Christine Katlama

Publications of Christine Katlama

• Hepatic steatosis in HIV-HCV coinfected patients receiving antiretroviral therapy is associated with HCV-related factors but not antiretrovirals.

  Authors: Valérie Martinez, Thi Dieu Ngan Ta, Zahra Mokhtari, Marguerite Guiguet, Patrick Miailhes, Marc-Antoine Valantin, Fréderic Charlotte, Philippe Bertheau, Jean-Michel Molina, Christine Katlama, Eric Caumes

  BMC research notes. 04/2012; 5(1):180.

  ABSTRACT: BACKGROUND: In HIV and hepatitis C virus (HCV) coinfected patients, the role of antiretroviral therapy (ART) on hepatic steatosis (HS) remains controversial. METHODS: HIV/HCV coinfectedABSTRACT: BACKGROUND: In HIV and hepatitis C virus (HCV) coinfected patients, the role of antiretroviral therapy (ART) on hepatic steatosis (HS) remains controversial. METHODS: HIV/HCV coinfected patients receiving ART and previously untreated for HCV who underwent a liver biopsy were included. Cumulative duration of exposure to each antiretroviral was recorded up to liver biopsy date. Logistic regression analyses evaluated factors associated with steatosis and its severity. RESULTS: 184 patients were included: median age 41 years, 84% male, 89% Caucasian, 61% with a past history of intravenous drug use. HCV genotypes were 1 (55%), 2 (6%), 3 (26%), and 4 (13%). Median HCV-RNA was 6.18 log10 IU/ml. HIV-RNA was undetectable (<400 copies/ml) in 67% of patients. Median CD4 count was 321/mm3. All patients had been exposed to nucleoside reverse transcriptase inhibitors (median cumulative exposure 56 months); 126 received protease inhibitors (23 months), and 79 non-nucleoside reverse transcriptase inhibitors (16 months). HS was observed in 102 patients (55%): 41% grade 1; 5% grade 2, and 9 % grade 3. In multivariate analysis, HCV genotype 3 and HCV viral load were moderately associated with mild steatosis but strongly with grade 2-3 steatosis. After adjustment for the period of biopsy, no association was detected between HS and exposure to any antiretroviral class or drug, or duration of ART globally or comparing genotype 3 to others. CONCLUSIONS: Among our ART-treated HIV-HCV cohort predominantly infected with genotype 1, 55% of patients had HS which was associated with HCV-related factors, but not ART class or duration of exposure.

• Circulating interleukin-6 levels correlate with residual HIV viraemia and markers of immune dysfunction in treatment-controlled HIV-infected patients.

  Authors: Jean-Philippe Bastard, Cathia Soulié, Soraya Fellahi, Stephanie Haïm-Boukobza, Anne Simon, Christine Katlama, Vincent Calvez, Anne-Geneviève Marcelin, Jacqueline Capeau

  Antiviral therapy. 03/2012;

  BACKGROUND: Antiretroviral therapy (ART)-controlled HIV-infected patients have elevated levels of systemic inflammatory markers, C-reactive protein (CRP) and interleukin (IL)-6, which correlate withBACKGROUND: Antiretroviral therapy (ART)-controlled HIV-infected patients have elevated levels of systemic inflammatory markers, C-reactive protein (CRP) and interleukin (IL)-6, which correlate with increased cardiovascular risk and/or mortality. Persistent low-level viral replication could be involved in this inflammatory state. We evaluated whether residual viral load (VL) correlated with the level of systemic inflammatory/immune markers in ART-controlled HIV-infected patients. METHODS: We evaluated 122 antiretroviral-controlled patients with VL 1-500 copies/ml for circulating levels of high-sensitivity (hs)CRP, hsIL-6, IL-8, soluble (s)CD14 and soluble tumour necrosis factor (TNF) receptors, sTNFR1 and sTNFR2. RESULTS: The patients were 80.3% men, the median age was 47 years, the median CD4(+) T-cell count was 519 cells/mm(3), the median nadir CD4(+) T-cell count was 180 cells/mm(3), the median VL was 28 copies/ml and the median body mass index was 23.3 kg/m(2). The median (range) values for IL-6, CRP, IL-8, sCD14, sTNFR1 and sTNFR2 were 0.685 pg/ml (0.15-5.46), 1.8 mg/l (0.2-9.7), 10.0 pg/ml (1.6-71.1), 1,174 ng/ml (214-3,145), 1,112 pg/ml (583-5,834) and 2,412 pg/ml (1,142-7,688), respectively. IL-6 values correlated positively with HIV VL (rho=0.217, P=0.017). The VL threshold value for significantly increased IL-6 was 31 copies/ml (P=0.023). IL-6 values correlated with markers of immune dysfunction: the CD4/CD8 ratio (rho=-0.248, P=0.011), CD4 nadir level (rho=-0.186, P=0.04) and nadir CD4/CD8 ratio (rho=-0.257, P=0.008). They negatively correlated with markers of immune activation sCD14 (rho=-0.236, P=0.011) and IL-8 (rho=-0.290, P=0.002). We found no correlation between VL and CRP or other markers of inflammation/immune dysfunction including sTNFR1, sTNFR2, sCD14 and IL-8. CONCLUSIONS: We report here that low-range IL-6 levels correlated with low-range VL and inversely with sCD14 and IL-8. Our findings suggest that maintaining VL<30 copies/ml in HIV-infected patients might therefore reduce IL-6.

