Biomedical subjects

Jacques Reynes

Publications and source records attributed to Jacques Reynes.

44 records · Page 3Linked to original sources

PubMed2003

Reasons for early abacavir discontinuation in HIV-infected patients.

OBJECTIVE: To determine incidence of and reasons for discontinuation of abacavir within the first 6 months of therapy. METHODS: Retrospective study performed in the cohort of HIV-infected adults who started abacavir in a medical unit between 1997 and December 2000. All adverse drug reactions (ADRs) (especially hypersensitivity) observed in this cohort were reported. The association between drugs and complications were evaluated, using the French method to assess unexpected and toxic drug reactions. According to the variables studied, statistical analysis was performed using the chi2 test, Fisher's exact test, Mann-Whitney, Wilcoxon, or Kruskal-Wallis tests. RESULTS: All 331 patients treated with abacavir during this time period were included in this study. Early discontinuation of abacavir was observed in 34.1% of patients, the main reasons being adverse effects (20.8%), virologic failure (3.3%), drug holidays (2.7%), poor adherence (2.7%), and death (1.8%). Adverse effects were mostly represented by hypersensitivity reactions. After retrospective analysis, abacavir was stopped for likely hypersensitivity in 8.5% of patients, for doubtful hypersensitivity in 4.2%, and for other adverse effects in 8.1% of patients. CONCLUSIONS: This study shows that abacavir is mainly stopped during the first 6 months of therapy for ADRs. The rate of likely hypersensitivity reaction observed in this study (8.5%) is higher than that observed in clinical trials (5%). After retrospective evaluation, the causality assessment of abacavir is not always certain.

Adult↗

PubMed2002

Cell surface CCR5 density determines the postentry efficiency of R5 HIV-1 infection.

We have recently reported that the mean number of CCR5 coreceptors at the surface of CD4(+) T cells (CCR5 density) correlates with viral load and disease progression in HIV-1-infected persons. Here, we definitively establish that CCR5 density determines the level of virus production and identify the stages of HIV-1 replicative cycle modulated by this effect. We show, by transducing the CCR5 gene into CCR5(+) cells, that CCR5 overexpression resulted in an HIV-1 overinfectability. We sorted HOS-CD4(+)-CCR5(+) cells into two subpopulations, HOS(high) and HOS(low), the former expressing seven times more cell surface CCR5 molecules than the latter. Virus production was 30-80 times higher in HOS(high) cells than in HOS(low) cells after a single round of infection. In contrast, only twice as many viral particles entered the cytosol of HOS(high) cells as compared with the cytosol of HOS(low) cells. Yet, seven times as many early, and 24 times as many late, reverse transcription products were found in HOS(high) cells as compared with HOS(low) cells. Moreover, a 24- to 30-fold difference in the number of copies of integrated HIV-1 DNA was observed. No difference in HIV-1 LTR activation between the two cell lines was evident. Finally, we show that the higher virus production observed in HOS(high) cells is inhibited by pertussis toxin, a Galphai protein inhibitor. Thus, CCR5 density mainly modulates postentry steps of the virus life cycle, particularly the reverse transcription. These data explain why CCR5 density influences HIV-1 disease progression and underline the therapeutic interest of lowering CCR5 expression.

Cell Line, Transformed↗

PubMed2002

Dynamics of spontaneous HIV-1 specific and non-specific B-cell responses in patients receiving antiretroviral therapy.

