Pascal Pugliese

A large French prospective cohort of HIV‐infected patients: the Nadis Cohort

The aim of this article is to describe the development of a dynamic French cohort of HIV‐infected patients, the methodological issues and decisions made, and the characteristics of the patients currently enrolled.

Risk Factors of Chronic Kidney Disease in HIV-infected Patients

BACKGROUND AND OBJECTIVES The main aim of this study was determining the risk factors of chronic kidney disease (CKD) in HIV-1-infected patients. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Patients were followed from seven large HIV reference centers in France that maintain prospective databases on HIV-1-infected patients. The main outcome was the time to CKD defined as two consecutive measures of estimated GFR ≤60 ml/min per 1.73 m² over ≥3 months. A Coxs model with delayed entry was used to search predictive factors of time to CKD. RESULTS From 1993 to 2006, 349 out of 7378 patients were found to have CKD. Of these, 166 had hypertension, 33 had diabetes, and 26 were antiretroviral therapy-naïve. Occurrence of acute kidney injury (hazard ratio [HR] = 2.40) and hypertension (HR = 2.39) were strongly associated with an increased risk of CKD. Patients with a durable level of CD4 count >200 cells/mm³ had a lower risk of CKD (HR = 0.63). Recent exposure to indinavir (HR = 2.03), totenofovir (HR = 1.55), and abacavir (HR = 1.37) were associated with an increased risk of CKD. Past exposure to tenofovir was also associated with an increased risk of CKD (HR = 2.23), and a trend toward significance was observed for past exposure to indinavir (HR = 1.28). CONCLUSIONS CKD was not rare in HIV-infected patients and occurs preferentially in HIV-infected patients exposed to certain ARVs, specifically abacavir, indinavir and tenofovir. This requires closer monitoring of renal function in patients exposed to one of these drugs.

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.

Do viral load and CD8 cell count at initiation of tritherapy influence the increase of CD4 T-cell count?

Background:Tritherapies including protease inhibitors improve clinical status and usually increase CD4 T cell count. However, the dissociation between the marked decreases in viral load and the incomplete restoration of CD4 cell counts with a three-drug combination has been reported. We assessed this potential difference among our patients. Methods:Patients were enrolled when a protease inhibitor was prescribed to them for the first time. Using a computerized medical record (ADDIS®), we retrospectively assessed a potential relationship between the increase in CD4 T cells (δCD4) at M3, M6 and variables including sex, age, CDC staging, protease inhibitor, prior antiviral therapy, CD8 and viral load at baseline. We used Epi-Info 6.4 and BMDP software. Results:Data were analyzed on 154 patients. The median CD4 T cell count was 157 at baseline, 215 at month 3 and 202 at month 6. The median viral load was 52 000 copies at baseline, 530 at month 3 and 500 at month 6. In a univariate analysis, a significant relationship was found between δCD4 and CD8 at baseline. A statistically significant negative correlation appeared between the CD8 cell count at baseline and δCD4 at M6 (r = −0.28, Pearson). Moreover, we found that there also was a relationship between δCD4 and viral load at baseline. There was a correlation between δCD4 at M6 and the viral load at MO (r = 0.37, Pearson). In a multiple regression model, after CD8 count at baseline had been accounted for, we found a significant correlation between δCD4 and viral load at baseline (multiple r = 0.33 at M3, and 0.40 at M6). Conclusions:Patients with a low viral load do not benefit from as great an increase in CD4 T cell count as others when they receive a tritherapy including protease inhibitors. These results suggest that another mechanism rather than direct viral pathogenicity leads to CD4 T cell destruction. This mechanism may not be efficiently stopped by antiviral therapy, especially protease inhibitors.

Levels of intracellular HIV-DNA in patients with suppressive antiretroviral therapy.

Objective:The objective of this study is to study factors associated with HIV-DNA levels in chronically infected patients on long-term suppressive antiretroviral therapy (ART). Design:A cross-sectional, multicentre study of patients receiving ART for more than 3 years, HIV-RNA less than 50 copies/ml for more than 2 years and CD4+ cell count more than 350 cells/&mgr;l. Method:Factors associated with low (<150) or high (>1000), compared with intermediate (150–1000 copies/106 PBMCs) levels of HIV-DNA were investigated using multinomial logistic regression. Results:Five hundred and twenty-two patients who initiated ART during the chronic phase were included (71% male; median peak HIV-RNA: 4.88 log10 copies/ml, CD4+ cell count nadir: 222 cells/&mgr;l). Median ART duration was 13 years [interquartile range (IQR) 7–17], viral suppression was 5.7 years (IQR 3.9–8.5) and 66% of the patients never experienced ART failure. Median HIV-DNA was 323 copies/106 PBMCs (IQR, 129–717) with low, intermediate and high levels observed in 28.3, 55.4 and 16.3%, respectively. In multivariable analysis, women were more likely to achieve a low level of HIV-DNA. Each additional year with suppressed HIV-RNA increased the likelihood of low level and decreased the likelihood of high level of HIV-DNA. Peak HIV-RNA higher than 5log10 was always associated with a decreased risk of low and an increased risk of high HIV-DNA. For patients with peak HIV-RNA lower than 5log10, past ART failure was associated with high level of HIV-DNA. Conclusion:Chronically HIV-infected patients with long-term suppressive ART can achieve low total HIV-DNA but one over six still presented HIV-DNA above 1000 copies/106 PBMCs despite long-term viral suppression.

