Sylvie Bregigeon

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.

Etravirine-raltegravir, a marked interaction in HIV-1-infected patients: about four cases.

We wish to comment on the recent Editorial review on maraviroc by Soriano et al. [1]. Their suggestion that the drug could be used for managing the subset of patients unable to show an adequate CD4 cell recovery despite achieving sustained virological suppression with highlyactive antiretroviral therapy (HAART) [1] has been tested in a recent nonrandomized, prospective, open-label, proof-of-concept pilot study with a minimum follow-up of 150 days, where maraviroc 300 mg was added to an ongoing HAART regimen in nine HIV-infected individuals on stable HAART with HIV-1 RNA less than 50 copies/ml for at least 1 year and a stable CD4þ cell count of less than 250 cells/mm [2]. Although two patients showed dramatic increases in CD4 cell counts (þ112 and þ130), the average change was þ14 cells for all patients, and was not statistically significant (P> 0.39). Obviously, further studies with a longer follow-up will be required to eventually demonstrate a significant effect of maraviroc.

Severe Pulmonary Arterial Hypertension in Patients Treated for Hepatitis C With Sofosbuvir

Development of direct-acting antiviral agents against hepatitis C virus (HCV) has changed the management of chronic HCV infection. We report three cases of newly diagnosed or exacerbated pulmonary arterial hypertension (PAH) in patients treated with sofosbuvir. All patients had PAH-associated comorbidities (HIV coinfection in two, portal hypertension in one) and one was already being treated for PAH. At admission, all patients presented with syncope, World Health Organization functional class IV, right-sided heart failure, and extremely severe hemodynamic parameters. After specific PAH therapy, the clinical and hemodynamic properties for all patients were improved. Severity and acuteness of PAH, as well as chronology, could suggest a causal link between HCV treatment and PAH onset. We hypothesize that suppression of HCV replication promotes a decrease in vasodilatory inflammatory mediators leading to worsening of underlying PAH. The current report suggests that sofosbuvir-based therapy may be associated with severe PAH.

Relapse of hepatitis C virus after 14 months of sustained virological response following pegylated-interferon alpha plus ribavirin therapy in a human immunodeficiency virus type 1 infected patient

It has been demonstrated that sustained virological response (SVR) in patients with chronic hepatitis C indicates resolution of infection. We describe a late hepatitis C virus (HCV) relapse with nearly identical HCV genotype 1a RNA, 14 months after a SVR achievement following a 12-month pegylated-interferon plus ribavirin treatment in a human immunodeficiency virus (HIV) infected patient. This virological relapse occurred concomitantly with interruption of highly active antiretroviral therapy and subsequent increased immunosuppression. HCV retreatment was successful and HCV RNA was undetectable at 50 months of follow-up. This case suggests that late relapse of HCV infection in HIV-positive patients with SVR is possible in case of increased immunodeficiency related to highly active antiretroviral therapy interruption. In such circumstances, a close monitoring of HCV viremia and aminotransferases should be performed.

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.

Hepatitis C virus NS3 protease genotyping and drug concentration determination during triple therapy with telaprevir or boceprevir for chronic infection with genotype 1 viruses, southeastern France

Telaprevir and boceprevir, the two first hepatitis C virus (HCV) NS3 protease inhibitors (PIs), considerably increase rates of sustained virologic response in association with pegylated interferon and ribavirin in chronic HCV genotype 1 infections. The 30 first patients treated by telaprevir or boceprevir including anti‐HCV therapies since 2011 in Marseille University hospitals, France, were monitored. HCV loads and plasmatic concentrations of telaprevir and boceprevir were determined on sequential blood samples. HCV NS3 protease gene population sequencing was performed at baseline of treatment and in case of treatment failure. Fifteen patients (including 7 co‐infected with HIV) received telaprevir and the other 15 patients (including 4 co‐infected with HIV) received boceprevir. At baseline, HCV NS3 protease from six patients harbored amino acid substitutions associated with PI‐resistance. Treatment failure occurred at week 12 for 7 patients. Amino acid substitutions associated with PI‐resistance were observed in six of these cases. HCV NS3 R155K and T54A/S mutants, all of genotype 1a, were found from four patients. Median (interquartile range) plasma concentrations were 3,092 ng/ml (2,320–3,525) for telaprevir and 486 ng/ml (265–619) for boceprevir. For HIV–HCV co‐infected patients, median concentrations were 3,162 ng/ml (2,270–4,232) for telaprevir and 374 ng/ml (229–519) for boceprevir. Plasma drug concentration monitoring revealed undetectable concentrations for two patients at week 4, and probable non‐adherence to therapy for another patient. These findings indicate that routine HCV NS3 protease sequencing and plasma PI concentration monitoring might be helpful to characterize cases of therapy failure, at a cost dramatically low compared to that of anti‐HCV therapy. J. Med. Virol. 86:1868–1876, 2014.