• Emergence of cytomegalovirus resistance to foscarnet in a patient receiving foscarnet salvage therapy for multidrug-resistant HIV infection.

  Authors: David Boutolleau, Ana Canestri, Sonia Burrel, Marc Wirden, Sophie Seang, Cyril Clavel-Osorio, Anne-Geneviève Marcelin, Christine Katlama, Henri Agut

  Journal of clinical virology : the official publication of the Pan American Society for Clinical Virology. 03/2012;

  Foscarnet (FOS) is a pyrophosphate analogue that inhibits both cytomegalovirus (CMV) and human immunodeficiency virus (HIV) replication. We describe herein the emergence of CMV resistance to FOS in aFoscarnet (FOS) is a pyrophosphate analogue that inhibits both cytomegalovirus (CMV) and human immunodeficiency virus (HIV) replication. We describe herein the emergence of CMV resistance to FOS in a 54-year-old man receiving FOS salvage therapy because of multidrug-resistant HIV-1 infection. Oral valganciclovir (VGCV) treatment allowed subsequently the improvement of FOS-resistant CMV infection.

• Erythrocyte and plasma ribavirin concentrations in the assessment of early and sustained virological responses to pegylated interferon-alpha 2a and ribavirin in patients coinfected with hepatitis C virus and HIV.

  Authors: Stéphanie Dominguez, Jade Ghosn, Bruno Cassard, Giovanna Melica, Isabelle Poizot-Martin, Caroline Solas, Anne-Sophie Lascaux, Magali Bouvier-Alias, Christine Katlama, Yves Lévy, Gilles Peytavin

  The Journal of antimicrobial chemotherapy. 03/2012;

  OBJECTIVES: To determine the relationship between erythrocyte and plasma ribavirin concentrations in hepatitis C virus (HCV)/HIV-coinfected patients, and to correlate ribavirin exposure with earlyOBJECTIVES: To determine the relationship between erythrocyte and plasma ribavirin concentrations in hepatitis C virus (HCV)/HIV-coinfected patients, and to correlate ribavirin exposure with early and sustained virological response (EVR and SVR) and haemoglobin level reductions. METHODS: Clinical and biological data from 68 HCV/HIV-coinfected patients were recorded at baseline, week 4 (W4), week 12 and at 24 weeks after completion of treatment. Plasma and erythrocyte ribavirin concentrations were determined 12 h after the final ribavirin dose (C(min)). RESULTS: Erythrocyte ribavirin concentrations were 100-fold higher than plasma concentrations, with a significant relationship between them (P < 0.05). In patients with HCV genotype 1 or 4, a plasma ribavirin C(min) threshold of 1.95 mg/L at W4 tended to predict EVR [sensitivity 44%; specificity 87%; AUC 0.67 (95% CI 0.50-0.84)] and was predictive of SVR [sensitivity 58%; specificity 84%; AUC 0.71 (95% CI 0.51-0.90)]. Among patients with these HCV genotypes, an erythrocyte ribavirin C(min) threshold of 146 mg/L at W4 was found to be the best value for discriminating between responders and non-responders for both EVR [sensitivity 67%; specificity 75%; AUC 0.58 (95% CI 0.24-0.93)] and SVR [sensitivity 50%; specificity 80%; AUC 0.70 (95% CI 0.39-1.01)]. We also demonstrated a significant relationship between reduced haemoglobin levels and plasma ribavirin C(min) at W4 (P = 0.05). CONCLUSIONS: Therapeutic drug monitoring may be useful for the management of anti-HCV treatment in HCV/HIV-coinfected patients.

• Resistant minority species are rarely observed in patients on darunavir/ritonavir monotherapy.