Efficacy and safety of dolutegravir and rilpivirine dual therapy as a simplification strategy: a cohort study

P Gantner, L Cuzin, C Allavena, A Cabie, P Pugliese, M-A Valantin, F Bani-Sadr, V Joly, T Ferry, I Poizot-Martin, R Garraffo, G Peytavin, S Fafi-Kremer and D Rey on behalf of the Dat’AIDS study group* Virology Laboratory, Hôpitaux Universitaires de Strasbourg, Strasbourg, France, INSERM, UMR 1027, Toulouse, France, Universit e de Toulouse III, Toulouse, France, CHU Toulouse, COREVIH Toulouse, Toulouse, France, Infectious Diseases Department, CHU de Nantes, Nantes, France, Infectious Diseases Department, CHU de Fort-de-France, Martinique, France, Infectious Diseases Department, CHU de Nice, Nice, France, Infectious Diseases Department, APHP Hôpital Piti e Salpêtri ere, Paris, France, Institut Pierre Louis d’ epid emiologie et de Sant e Publique (UMRS 1136), UPMC Univ Paris 06, INSERM, Sorbonne Universit es, Paris, France, Infectious Diseases Department, CHU de Reims, Reims, France, Infectious Diseases Department, APHP Hôpital Bichat, Paris, France, Infectious Diseases Department, Hospices civils de Lyon, Lyon, France, APHM Hôpital Sainte-Marguerite, Immuno-Hematology Clinic, Aix-Marseille University, Marseille, France, Pharmacology Laboratory, CHU de Nice, Nice, France, AP-HP, Pharmacology Laboratory, Hôpital Bichat-Claude Bernard, Paris, France, IAME, UMR 1137, Sorbonne Paris Cit e, INSERM, Universit e Paris Diderot, Paris, France and Le Trait d’Union, HIV-Infection Care Center, Hôpitaux Universitaires de Strasbourg, Strasbourg, France

Impact of age-related comorbidities on five-year overall mortality among elderly HIV-infected patients in the late HAART era — Role of chronic renal disease

ObjectivesTo identify main prognostic factors for 5-year mortality among age-related comorbidities (ARCs) in older people living with HIV (PLHIV).DesignA prospective, multicentre cohort study with a 5-year follow-up period in the late HAART era (from January 2008 to December 2012).SettingThe Dat’AIDS cohort involving 12 French hospitals.ParticipantsAll actively followed HIV-1 infected patients aged 60 or older.MeasurementsThe study endpoint was all-cause five-year mortality. The following ARCs were considered: chronic renal disease, cardiovascular diseases, cancer, chronic pulmonary disease, cirrhosis, diabetes and nutritional status. Hepatitis C (HCV), hepatitis B (HBV) co-infection and sociodemographic characteristics were also evaluated. Cox’s Proportional Hazards model was used for multivariate analysis.ResultsAmong 1415 PLHIV aged 60 or more patients included, mean age was 66±5.5 years; 154 died (mortality rate 2.47/100 patientyears). The most prevalent ARCs were chronic renal disease (20.1%), diabetes (14.2%) and cardiovascular diseases (12.2%). By multivariate analysis, chronic renal disease (adjusted hazard ratio (aHR)=2.25; 95% confidence interval (CI) [1.58-2.21]; p<10-4), cardiovascular diseases (aHR=2.40; 95%CI[1.64-3.52]; p<10-4), non-HIV related cancer (aHR=1.91; 95%CI[1.20-3.05]; p=0.007), cirrhosis (aHR=2.99; 95%CI[1.68-5.33]; p<10-3), HCV co-infection (aHR=2.00; 95%CI[1.18-3.38]; p=0.009), low body mass index (aHR=2.42; 95%CI[1.46-4.01]; p<10-3) and CD4 cell count < 200cells/μl (aHR=2.23; 95%CI[1.36-3.65]; p=0.002) were independently associated with 5 year mortality.ConclusionDue to a high prevalence, chronic renal disease and cardiovascular disease are main prognostic factors for 5-year mortality among aged PLHIV.

An undetectable polymerase chain reaction signal in routine HIV plasma viral load monitoring is associated with better virological outcomes in patients receiving highly active antiretroviral therapy.

The aim of the study was to assess whether patients with undetectable viraemia [a negative polymerase chain reaction result (PCRneg)] and those with plasma viral load (PVL) < 40 HIV‐1 RNA copies/mL but a detectable (positive) PCR signal (PCRpos) had different outcomes in terms of the development of blips and virological failure (VF).

Atazanavir in Patients with Persistent Viral Replication Despite HAART: Results from the French Prospective NADIS Cohort

Abstract Objective: To assess virological efficacy of a ritonavir-boosted atazanavir (ATV/r)-containing regimen in patients with persistent viral replication despite HAART. Patients and Method: Prospective cohort of French HIV-infected patients. Patients were included if pretreated and viral load (VL) >400 copies/mL at the time of ATV/r first prescription (baseline). Demographic and epidemiologic data, therapeutic history, and clinical and biological values at baseline and during follow-up were analyzed. Primary endpoint was failure of the regimen defined as either VL >400 copies/mL at Week 24 or treatment interruption before Week 24. Multivariate analysis was performed of baseline characteristics related with treatment failure. Results: There were 424 patients with available data. Primary endpoint was met by 36%: 24% VL >400 copies/mL and 12% treatment interruption. Treatment interruption due to drug-related toxicity was significantly more frequent in women (20.5% vs. 8.8%, p = .001). Female gender (adjusted odds ratio [OR] = 1.91), previous use of lopinavir (LPV; OR = 2.76), number of new drugs and of active drugs in the regimen (OR = 0.48 and 0.3, respectively), and baseline VL (OR = 1.75) were independently related with treatment failure. Conclusion: ATV/r-containing regimens, because of low pill burden and good tolerance, can be a useful strategy as long as the patients did not suffer previous LPV failures. The issue of gender deserves further studies in larger populations.

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.