odds of abnormal cognitive impairment screens in people with HIV.

OBJECTIVE: Evaluate whether prefrail and frail people with HIV (PWH) have a higher risk of cognitive impairment on screens. METHODS: Analysis of PWH aged 70 or older included in the ANRS EP66 SEPTAVIH cohort, on antiretroviral therapy for at least 12 months and with a MoCA test at enrolment. Adjusted risk of a Montreal Cognitive Assessment (MoCA) less than 26 was compared in frail/prefrail versus robust PWH. RESULTS: A total of 503 PWH were enrolled with a median age of 73 years, IQR [71-77], 81.5% were male, 73.8% were French natives, 32.9% had low socio-economic status (EPICES score >30.2), and 41.3% were college graduates; 27.3% had a history of clinical AIDS. A total of 294 (58.5%) PWH had a MoCA score less than 26; 182 (36%) a MoCA score 23 or less. Frailty, prefrailty and robustness were found in 13.1, 63.6 and 23.3% participants, respectively. PWH with a MoCA less than 26 had a significantly higher risk of being frail/prefrail, this before [odds ratio (OR) = 2.31; 95% confidence interval (CI) 1.50-3.57], and after adjustment for confounders (OR = 1.80; 95% CI 1.07-3.01). The risk of being frail/prefrail in patients with a MoCA 23 or less was higher (adjusted OR = 2.75; 95% CI 1.46-5.16). Other factors independently associated with a MoCA less than 26 were older age, birth outside of France and a lower education level and being diabetic. CONCLUSION: Abnormal MoCA screens were frequent in our cohort of PWH aged 70 or older with controlled HIV disease. Cognitive impairment should be systematically screened in frail/prefrail PWH. Frailty/prefrailty, diabetes and social factors, but not HIV-related factors, are important determinants of cognitive function in PWH with controlled disease.

Liver stiffness and fibrosis-4 alone better predict liver events compared with aspartate aminotransferase to platelet ratio index in a cohort of human immunodeficiency virus and hepatitis C virus co-infected patients from ANRS CO13 HEPAVIH cohort.

OBJECTIVES: HIV/hepatitis C virus (HCV) co-infection leads to major complications, and noninvasive markers developed to stage liver fibrosis could be used as prognostic markers. We aimed to compare the performances of liver stiffness (LS), fibrosis-4 (FIB-4), and aspartate aminotransferase to platelet ratio index (APRI) to predict liver-related events in HIV/HCV co-infected patients. PATIENTS AND METHODS: HIV/HCV co-infected patients from the ANRS CO13 HEPAVIH cohort were included if they had LS, FIB-4, and APRI measurements done in a window of 3 months. Primary outcome was the time between inclusion and occurrence of a liver-related event. Univariable and multivariable Fine and Gray models were performed. Predictive performances were compared by the area under the receiver operating characteristic (AUROC) differences after correction of optimistic by bootstrap samples. Best cutoffs to predict liver-related events were estimated by sensitivity and specificity maximization. RESULTS: A total of 998 patients were included. Overall, 70.7% were men. Their median age was 46.8 years. According to LS value, 204 (20.4%) patients had cirrhosis. Overall, 39 patients experienced at least one liver-related event. In univariable analysis, LS AUROC curve was significantly superior to FIB-4 and APRI AUROC curves, being 87.9, 78.2, and 75.0%, respectively. After adjustment on age, CD4 levels, and insulin resistance, no differences were observed. The best cutoffs to identify patients at low or high risk of liver-related events were below 8.5, 1.00, and 0.35 and above 16.5, 4.00, and 1.75 for LS, FIB-4, and APRI, respectively. CONCLUSION: To predict HCV-related events, APRI had lower performance than LS and FIB-4. FIB-4 is as good as LS to predict HCV-related events, suggesting that it can be used for the management of HIV/HCV co-infected patients and replace LS.