  Authors: Sidonie Lambert-Niclot, Philippe Flandre, Marc-Antoine Valantin, Gilles Peytavin, Sophie Sayon, Laurence Morand-Joubert, Constance Delaugerre, Michele Algarte-Genin, Christine Katlama, Vincent Calvez, Anne-Genevieve Marcelin

  The Journal of antimicrobial chemotherapy. 03/2012;

  OBJECTIVES: To analyse the emergence of resistant viruses in patients failing darunavir monotherapy, including minority species, and to investigate the impact of baseline reverse transcriptase (RT),OBJECTIVES: To analyse the emergence of resistant viruses in patients failing darunavir monotherapy, including minority species, and to investigate the impact of baseline reverse transcriptase (RT), protease (PR) and gag resistance mutations on virological failure (VF) occurrence. METHODS: Nine of the 225 HIV-1-infected patients enrolled in the MONOI trial (darunavir/ritonavir monotherapy or darunavir/ritonavir + two nucleoside reverse transcriptase inhibitors in a switch strategy) experienced VF, defined as two plasma HIV-1 viral loads >400 copies/mL at least 2 weeks apart. Among these nine patients with VF, five were in the darunavir/ritonavir monotherapy arm and four were in the darunavir/ritonavir triple therapy arm. Bulk sequences of the PR, RT and gag genes at baseline (on DNA) and at the time of VF (on RNA) were determined for all patients with two viral loads >50 copies/mL at least 2 weeks apart (n = 47). PR and gag gene clonal analysis was performed on plasma samples of the nine patients with VF. RESULTS: There was no association between mutations in RT, PR and gag genes in DNA and VF occurrence. None of the patients demonstrated selection of darunavir resistance mutations among the 47 patients with a viral load >50 copies/mL at least 2 weeks apart. The virus of one of the nine patients with VF presented minority variants with darunavir resistance mutations at positions 32, 47 and 50. Clonal analysis of the gag region for the nine patients with VF did not show any selection of minority variants. CONCLUSIONS: In patients with failure on darunavir/ritonavir monotherapy we did not find any selection of darunavir resistance mutations using standard genotype testing. However, the virus of one patient among nine failures presented minority variants plus darunavir resistance mutations.

• Dolutegravir for the treatment of HIV.

  Authors: Christine Katlama, Robert Murphy

  Expert opinion on investigational drugs. 03/2012; 21(4):523-30.

  Introduction: Development of new antiretroviral drugs which are highly potent, tolerable over the long term and with a high genetic barrier to resistance is essential for the treatment of a chronicIntroduction: Development of new antiretroviral drugs which are highly potent, tolerable over the long term and with a high genetic barrier to resistance is essential for the treatment of a chronic viral disease that requires life-long therapy with near-perfect medication adherence. Integrase inhibitors (INI) are a new class of antiretroviral drugs that block the action of HIV integrase, which catalyses several key steps in the virus life cycle which are essential for insertion of the viral genome into the DNA of host cell. Areas covered: Dolutegravir (DTG), a second-generation INI currently in the late stage of clinical development, is an effective orally available drug with a long half-life that does not need to be pharmacologically enhanced, is effective as a once daily drug in the absence of INI resistance mutations and twice daily in presence of INI resistance mutations. Expert Opinion: DTG, as other drugs in the INI class, appears safe and well tolerated. Results from ongoing large Phase III studies will bring more generalizable and robust information on the long-term effects of DTG.

• Long-term Efficacy and Safety of Raltegravir, Etravirine, and Darunavir/Ritonavir in Treatment-Experienced Patients: Week 96 Results from the ANRS 139 TRIO Trial.

  Authors: Catherine Fagard, Céline Colin, Charlotte Charpentier, Agathe Rami, Christine Jacomet, Patrick Yeni, Daniel Vittecoq, Christine Katlama, Jean-Michel Molina, Diane Descamps, Geneviève Chene, Yazdan Yazdanpanah

  Journal of acquired immune deficiency syndromes (1999). 01/2012;

  ABSTRACT: Among 103 patients with multidrug-resistant HIV who initiated raltegravir, etravirine, and darunavir/ritonavir-containing regimen in the ANRS 139 TRIO trial, 100 participated in extendedABSTRACT: Among 103 patients with multidrug-resistant HIV who initiated raltegravir, etravirine, and darunavir/ritonavir-containing regimen in the ANRS 139 TRIO trial, 100 participated in extended follow-up and continued study treatment until W96. Among them, 87 (87%) received an optimized background therapy including either nucleoside reverse transcriptase inhibitors or enfuvirtide, they were 78 (78%) at W96. At W96, 88% achieved durable virologic response (<50 copies/mL). CD4 response was maintained (median change of +150 cells/mm). No major toxicity was reported. This triple drug combination showed sustained efficacy and thus, should be strongly considered for patients with multi-class resistant virus.

• Week 96 Efficacy, Virology and Safety of Darunavir/r Versus Lopinavir/r in Treatment-Experienced Patients in TITAN.

  Authors: Denes Banhegyi, Christine Katlama, Clovis Arns da Cunha, Stefan Schneider, Anita Rachlis, Cassy Workman, Sandra De Meyer, Ann Vandevoorde, Tom Van De Casteele, Frank Tomaka

  Current HIV research. 01/2012; 10(2):171-81.