OBJECTIVES: As spontaneous anti-HIV-1 antibody and IgG secretion by peripheral blood mononuclear cells (PBMC) reflect immune system activation by HIV-1 antigens, we evaluated the impact of antiretroviral therapies on HIV-1 specific and non-specific B cell responses. METHODS: Anti-HIV-1 antibody and non-specific IgG were measured by ELISA in supernatants of PBMC cultured during 7 day from 30 patients initiating an antiretroviral therapy at baseline, 8, 16, 24, 36 and 48 weeks. RESULTS: An early and sustained fall in plasma viral load to below the detection limit (20 copies/ml) was observed in 17 sustained responder patients (SR), whereas HIV-1 RNA remained detectable in 13 others incomplete responders. In both groups, HIV-1 specific antibody secretion decreased significantly in parallel with plasma viral load and polyclonal immunoglobulin production became similar to that of PBMC controls. However, HIV-1 specific antibody production became negative in only six SR, exhibiting a greater increase of CD4 T-cell counts and higher levels of the spontaneous HIV-1 specific IgA secretion at baseline than the other SR. CONCLUSIONS: Antiretroviral therapy induced a rapid and dramatic decrease of spontaneous HIV-1 specific and non-specific B cell responses. These results pointed out that HIV-1 specific antibody secretion persisted in 11 out of 17 SR patients, suggesting persistent immune system activation by residual HIV-1 antigens.

Adult↗

PubMed2002

Spontaneous secretion of immunoglobulins and anti-HIV-1 antibodies by in vivo activated B lymphocytes from HIV-1-infected subjects: monocyte and natural killer cell requirement for in vitro terminal differentiation into plasma cells.

Peripheral blood mononuclear cells from HIV-1-infected subjects secrete spontaneously in vitro immunoglobulins (Ig) and anti-HIV-1 antibodies (Ab). Purified B lymphocytes secrete only minute amounts of Ig and anti-HIV-1 Ab compared with unfractionated cells. Monocytes and natural killer cells enhanced both secretions by cell-to-cell contacts, involving adhesion and CD27, CD80 costimulatory molecules and IL-6. Cell interactions prolonged the survival and allowed the terminal maturation of in vivo activated B cells. The secreting cell precursors were highly differentiated B cells expressing a broad diversity of maturation markers (CD27(+), CD38(+), CD20(+/-), CD37(+/-), CD71(+/-), HLA-DQ(+/-), sIg(+/-)) but not sIgD, CD28, or CD40. This phenotype and the cytologic aspect of purified B cells suggest that these cells are early plasma cells originated from germinal center. Ex vivo secreting peripheral B cells had probably gone beyond the CD40/CD40 ligand interaction; then following CD28/CD80 and CD27/CD27 ligand (CD70) interactions in the presence of IL-6, they achieved in vitro their differentiation into plasma cells.

Acquired Immunodeficiency Syndrome↗

PubMed2002

Pharmacokinetics of plasma enfuvirtide after subcutaneous administration to patients with human immunodeficiency virus: Inverse Gaussian density absorption and 2-compartment disposition.

OBJECTIVE: Enfuvirtide (T-20) is the first of a novel class of human immunodeficiency virus (HIV) drugs that block gp41-mediated viral fusion to host cells. The objectives of this study were to develop a structural pharmacokinetic model that would adequately characterize the absorption and disposition of enfuvirtide pharmacokinetics after both intravenous and subcutaneous administration and to evaluate the dose proportionality of enfuvirtide pharmacokinetic parameters at a subcutaneous dose higher than that currently used in phase III studies. METHODS: Twelve patients with HIV infection received 4 single doses of enfuvirtide separated by a 1-week washout period in an open-label, randomized, 4-way crossover fashion. The doses studied were 90 mg (intravenous) and 45 mg, 90 mg, and 180 mg (subcutaneous). Serial blood samples were collected up to 48 hours after each dose. Plasma enfuvirtide concentrations were measured with use of a validated liquid chromatography-tandem mass spectrometry method. RESULTS: Enfuvirtide plasma concentration-time data after subcutaneous administration were well described by an inverse Gaussian density function-input model linked to a 2-compartment open distribution model with first-order elimination from the central compartment. The model-derived mean pharmacokinetic parameters (+/-SD) were volume of distribution of the central compartment (3.8 +/- 0.8 L), volume of distribution of the peripheral compartment (1.7 +/- 0.6 L), total clearance (1.44 +/- 0.30 L/h), intercompartmental distribution (2.3 +/- 1.1 L/h), bioavailability (89% +/- 11%), and mean absorption time (7.26 hours, 8.65 hours, and 9.79 hours for the 45-mg, 90-mg, and 180-mg dose groups, respectively). The terminal half-life increased from 3.46 to 4.35 hours for the subcutaneous dose range from 45 to 180 mg. CONCLUSIONS: An inverse Gaussian density function-input model linked to a 2-compartment open distribution model with first-order elimination from the central compartment was appropriate to describe complex absorption and disposition kinetics of enfuvirtide plasma concentration-time data after subcutaneous administration to patients with HIV infection. Enfuvirtide was nearly completely absorbed from subcutaneous depot, and pharmacokinetic parameters were linear up to a dose of 180 mg in this study.