Factors associated with DAA virological treatment failure and resistance-associated substitutions description in HIV/HCV coinfected patients.

AIM: To describe factors associated with treatment failure and frequency of resistance-associated substitutions (RAS). METHODS: Human immunodeficiency virus (HIV)/hepatitis C virus (HCV) coinfected patients starting a first direct-acting antiviral (DAA) regimen before February 2016 and included in the French ANRS CO13 HEPAVIH cohort were eligible. Failure was defined as: (1) non-response [HCV-RNA remained detectable during treatment, at end of treatment (EOT)]; and (2) relapse (HCV-RNA suppressed at EOT but detectable thereafter). Sequencing analysis was performed to describe prevalence of drug class-specific RAS. Factors associated with failure were determined using logistic regression models. RESULTS: Among 559 patients, 77% had suppressed plasma HIV-RNA < 50 copies/mL at DAA treatment initiation, 41% were cirrhotic, and 68% were HCV treatment-experienced. Virological treatment failures occurred in 22 patients and were mainly relapses (17, 77%) then undefined failures (3, 14%) and non-responses (2, 9%). Mean treatment duration was 16 wk overall. Post-treatment NS3, NS5A or NS5B RAS were detected in 10/14 patients with samples available for sequencing analysis. After adjustment for age, sex, ribavirin use, HCV genotype and treatment duration, low platelet count was the only factor significantly associated with a higher risk of failure (OR: 6.5; 95%CI: 1.8-22.6). CONCLUSION: Only 3.9% HIV-HCV coinfected patients failed DAA regimens and RAS were found in 70% of those failing. Low platelet count was independently associated with virological failure.

Factors associated with non-AIDS-defining cancers and non HCV-liver related cancers in HIV/HCV-coinfected patients- ANRS-CO13 HEPAVIH cohort.

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.

COPD in HIV-Infected Patients: CD4 Cell Count Highly Correlated.

BACKGROUND: COPD is a frequent and significant cause of respiratory morbidity in HIV-infected patients despite the control of HIV. We aimed to analyze the factors correlated with COPD in this population to evaluate the existence of specific indicators of vulnerability in this population. METHODS AND FINDINGS: 623 HIV-infected outpatients were enrolled during one year. This population was characterised by a dedicated questionnaire and electronic patient records. COPD screening was performed according to recommended spirometric criteria. The prevalence of COPD was 9.0%. Age and smoking were independently correlated with COPD (OR, 1.61 per 10 years increase, P = 0.007; OR, 1.28 per 10 pack-year increase, P = 0.003, respectively). Body mass index (BMI) and CD4 cell-count were independently and negatively correlated with COPD (OR, 0.78, P < 0.001; 0R, 0.77 per 100 cell/mm3 increase, P < 0.001, respectively). Among COPD patients, 77% did not know their diagnosis. Five COPD-patients never smoked and 44.2% did not have any respiratory symptoms and so were not eligible to perform a spirometry according to the guidelines. CONCLUSIONS: In addition to known risk factors, immune defect through CD4 cell count was independently and strongly correlated with COPD. COPD is largely underdiagnosed and thus unmanaged. However, early management and urgent smoking cessation are essential to improve prognosis. Clinicians' awareness on the particular vulnerability for COPD in HIV-infected patients is crucial. Moreover, indications to perform conventional spirometry to diagnose COPD may include more parameters than tobacco-smoking and respiratory complaints with a particular concern toward patients with a profound CD4 cell count defect.

Direct-acting antiviral treatment in adults infected with hepatitis C virus: Reactivation of hepatitis B virus coinfection as a further challenge.

