Véronique Obry-Roguet

Renal impairment in patients receiving a tenofovir-cART regimen: impact of tenofovir trough concentration.

Objective:Tenofovir disoproxil fumarate (TDF) is known to induce renal dysfunction in HIV-infected patients. The aim of this retrospective study was to evaluate the correlation between TDF trough concentration (Ctrough-TDF) and glomerular filtration rate (GFR) in a cohort of patients on antiretroviral therapy. Methods:A total of 163 patients with at least one determination of Ctrough-TDF between 17–24 hours were retrospectively selected from a computerized database and distributed into 3 groups defined by TDF concentrations <40 (11.7%), between 40 and 90 (36.8%), and >90 (high-level group, 51.5%) ng/mL. GFR was measured by Cockcroft–Gault, Modification of Diet in Renal Disease, and Chronic Kidney Disease Epidemiology Collaboration formulae at the times of TDF initiation and Ctrough-TDF determination and after 12 months. Results:At the time of Ctrough-TDF measurement, median duration of TDF-based therapy was 21.1 months. GFR was significantly decreased in high-level group (−8.5 mL/min; P < 0.001) whatever the method used. GFR decline was significantly associated with an older age. Gender-stratified analysis showed that the early impact of Ctrough-TDF >90 ng/mL was significant in women only. After 12 months, the decrease in GFR in patients with high Ctrough-TDF was observed in both men and women (−8.27; P = 0.003). Conclusions:The high prevalence of elevated Ctrough-TDF and its correlation with an increased risk of renal impairment support the usefulness of therapeutic drug monitoring for TDF, particularly in women and older patients.

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.

Lack of correlation between the size of HIV proviral DNA reservoir and the level of immune activation in HIV-infected patients with a sustained undetectable HIV viral load for 10 years

BACKGROUND The persistence of HIV residual replication in patients with an undetectable plasma viral load (pVL) may limit immune recovery and facilitate inflammation-induced comorbidities. OBJECTIVE The objective was to evaluate any correlation between immune restoration and intracellular [IC] HIV-DNA in cART-treated patients with a sustained undetectable pVL. STUDY DESIGN This retrospective cross sectional study included 62 patients with a median duration of undetectable pVL of 10.3 years. IC HIV DNA in peripheral mononuclear blood cells (PBMCs) and T cell subsets were measured at the last visit. pVL, CD4(+) and CD8(+) T cell counts were retrospectively collected from the onset of long-term inhibition by antiretroviral treatment. The patients were separated into two groups: 27 non-blippers (sustained pVL< threshold value during all the visits) and 35 blippers ( ≥ 1 episodes of pVL> threshold but < 1000 copies/ml). The median pVL in blippers was 115 copies/ml. RESULTS The median IC HIV DNA rate was 34 copies/10(6) PBMCs (71% ≥ 20 copies/10(6) PBMCs) with no significant difference between the groups. The proportion of CD8(+)CD38(+) and CD8(+)DR(+) T cells was higher in blipper patients, but the difference was only significant for the CD8(+)DR(+) marker (p = 0.036). No correlation was found between markers of immune activation on CD4(+) and CD8(+) T cells and the IC HIV-DNA level. CONCLUSION No relation was found between the size of HIV reservoirs and immune activation in patients with sustained undetectable pVL. Mechanisms of immune activation have to be better understood in order to define specific therapeutic interventions.

High level of HPV 16 and 18 DNA load in anal swabs from male and female HIV-1 infected patients

BACKGROUND Despite HAART, the prevalence and incidence of anal cancer in HIV-infected individuals have increased. Recently, the relationship between the severity of cervical lesions and oncogenic HPV load was demonstrated; however, few studies have assessed the level and the significance of oncogenic HPV load in patients at risk for anal neoplasia. OBJECTIVES To assess HPV genotypes and HPV 16/18 DNA load in HIV-1 infected patients at risk for anal neoplasia. STUDY DESIGN Cross-sectional pilot study from male and female HIV-1 infected individuals at risk for anal neoplasia in an outpatient HIV Clinical Unit of Marseilles university Hospitals. RESULTS Anal HPV was found in 79% of the patients whereas high-risk (HR) HPV types and infection with multiple HPV types were found in 83% and 61% of the patients, respectively. Using a sensitive real-time PCR, median HPV 16 and 18 DNA load were 5 x 10(6) copies/10(6) cells and 3.2 x 10(5) copies/10(6) cells, respectively. Notably, there were no significant differences in the HPV 16/18 viral loads with respect to the anoscopic results. CONCLUSIONS Longitudinal studies are needed to evaluate the link between high anal HPV DNA load and progression to anal squamous intraepithelial lesions and anal cancer.