  Long-term potent activity of antiretrovirals is essential for HIV-1-infected, treatment-experienced patients. TITAN (TMC114/r In Treatment-experienced pAtients Naive to lopinavir) compared Week-96Long-term potent activity of antiretrovirals is essential for HIV-1-infected, treatment-experienced patients. TITAN (TMC114/r In Treatment-experienced pAtients Naive to lopinavir) compared Week-96 efficacy and safety of darunavir/ritonavir (DRV/r) versus lopinavir/ritonavir (LPV/r). Treatment-experienced, LPV-naive, HIV-1-infected patients were randomised to DRV/r 600/100 mg bid or LPV/r 400/100 mg bid plus optimised background regimen (≥ 2 NRTIs/NNRTIs). 595 patients were enrolled (mean baseline HIV-1 RNA: 4.30 log10 copies/mL; median CD4 count: 232 cells/mm3). At Week 96, more DRV/r than LPV/r patients achieved HIV-1 RNA < 400 copies/mL (66.8% versus 58.9% [intent-to-treat (ITT)/time-to-loss of virological response (TLOVR)], estimated difference 8.7%, 95% confidence interval [CI]: 0.7-16.7), demonstrating the primary endpoint of non-inferiority of DRV/r (p < 0.001); the difference in response was statistically significant (p=0.034). For the secondary efficacy parameter (HIV-1 RNA < 50 copies/mL) at Week 96, response to DRV/r was 60.4% versus 55.2% for LPV/r (ITT-TLOVR), estimated difference 5.8%, 95% CI: -2.3-13.9. Virological failure (VF; HIV-1 RNA > 400 copies/mL) with DRV/r (13.8%) was nearly half that with LPV/r (25.6%). Discontinuations due to adverse events were 8.1% for both DRV/r and LPV/r. Treatment-related grade 2-4 diarrhoea was 8.1% (DRV/r) versus 15.2% (LPV/r). Increases in triglycerides and total cholesterol were less pronounced with DRV/r. At 96 weeks, noninferiority (HIV-1 RNA < 400 copies/mL) of DRV/r over LPV/r was maintained; the difference in response was statistically significant. VF rate and treatment-related grade 2-4 diarrhoea were lower with DRV/r versus LPV/r.

• Unexpected atazanavir-associated biliary lithiasis in an HIV-infected patient.

  Authors: Eve Courbon, François Laylavoix, Cathia Soulié, Christine Le Beller, Vincent Calvez, Christine Katlama, Gilles Peytavin

  The Journal of antimicrobial chemotherapy. 01/2012; 67(1):250-1.

• E17A mutation in HIV-1 Vpr confers resistance to didanosine in association with thymidine analog mutations.

  Authors: Slim Fourati, Isabelle Malet, Carolin A Guenzel, Cathia Soulie, Priscilla Maidou-Peindara, Laurence Morand-Joubert, Marc Wirden, Sophie Sayon, Gilles Peytavin, Anne Simon, Christine Katlama, Serge Benichou, Vincent Calvez, Anne-Geneviève Marcelin

  Antiviral research. 11/2011; 93(1):167-74.

  HIV-1 accessory Vpr protein is involved in the reverse transcription process and has been shown to modulate the virus mutation rate. This process may play a role in the kinetics of appearance of drugHIV-1 accessory Vpr protein is involved in the reverse transcription process and has been shown to modulate the virus mutation rate. This process may play a role in the kinetics of appearance of drug resistance mutations under antiretroviral treatment. Vpr sequences were analyzed from plasma viruses derived from 97 HIV-1-infected individuals failing antiretroviral treatment and 63 antiretroviral-naïve patients. Vpr genetic variability was analyzed for association with specific drug treatment and drug resistance mutations. Biological and virological experiments were employed to characterize a mutation in Vpr found to be associated with virological failure. E17A mutation located in the first α-helix of Vpr was more prevalent in HAART-treated individuals compared to untreated individuals. E17A was associated with thymidine analog mutations (TAMs) in reverse transcriptase M41L, L210W and T215Y and with the use of didanosine in the patients' treatment histories. E17A had no impact on the biochemical and functional properties of Vpr, and did not affect kinetics of replication of wild-type or TAMs-containing viruses. However, its association with TAMs and the use of didanosine was consistent with phenotypic susceptibility assays showing a significant 3-fold decrease in didanosine susceptibility of viruses harboring Vpr E17A combined with TAMs compared to viruses harboring TAMs alone. These findings highlight a novel role of Vpr in HIV-1 drug resistance. Vpr E17A confers resistance to didanosine when associated with TAMs. Whether Vpr E17A facilitates excision of didanosine is still to be determined.

• Ten-year diabetes incidence in 1046 HIV-infected patients started on a combination antiretroviral treatment.

  Authors: Jacqueline Capeau, Vincent Bouteloup, Christine Katlama, Jean-Philippe Bastard, Vincent Guiyedi, Dominique Salmon-Ceron, Camelia Protopopescu, Catherine Leport, Francois Raffi, Geneviève Chêne

  AIDS (London, England). 11/2011; 26(3):303-14.