Use of direct-acting antiviral drugs (DAAs) greatly improves management of adults infected with hepatitis C virus (HCV) whether patients are treatment-naive or unsuccessfully pre-treated. Several inhibitors of viral nonstructural proteins (NS3/4A protease, NS5A and NS5B polymerase) allow a rapid HCV clearance and increase rates of sustained virological response. Both the EASL and AASLD guidelines have recently published up-to-date recommendations for their use, addressing each HCV genotype and particular situations. However, management of patients coinfected with hepatitis B virus (HBV) has been developed by these guidelines with reference to cases of HBV reactivation reported during previous anti-HCV regimens containing interferon known active against both HBV and HCV. In the setting of the interferon-free HCV therapies with DAAs only, the possibility of HBV reactivation during treatment of hepatitis C is raised due to viral interferences in HCV/HBV coinfected persons. Herein, we report a case of early HBV reactivation during DAAs-based anti-HCV treatment (ledipasvir/sofosbuvir) in a patient having a resolved HBV infection and chronically infected with HCV genotype 4 and HIV. Moreover, we review similar recent cases of HBV reactivation in patients infected with HBV and HCV genotype 1 during treatment of hepatitis C by regimen incorporating other combination of DAAs (sofosbuvir/simeprevir or daclatasvir/asunaprevir). Due to the potential risk of early HBV reactivation in HCV/HBV-coinfected patients during interferon-free DAAs-based HCV therapies, altogether these cases highlight the necessity to closely monitor HBV coinfection, regardless its stage (chronic, occult, resolved), whatever HCV genotype or class of DAAs used.

Virological response and resistance mutations to NS3/4A inhibitors in hepatitis C virus-human immunodeficiency virus coinfection.

AIM: To evaluate virological response to telaprevir or boceprevir in combination with pegylated interferon and ribavirin and resistance mutations to NS3/4A inhibitors in hepatitis C virus-human immunodeficiency virus (HCV-HIV) coinfected patients in a real life setting. METHODS: Patients with HCV genotype 1-HIV coinfection followed in Nice University Hospital internal medicine and infectious diseases departments who initiated treatment including pegylated interferon and ribavirin (PegIFN/RBV) + telaprevir or boceprevir, according to standard treatment protocols, between August 2011 and October 2013 entered this observational study. Patient data were extracted from an electronic database (Nadis(®)). Liver fibrosis was measured by elastometry (Fibroscan(®)) with the following cut-off values: F0-F1: < 7.1 kPa, F2: 7.1-9.5 kPa, F3: 9.5-14.5 kPa, F4: ≥ 14.5 kPa. The proportion of patients with sustained virological response (SVR) twelve weeks after completing treatment, frequency and type of adverse events, and NS3/4A protease inhibitor mutations were described. RESULTS: Forty-one patients were included: 13 (31.7%) patients were HCV-treatment naïve, 22 (53.7%) had advanced liver fibrosis or cirrhosis (Fibroscan stage F3 and F4); none had decompensated cirrhosis or hepatocellular carcinoma; all were receiving antiretroviral treatment, consisting for most them (83%) in either a nucleoside reverse-transcriptase inhibitor/protease inhibitor or/integrase inhibitor combination; all patients had undetectable HIV-RNA. One patient was lost to follow-up. SVR was achieved by 52.5% of patients. Five patients experienced virological failure during treatment and four relapsed. Seven discontinued treatment due to adverse events. Main adverse events included severe anemia (88%) and rash (25%). NS3/4A protease mutations were analyzed at baseline and at the time of virological failure in the 9 patients experiencing non-response, breakthrough or relapse. No baseline resistance mutation could predict resistance to HCV protease inhibitor-based treatment. CONCLUSION: Telaprevir and boceprevir retain their place among potential treatment strategies in HIV-HCV coinfected patients including those with advanced compensated liver disease and who failed previous PegIFN/RBV therapy.

Potential for Drug-Drug Interactions between Antiretrovirals and HCV Direct Acting Antivirals in a Large Cohort of HIV/HCV Coinfected Patients.