Impact of hepatitis C virus coinfection on T-cell dynamics in long-term HIV-suppressors under combined antiretroviral therapy

Objective:The objective of this study is to evaluate the impact of hepatitis C virus (HCV) serostatus on the evolution of CD8+ cells and CD4+ : CD8+ ratio in HIV-infected patients on combined antiretroviral therapy (cART) who achieve sustained undetectable viral load (HIV-pVL). Design and methods:A longitudinal study performed in an outpatient HIV-unit following 1495 HIV-infected patients. Data of patients on cART achieving undetectable HIV-pVL for at least 3 years were collected retrospectively from our medical e-database NADIS from January 1997 to April 2005, a period defined in order to select patients who were naive of hepatitis treatment. T-cell counts were assessed every 6 months from HIV-suppression over the study period. Results:Two hundred and twenty-six HIV mono-infected (group 1) and 130 HCV-coinfected patients (group 2; genotype prevalence: 42% HCV-G1, 26% HCV-G3, 11% HCV-G4 and 21% HCV-G2) fulfilled the selection criteria. cART regimens were comparable between the groups, as were CD4+ and CD8+ cell counts at the first undetectable HIV-pVL. After 3 years, both groups displayed similar CD4+ cell reconstitution, although CD4+ percentage was higher in group 1 (30.3 ± 1.1 vs. 27 ± 1.1%; P < 0.001). HIV suppression led to a significant drop of median CD8+ cell counts in group 1 (P = 0.027), but not in group 2, which displayed higher CD8+ cell counts all through the follow-up (mean diff. = 135.71 ± 26.89 cells/&mgr;l, P < 0.001). Moreover, the fraction of patients reaching CD4+ : CD8+ ratio ≥ 1 was lower in group 2 (14 vs. 27.7%; P < 0.05). Conclusion:Despite sustained HIV suppression under cART, HCV coinfection was found to hamper CD8+ downregulation. Further studies will determine the impact of treatment with direct-acting antiviral agents on the CD8+ pool, and the advantage of systematic HCV-targeted therapy for HIV/HCV-coinfected patients.

Impact of tenofovir dose adjustment on both estimated glomerular filtration rate and tenofovir trough concentration.

BACKGROUND Tenofovir disoproxil fumarate (TDF)-based regimen is a treatment option for HIV-infected patients. TDF dose adjustment is recommended in patients with impaired renal function. We assessed the impact of TDF dose adjustment on renal function and tenofovir trough concentration. METHODS Fourteen HIV patients for whom TDF dose was adjusted (1 tablet/48 h) because of estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m2, and/or due to a tenofovir trough concentration >90 ng/ml between 2006 and 2013 were selected. The eGFR was measured at baseline and 3, 6 and 12 months after TDF dose adjustment. RESULTS A 50% TDF dose reduction resulted in a significant increase of the eGFR 3 months after dose adjustment (61.1 versus 72.8 ml/min/1.73 m2; P=0.003). Concomitantly, tenofovir trough concentration decreased from 175 to 66 ng/ml (P=0.009). Antiviral efficacy was maintained in all patients. CONCLUSIONS TDF dose adjustment combined with therapeutic drug monitoring may be useful especially in patients at risk of kidney dysfunction.

First-line cART regimen impacts the course of CD8+ T-cell counts in HIV-infected patients that achieve sustained undetectable viral load.