  To evaluate the incidence and determinants of diabetes in a cohort of HIV-infected adults initiated with combination antiretroviral treatment (cART) in 1997-1999 and followed up to 2009. ProspectiveTo evaluate the incidence and determinants of diabetes in a cohort of HIV-infected adults initiated with combination antiretroviral treatment (cART) in 1997-1999 and followed up to 2009. Prospective study of 1046 patients at 47 French clinical sites. Potential determinants of diabetes occurrence, defined by confirmed increased glycemia and/or initiation of antidiabetic treatment, were assessed by a proportional hazards model, including time-updated metabolic parameters and ART exposure. Among the cohort, representing 7846 person-years of follow-up (PYFU), 54% received indinavir, 75% stavudine and 52% didanosine. Overall, 111 patients developed diabetes, with an incidence of 14.1/1000 PYFU (14.6 in men, 12.6 in women). Incidence peaked in 1999-2000 (23.2/1000 PYFU) and decreased thereafter. The incidence of diabetes was associated [adjusted hazard ratio (aHR), all P<0.02] with older age (hazard ratio = 2.13 when 40-49 years, hazard ratio = 3.63 when ≥50 years), overweight (hazard ratio = 1.91 for a BMI 25-29 kg/m(2), hazard ratio = 2.85 >30 kg/m(2)), waist-to-hip ratio (hazard ratio = 3.87 for ≥0.97 male/0.92 female), time-updated lipoatrophy (hazard ratio = 2.14) and short-term exposure to indinavir (0-1 year: hazard ratio = 2.53), stavudine (0-1 year: hazard ratio = 2.56, 1-2 years: hazard ratio = 2.65) or didanosine (2-3 years: hazard ratio = 3.16). Occurrence of diabetes was not associated with HIV-related markers, hepatitis C, hypertension or family history of diabetes. Insulin resistance was predictive for incident diabetes. In this nationwide cohort, followed for 10 years after cART initiation, diabetes incidence peaked in 1990-2000, was markedly higher than that reported for European uninfected or other HIV-infected populations (4-6/1000 PYFU) and linked with age and adiposity. Adiposity and glycemic markers should be monitored in aging HIV-infected patients.

• Factors associated with virological failure in HIV-1-infected patients receiving darunavir/ritonavir monotherapy.

  Authors: Sidonie Lambert-Niclot, Philippe Flandre, Marc-Antoine Valantin, Gilles Peytavin, Claudine Duvivier, Stephanie Haim-Boukobza, Michele Algarte-Genin, Yazdan Yazdanpanah, Pierre-Marie Girard, Christine Katlama, Vincent Calvez, Anne-Genevieve Marcelin

  The Journal of infectious diseases. 10/2011; 204(8):1211-6.

  Our objective was to determine virological and clinical characteristics associated with virological failure in human immunodeficiency virus (HIV)-infected patients switching to darunavir/ritonavirOur objective was to determine virological and clinical characteristics associated with virological failure in human immunodeficiency virus (HIV)-infected patients switching to darunavir/ritonavir (DRV/r) monotherapy. The main outcome was virologic rebound, defined as 2 consecutive measurements of HIV-1 plasma RNA viral load (VL) >50 copies/mL. A logistic model was used to investigate which variables were predictive of a virologic rebound at weeks 48 (W48) and 96 (W96). Receiving DRV/r monotherapy was associated with virologic rebound at W48 (P = .016) and W96 (P = .002), comparable to triple therapy. In the DRV/r monotherapy group, at W48, having a VL >50 copies/mL at day 0 and even a baseline ultrasensitive VL >1 copy/mL were predictive factors to virologic rebound (P = .042 and P = .025, respectively). At W96, shorter time of prior antiretrovial therapy (ART) exposure (odds ratio [OR] = 2.93 per 5 years decrease; P = .006), higher HIV-1 DNA at day 0 (OR = 2.66 per 1 log(10) copies/10(6) cells increase; P = .04) and adherence <100% (OR = 3.84 vs 100%; P = .02) were associated with an increased risk of rebound. Factors associated with virological failure in patients receiving DRV/r monotherapy were having an initial blip, shorter time of antiretroviral treatment before monotherapy, and an adherence <100% during monotherapy. The importance of prior duration exposure to ART was in agreement with the impact of HIV-1 blood reservoir and VL level at baseline.

• Raltegravir once daily or twice daily in previously untreated patients with HIV-1: a randomised, active-controlled, phase 3 non-inferiority trial.