Frailty in HIV infected people: a new risk factor for bone mineral density loss

Objective: The study aims to assess the association between bone mineral density (BMD) and frailty in a cohort of HIV-infected patients. Design: A cross-sectional study in an HIV outpatient unit where nearly 1000 patients are monitored. Methods: Study participants undergoing bone densitometry were proposed an evaluation of frailty using criteria of the Cardiovascular Health Study (CHS) and the Study of Osteoporotic Fractures (SOF). Frailty markers were weight-loss, self-reported exhaustion, physical activity, grip strength, chair stands, and slow gait. Patients’ characteristics were collected from an electronic medical record. Associations of frailty with BMD and osteoporosis were tested using multivariate linear and logit regression models, respectively. Results: In total, 175 HIV-infected patients, 121 (69.14%) men, were analyzed. Prevalence of frailty markers, osteopenia, and osteoporosis were comparable among sexes. Despite a younger age, spinal and femoral neck BMD were lower in women (P < 0.05). Linear regression model adjusting by age, duration of HIV follow-up, BMI, smoking status, osteoarthritis, osteoporosis treatment, and the age at menopause showed a negative association of spinal and femoral BMD with frailty according to SOF criteria in women (P < 0.05). In men, SOF-defined frailty was associated with osteoporosis (odds ratio 28.79; 95% confidence interval 2.15–386.4) in a model adjusting for age, duration of HIV follow-up, CD4+ nadir, CD4+ T-cell count, tobacco consumption, exposure to tenofovir (TDF) and protease inhibitors. No significant associations were found between BMD and CHS-defined frailty. Conclusion: Our study shows that frailty according to SOF criteria is associated with low spinal BMD values in female and osteoporosis in male HIV-infected patients.

Hepatitis C Virus of Subtype 2l in Marseille, Southeastern France

The rate of eradication of chronic hepatitis C considerably increases with direct-acting antiviral agents, particularly hepatitis C virus (HCV) polymerase inhibitors. While implementing full-length HCV NS5B polymerase sequencing in our clinical microbiology laboratory, we identified atypical HCV sequences, classified as subtype 2l, from 2 patients. HCV-2l NS5B polymerase sequences were detected from 5 and 14 additional patients by screening our laboratory hepatitis virus sequence database and the NCBI GenBank sequence database. Phylogenetic analyses show unambiguously that all HCV-2l sequences are clustered apart from HCV 2 non-l sequences, which compose a second cluster. Mean (±SD) nucleotide identity between near full-length NS5B fragments of subtype 2l was 93.4 ± 0.8% (range: 92.4-95.1). Of note, all HCV-2l sequences obtained in our laboratory and in other centers were from serum samples collected in France. Analysis of the HCV-2l NS5B polymerase amino acid sequences at 30 positions critical for interaction with or resistance to HCV polymerase inhibitors showed specific patterns.

Mandibular osteonecrosis and dental exfoliation after trigeminal zoster in an HIV-infected patient: case report and review of the literature.

Mandibular osteonecrosis and dental exfoliation after trigeminal zoster in an HIV-infected patient: case report and review of the literature.

Emergence of uncommon HIV-1 non-B subtypes and circulating recombinant forms and trends in transmission of antiretroviral drug resistance in patients with primary infection during the 2013-2015 period in Marseille, Southeastern France: TAMALET et al.

Primary HIV‐1 infections (PHI) with non‐B subtypes are increasing in developed countries while transmission of HIV‐1 harboring antiretroviral resistance‐associated mutations (RAMs) remains a concern. This study assessed non‐B HIV‐1 subtypes and RAMs prevalence among patients with PHI in university hospitals of Marseille, Southeastern France, in 2005‐2015 (11 years). HIV‐1 sequences were obtained by in‐house protocols from 115 patients with PHI, including 38 for the 2013‐2015 period. On the basis of the phylogenetic analysis of the reverse transcriptase region, non‐B subtypes were identified in 31% of these patients. They included 3 different subtypes (3A, 1C, 4F), 23 circulating recombinant forms (CRFs) (CRF02_AG, best BLAST hits being CRF 36_cpx and CRF30 in 7 and 1 cases, respectively), and 5 unclassified sequences (U). Non‐B subtypes proportion increased significantly, particularly in 2011‐2013 vs in 2005‐2010 (P = .03). CRF02_AG viruses largely predominated in 2005‐2013 whereas atypical strains more difficult to classify and undetermined recombinants emerged recently (2014‐2015). The prevalence of protease, nucleos(t)ide reverse transcriptase, and first‐generation nonnucleoside reverse transcriptase inhibitors–associated RAMs were 1.7% (World Health Organization [WHO] list, 2009/2.6% International AIDS Society [IAS] list, 2017), 5.2%/4.3%, and 5.2%/5.2%, respectively. Etravirine/rilpivirine‐associated RAM (IAS) prevalence was 4.3%. Men who have sex with men (MSM) were more frequently infected with drug‐resistant viruses than other patients (26% vs 7%; P = .011). The recent increase of these rare HIV‐1 strains and the spread of drug‐resistant HIV‐1 among MSM in Southeastern France might be considered when implementing prevention strategies and starting therapies.