Abstract The aim of the study was to investigate the impact of first-line combined antiretroviral therapy (cART) regimen on the course of CD8+ T-cell counts in human immunodeficiency virus (HIV)-infected patients. A retrospective observational study conducted on the French DAT’AIDS Cohort of HIV-infected patients. We selected 605 patients initiating a first-line cART between 2002 and 2009, and which achieved a sustained undetectable HIV plasma viral load (pVL) for at least 12 months without cART modification. The evolution of CD8+ T-cell counts according to cART regimen was assessed. CD8+ T-cell counts were assessed in 572 patients treated with 2NRTIs+1PI/r (n= 297), 2NRTIs+1NNRTI (n= 207) and 3NRTIs (n= 68). In multivariate analysis, after 12 months of follow-up, the 3NRTIs regimen was associated with a significantly smaller decrease of CD8+ T-cell count compared with NNRTI-containing regimens (–10.2 cells/&mgr;L in 3NRTIs vs –105.1 cells/&mgr;L; P=0.02) but not compared with PI-containing regimens (10.2 vs –60.9 cells/&mgr;L; P=0.21). After 24 months, the 3NRTIs regimen was associated with a smaller decrease of CD8+ T-cell count and % compared with PI/r- and NNRTI-containing regimens (0.2 in 3NRTIs vs –9.9 with PI/r-regimens, P=0.001, and vs –11.1 with NNRTI-regimens, p < 0.0001). A focus analysis on 11 patients treated with an INSTI-containing cART regimen during the study period showed after 12 months of follow-up, a median decrease of CD8+ T-cell count of –155 [inter quartile range: –302; –22] cells/&mgr;L. Our data highlight the fact that cART regimens have differential effects on CD8 pool down regulation.

A Case of Undiagnosed HIV Infection in a 57-Year-Old Woman with Multiple Myeloma: Consequences on Chemotherapy Efficiency and Safety

Background. Non-AIDS-defining cancers represent a rising health issue among HIV-infected patients. Nevertheless, HIV testing is not systematic during the initial cancer staging. Here, we report a case of HIV infection diagnosed three years after chemotherapy initiation for multiple myeloma. Results. A 57-year-old woman diagnosed with multiple myeloma underwent a first round of chemotherapy by bortezomib/lenalidomide and then with bortezomib/liposomal-doxorubicine/dexamethasone, with partial remission, poor hematological tolerance, and multiple episodes of pneumococcal infection. Allogenic stem cell transplantation was proposed leading to HIV testing, which revealed seropositivity, with an HIV viral load of 5.5 Log10/mL and severe CD4 T cell depletion (24 cells/mm3). Chemotherapy by bendamustin was initiated. Multidisciplinary staff decided the initiation of antiretroviral therapy with tenofovir/emtricitabin/efavirenz and prophylaxis against opportunistic infections. After 34 months, patient achieved complete remission, sustained HIV suppression, and significant CD4 recovery (450 cells/mm3), allowing effective pneumococcal immunization without relapse. Conclusion. Our case illustrates the drawback that ignored HIV infection is still causing to cancer patients receiving chemotherapy and highlights the importance of early HIV testing in oncology. A multidisciplinary approach including oncologists/hematologists, virologists, and pharmacists is recommended in order to avoid drug interactions between chemotherapy and antiretroviral drugs. Moreover, prophylactic medication is recommended in these patients regardless of CD4+ cell count at the initiation of chemotherapy.

Educational intervention and HIV infection: preliminary results

Methods We initiated in March 2009 an EIP in an HIV outdoor Clinical Unit witch follow about 1000 HIV infected patients with 40% HCV coinfected. This program included at last 3 educational consultations for each patient (at least 2 initial educational consultations permitted to do a personal educational diagnosis and to fix objectives with patients and at least 1 follow up educational consultation to validate experiences) and was performed by a specifically training nurse. This analysis focused on quality of life with a self administered questionnaire at inclusion in the program.

Impact of maraviroc on immune restoration in an advanced stage HIV-infected patient

Background Maraviroc is a CCR5 antagonist with clearly demonstrated virological efficacy in patients refractory to prior treatment and infected with an R5-tropic virus. This antiretroviral drug would appear to have a special immunomodulatory property, given the significantly higher increase in CD4 count in patients treated with maraviroc in clinical trials. We report the case of a severely immunocompromised patient in which the introduction of maraviroc reduced viral load to below the threshold of 40 copies/ml, with an increase in CD4 of over 100 in the space of 17 months. Methods