  Authors: Joseph J Eron, Jürgen K Rockstroh, Jacques Reynes, Jaime Andrade-Villanueva, Jose Valdez Ramalho-Madruga, Linda-Gail Bekker, Benjamin Young, Christine Katlama, Jose Maria Gatell-Artigas, Jose R Arribas [......] Matthew L Rizk, Larissa Wenning, Michael D Miller, Daria Hazuda, Mark J DiNubile, Randi Leavitt, Robin Isaacs, Michael N Robertson, Peter Sklar, Bach-Yen Nguyen

  The Lancet infectious diseases. 09/2011; 11(12):907-15.

  Twice-daily raltegravir with once-daily tenofovir-emtricitabine is an effective initial antiretroviral regimen for patients with HIV-1. On the basis of pharmacokinetic data suggesting efficacy ofTwice-daily raltegravir with once-daily tenofovir-emtricitabine is an effective initial antiretroviral regimen for patients with HIV-1. On the basis of pharmacokinetic data suggesting efficacy of once-daily raltegravir and because adherence is often improved with once-daily dosing, we aimed to compare these dosing schedules. In our international, double-blind, randomised, phase 3 non-inferiority study, we enrolled antiretroviral-naive patients with HIV RNA loads of more than 5000 copies per mL and no baseline resistance to tenofovir or emtricitabine at 83 centres worldwide. We randomly allocated patients (1:1) by use of a computer-generated sequence to receive raltegravir once daily (two 400 mg tablets taken together every 24 h), or twice daily (one 400 mg tablet every 12 h), both in combination with once-daily co-formulated tenofovir 300 mg plus emtricitabine 150 mg. The primary outcome was virological response at 48 weeks (viral RNA loads <50 copies per mL) in patients who received at least one dose of study drug, counting non-completers as failure. We assessed non-inferiority in terms of the proportion of patients in both treatment groups who achieved the primary outcome, with a non-inferiority margin of -10%. This study is registered with ClinicalTrials.gov, number NCT00745823. From Oct 15, 2008, to Nov 2, 2009, we randomly allocated 775 patients, of whom 382 (99%) of 386 patients in the once-daily group and 388 (99%) of 389 in the twice-daily group received at least one dose of study drug. At baseline, 304 (39%) of 770 treated patients had viral loads of more than 100,000 copies per mL and 188 (24%) had CD4 cell counts of fewer than 200 cells per μL. 318 (83%) of 382 patients in the once-daily group had virological response compared with 343 (89%) of 386 in the twice-daily group (difference -5·7%, 95% CI -10·7 to -0·83; p=0·044). Serious adverse events were reported in 26 (7%) of 382 once-daily recipients and 40 (10%) of 388 twice-daily recipients, and adverse events leading to discontinuation occurred in four (1%) patients in each group. Despite high response rates with both regimens, once-daily raltegravir cannot be recommended in place of twice-daily dosing. Merck.

• Influence of interferon-based therapy on liver fibrosis progression in HIV/HCV coinfected patients: a retrospective repeated liver biopsy analysis.

  Authors: Patrick Ingiliz, Marc-Antoine Valantin, Paul Preziosi, Laetitia Finzi, Raluka Pais, Larysa Fedchuk, Stéphanie Dominguez, Christine Katlama, Thierry Poynard, Yves Benhamou

  Journal of hepatology. 07/2011; 56(1):49-54.

  Hepatitis C virus (HCV) coinfection is one of the leading causes of mortality in human immunodeficiency virus-infected patients. The current standard of care leads to cure only in a part of theseHepatitis C virus (HCV) coinfection is one of the leading causes of mortality in human immunodeficiency virus-infected patients. The current standard of care leads to cure only in a part of these patients. The course of the disease is determined by the rapidity of liver fibrosis progression (LFP). The influence of interferon on LFP in coinfected patients has yet not been evaluated by comparative liver biopsies. We extracted data of patients who had serial liver biopsies from a hospital database. Histopathological findings were compared to factors possibly linked to fibrosis progression. Furthermore, we studied the impact of response to interferon treatment on fibrosis progression. Hundred and twenty-six patients were included, 68 had received anti-HCV treatment, and 58 had not. The median time between the first and the last biopsy was 4 years. Worsened fibrosis was observed in 35 of 58 (60%) untreated patients, and 22 of 50 (44%) patients in the nonresponder/relapser group, and in 5 out of 18 (28%) in the SVR group. Liver fibrosis evolution was significantly better in patients achieving a SVR than in untreated and NR/R patients (p<0.02, odds-ratio [95% CI] for improvement vs. stability vs. worsening=3.16 [1.24-8.07]). This result persisted after adjustment for known predictors of liver fibrosis progression, HBsAg, CD4, and alcohol consumption: adjusted odds ratio=2.89 [1.09-7.68], p=0.03. HCV treatment can stop fibrosis progression and induce its regression. Nonresponders to treatment may even have a fast fibrosis progression. It remains to be clarified if the same factors that induce nonresponse to treatment may also induce faster fibrosis progression.