OBJECTIVES: Development of direct acting antivirals (DAA) offers new benefits for patients with chronic hepatitis C. The combination of these drugs with antiretroviral treatment (cART) is a real challenge in HIV/HCV coinfected patients. The aim of this study was to describe potential drug-drug interactions between DAAs and antiretroviral drugs in a cohort of HIV/HCV coinfected patients. METHODS: Cross-sectional study of all HIV/HCV coinfected patients attending at least one visit in 2012 in the multicenter French Dat'AIDS cohort. A simulation of drug-drug interactions between antiretroviral treatment and DAAs available in 2015 was performed. RESULTS: Of 16,634 HIV-infected patients, 2,511 had detectable anti-HCV antibodies, of whom 1,196 had a detectable HCV-RNA and were not receiving HCV treatment at the time of analysis. 97.1% of these patients were receiving cART and 81.2% had a plasma HIV RNA <50 copies/mL. cART included combinations of nucleoside reverse transcriptase inhibitors with a boosted protease inhibitor in 43.6%, a non-nucleoside reverse transcriptase inhibitor in 17.3%, an integrase inhibitor in 15.4% and various combinations or antiretroviral drugs in 23.7% of patients. A previous treatment against HCV had been administered in 64.4% of patients. Contraindicated associations/potential interactions were expected between cART and respectively sofosbuvir (0.2%/0%), sofosbuvir/ledipasvir (0.2%/67.6%), daclatasvir (0%/49.4%), ombitasvir/boosted paritaprevir (with or without dasabuvir) (34.4%/52.2%) and simeprevir (78.8%/0%). CONCLUSIONS: Significant potential drug-drug interactions are expected between cART and the currently available DAAs in the majority of HIV/HCV coinfected patients. Sofosbuvir/ledipasvir and sofosbuvir/daclatasvir with or without ribavirin appeared the most suitable combinations in our population. A close collaboration between hepatologists and HIV/AIDS specialists appears necessary for the management of HCV treatment concomitantly to cART.

HIV-1 infection and first line ART induced differential responses in mitochondria from blood lymphocytes and monocytes: the ANRS EP45 "Aging" study.

BACKGROUND: The ANRS EP45 "Aging" study investigates the cellular mechanisms involved in the accelerated aging of HIV-1 infected and treated patients. The data reported focus on mitochondria, organelles known to be involved in cell senescence. METHODS: 49 HIV-1 infected patients untreated with antiretroviral therapy, together with 49 seronegative age- and sex-matched control subjects and 81 HIV-1 infected and treated patients, were recruited by 3 AIDS centres (Marseille, Montpellier, Nice; France; http://clinicaltrials.gov/, NCT01038999). In more than 88% of treated patients, the viral load was <40 copies/ml and the CD4+ cell count was >500/mm(3). ROS (reactive oxygen species) production and ΔΨm (inner membrane potential) were measured by flow cytometry in blood lymphocytes and monocytes (functional parameters). Three mitochondrial network quantitative morphological parameters were computed using confocal microscopy and image analysis. Three PBMC mitochondrial proteins (porin and subunits 2 and 4 of cytochrome C oxidase encoded by mtDNA or nuclear DNA, respectively) were analysed by western blotting. RESULTS: Quantitative changes in PBMC mitochondrial proteins were not induced by either HIV-1 infection or ART. Discriminant analysis integrating functional (ROS production and ΔΨm) or morphological (network volume density, fragmentation and branching) parameters revealed HIV-1 infection and ART differential effects according to cell type. First line ART tended to rescue lymphocyte mitochondrial parameters altered by viral infection, but induced slight changes in monocytes. No statistical difference was found between the effects of three ART regimens on mitochondrial parameters. Correlations between functional parameters and viral load confirmed the damaging effects of HIV-1 in lymphocyte mitochondria. CONCLUSIONS: In patients considered to be clinically stable, mitochondria exhibited functional and morphological modifications in PBMCs resulting from either direct or indirect effects of HIV-1 infection (lymphocytes), or from first line ART (monocytes). Together with other tissue impairments, these changes may contribute to global aging.