• Prevalence of resistance mutations related to integrase inhibitor S/GSK1349572 in HIV-1 subtype B raltegravir-naive and -treated patients.

  Authors: Isabelle Malet, Marc Wirden, Slim Fourati, Daniele Armenia, Bernard Masquelier, Lavinia Fabeni, Sophie Sayon, Christine Katlama, Carlo Federico Perno, Vincent Calvez, Anne-Geneviève Marcelin, Francesca Ceccherini-Silberstein

  The Journal of antimicrobial chemotherapy. 07/2011; 66(7):1481-3.

  To compare the frequency of previously in vitro-selected integrase mutations (T124A, T124A/S153F, S153Y, T124A/S153Y and L101I/T124A/S153Y) conferring resistance to S/GSK1349572 between HIV-1 subtypeTo compare the frequency of previously in vitro-selected integrase mutations (T124A, T124A/S153F, S153Y, T124A/S153Y and L101I/T124A/S153Y) conferring resistance to S/GSK1349572 between HIV-1 subtype B integrase inhibitor (INI)-naive and raltegravir-treated patients. Integrase sequences from 650 INI-naive patients and 84 raltegravir-treated patients were analysed. The T124A mutation alone and the combination T124A/L101I were more frequent in raltegravir-failing patients than in INI-naive patients (39.3% versus 24.5%, respectively, P = 0.005 for T124A and 20.2% versus 10.0%, respectively, P = 0.008 for T124A/L101I). The S153Y/F mutations were not detected in any integrase sequence (except for S153F alone, only detected in one INI-naive patient). T124A and T124A/L101I, more frequent in raltegravir-treated patients, could have some effect on raltegravir response and their presence could play a role in the selection of other mutations conferring S/GSK1349572 resistance. The impact of raltegravir-mediated changes such as these on the virological response to S/GSK1349572 should be studied further.

• Risk factors of chronic kidney disease in HIV-infected patients.

  Authors: Philippe Flandre, Pascal Pugliese, Lise Cuzin, Corinne Isnard Bagnis, Ivan Tack, André Cabié, Isabelle Poizot-Martin, Christine Katlama, Cécile Brunet-François, Yazdan Yazdanpanah, Pierre Dellamonica

  Clinical journal of the American Society of Nephrology : CJASN. 05/2011; 6(7):1700-7.

  The main aim of this study was determining the risk factors of chronic kidney disease (CKD) in HIV-1-infected patients. Patients were followed from seven large HIV reference centers in France thatThe main aim of this study was determining the risk factors of chronic kidney disease (CKD) in HIV-1-infected patients. 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 Cox's model with delayed entry was used to search predictive factors of time to CKD. 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). 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.

• Impact of adding enfuvirtide to the predictive value of the darunavir genotypic resistance score.

  Authors: Charlotte Charpentier, Sidonie Lambert-Niclot, Lucile Larrouy, Gilles Peytavin, Marc-Antoine Valantin, Roland Landman, Christine Katlama, Patrick Yeni, Mathieu Felices, Françoise Brun-Vézinet, Vincent Calvez, Anne-Geneviève Marcelin, Diane Descamps

  Journal of acquired immune deficiency syndromes (1999). 05/2011; 57(1):e15-7.

• CTL escape mediated by proteasomal destruction of an HIV-1 cryptic epitope.

  Authors: Sylvain Cardinaud, Gesa Consiglieri, Romain Bouziat, Alejandra Urrutia, Stéphanie Graff-Dubois, Slim Fourati, Isabelle Malet, Julien Guergnon, Amélie Guihot, Christine Katlama, Brigitte Autran, Peter van Endert, François A Lemonnier, Victor Appay, Olivier Schwartz, Peter M Kloetzel, Arnaud Moris

  PLoS pathogens. 05/2011; 7(5):e1002049.

  Cytotoxic CD8+ T cells (CTLs) play a critical role in controlling viral infections. HIV-infected individuals develop CTL responses against epitopes derived from viral proteins, but also againstCytotoxic CD8+ T cells (CTLs) play a critical role in controlling viral infections. HIV-infected individuals develop CTL responses against epitopes derived from viral proteins, but also against cryptic epitopes encoded by viral alternative reading frames (ARF). We studied here the mechanisms of HIV-1 escape from CTLs targeting one such cryptic epitope, Q9VF, encoded by an HIVgag ARF and presented by HLA-B*07. Using PBMCs of HIV-infected patients, we first cloned and sequenced proviral DNA encoding for Q9VF. We identified several polymorphisms with a minority of proviruses encoding at position 5 an aspartic acid (Q9VF/5D) and a majority encoding an asparagine (Q9VF/5N). We compared the prevalence of each variant in PBMCs of HLA-B*07+ and HLA-B*07- patients. Proviruses encoding Q9VF/5D were significantly less represented in HLA-B*07+ than in HLA-B*07- patients, suggesting that Q9FV/5D encoding viruses might be under selective pressure in HLA-B*07+ individuals. We thus analyzed ex vivo CTL responses directed against Q9VF/5D and Q9VF/5N. Around 16% of HLA-B*07+ patients exhibited CTL responses targeting Q9VF epitopes. The frequency and the magnitude of CTL responses induced with Q9VF/5D or Q9VF/5N peptides were almost equal indicating a possible cross-reactivity of the same CTLs on the two peptides. We then dissected the cellular mechanisms involved in the presentation of Q9VF variants. As expected, cells infected with HIV strains encoding for Q9VF/5D were recognized by Q9VF/5D-specific CTLs. In contrast, Q9VF/5N-encoding strains were neither recognized by Q9VF/5N- nor by Q9VF/5D-specific CTLs. Using in vitro proteasomal digestions and MS/MS analysis, we demonstrate that the 5N variation introduces a strong proteasomal cleavage site within the epitope, leading to a dramatic reduction of Q9VF epitope production. Our results strongly suggest that HIV-1 escapes CTL surveillance by introducing mutations leading to HIV ARF-epitope destruction by proteasomes.

• Old age and anti-cytomegalovirus immunity are associated with altered T-cell reconstitution in HIV-1-infected patients.

  Authors: Victor Appay, Solène Fastenackels, Christine Katlama, Hocine Ait-Mohand, Luminita Schneider, Amélie Guihot, Michael Keller, Beatrix Grubeck-Loebenstein, Anne Simon, Olivier Lambotte, Peter W Hunt, Steven G Deeks, Dominique Costagliola, Brigitte Autran, Delphine Sauce

  AIDS (London, England). 03/2011; 25(15):1813-22.

  Increasing evidence supports a parallel between HIV-1 infection and immune aging, which is particularly apparent with common changes in naive versus memory T-cell proportions. Here, we aimed atIncreasing evidence supports a parallel between HIV-1 infection and immune aging, which is particularly apparent with common changes in naive versus memory T-cell proportions. Here, we aimed at refining the value of common T-cell-associated markers of immunosenescence during HIV disease progression or aging, and at exploring further the impact in this context of old age as well as cytomegalovirus (CMV) co-infection, which is predominant in HIV-1-infected individuals. Frequencies of naive or CD57(+) memory T cells as well as the magnitude of CMV-pp65 T cells were measured in HIV-1-infected patients grouped according to disease progression status, treatment and age. Our results indicate that the decline in naive T-cell levels rather than the accumulation of CD57(+) senescent T cells identifies best the premature development of an immunosenescence phenotype with HIV disease progression. Moreover, advanced age or mounting of strong CMV-specific responses impact independently on CD4(+) T-cell counts and recovery with antiretroviral therapy. The present findings indicate that HIV-1 infection amplifies the effect of age on naive T-cell levels, and highlight the constraint on the capacity of treated patients to reconstitute their CD4(+) T-cell compartment due to age and CMV co-infection.

• HIV disease progression despite suppression of viral replication is associated with exhaustion of lymphopoiesis.

  Authors: Delphine Sauce, Martin Larsen, Solène Fastenackels, Michèle Pauchard, Hocine Ait-Mohand, Luminita Schneider, Amélie Guihot, Faroudy Boufassa, John Zaunders, Malika Iguertsira [......] Anthony D Kelleher, Anne Simon, Laurence Meyer, Dominique Costagliola, Steven G Deeks, Olivier Lambotte, Brigitte Autran, Peter W Hunt, Christine Katlama, Victor Appay

  Blood. 03/2011; 117(19):5142-51.

  The mechanisms of CD4(+) T-cell count decline, the hallmark of HIV disease progression, and its relationship to elevated levels of immune activation are not fully understood. Massive depletion ofThe mechanisms of CD4(+) T-cell count decline, the hallmark of HIV disease progression, and its relationship to elevated levels of immune activation are not fully understood. Massive depletion of CD4(+) T cells occurs during the course of HIV-1 infection, so that maintenance of adequate CD4(+) T-cell levels probably depends primarily on the capacity to renew depleted lymphocytes, that is, the lymphopoiesis. We performed here a comprehensive study of quantitative and qualitative attributes of CD34(+) hematopoietic progenitor cells directly from the blood of a large set of HIV-infected persons compared with uninfected donors, in particular the elderly. Our analyses underline a marked impairment of primary immune resources with the failure to maintain adequate lymphocyte counts. Systemic immune activation emerges as a major correlate of altered lymphopoiesis, which can be partially reversed with prolonged antiretroviral therapy. Importantly, HIV disease progression despite elite control of HIV replication or virologic success on antiretroviral treatment is associated with persistent damage to the lymphopoietic system or exhaustion of lymphopoiesis. These findings highlight the importance of primary hematopoietic resources in HIV pathogenesis and the response to antiretroviral treatments.