Absorption↗

PubMedDate not supplied

Concomitant use of an active boosted protease inhibitor with enfuvirtide in treatment-experienced, HIV-infected individuals: recent data and consensus recommendations.

Recent data from clinical trials investigating the efficacy of enfuvirtide, a fusion inhibitor, in treatment-experienced patients have revealed that the addition of enfuvirtide (ENF) to an active boosted protease inhibitor regimen doubles the rate of virological response. At week 48 of the TORO studies, 55% of patients previously naive to and receiving lopinavir/ritonavir (LPV/r) with ENF achieved a viral load of <400 copies/mL compared with 24% of patients treated with LPV/r alone. At week 24 of the RESIST studies, 70% of previously ENF-naive patients who took both ENF and tipranavir/ritonavir (TPV/r) achieved a >or=1 log10 reduction in viral load compared with 37% of such patients treated with TPV/r alone. Similarly, concomitant use of TMC114/ritonavir (TMC114/r) with ENF, compared with TMC114/r alone, increased the number of patients with <50 copies/mL from 46% to 64% in a combined 24-week analysis from the POWER trials. Data from these trials suggest that combining one agent from a new class with a new agent from a previously exposed class offers a greater chance of achieving full virological control than either type of agent alone. Undetectable viraemia should be the primary objective for treatment-experienced patients requiring a switch in therapy, and the present data support the combination of an active boosted protease inhibitor with an agent from a new class (e.g., ENF) for triple-class-experienced patients.

Antiretroviral Therapy, Highly Active↗

PubMedDate not supplied

[Assessment of renal abnormalities in 107 HIV patients treated with tenofovir].

OBJECTIVES: The objectives of our study were to assess frequency, severity and outcome of renal abnormalities, as well as to determine the risk of developing hypophosphataemia in HIV-infected patients receiving tenofovir. METHODS: An observational study was conducted in real-life conditions, during a 6-month period, in 107 HIV patients receiving tenofovir. RESULTS: Mild-to-moderate hypophosphataemia (<0.77 mmol/L) occurred during follow-up, at least once in 43% of patients and at least twice in 27%. Antiretroviral therapy including ritonavir + lopinavir was significantly associated with the occurrence of hypophosphataemia (relative risk = 2.6; p = 0.03). Frequency of abnormal proteinuria was 22%. CONCLUSION: Creatinine clearance, phosphataemia, proteinuria and glycosuria should be closely monitored in patients receiving tenofovir therapy.

Adenine↗

PubMedDate not supplied

Necrotizing cutaneous lesions complicating treatment with pegylated-interferon alfa in an HIV-infected patient.

Pegylated interferon alfa is a pegylated formulation of recombinant human interferon (IFN) conjugated with polyethylene-glycol (PEG). The major advantages of this formulation, compared to standard IFN, is a prolonged half-life which allows for once-weekly injection. Its antiviral efficacy in association with ribavirin as a new standard treatment of chronic hepatitis C has been recently documented. Efficacy of PEG-IFN in the therapy of HIV infection is currently being evaluated in prospective pilot studies. We describe herein the first observation of cutaneous necrosis at the sites of PEG-IFN injection in an HIV-infected patient. A 50-year-old man, HIV infected, was treated with antiretroviral bitherapy combining zidovudine and didanosine for 30 months. Weekly subcutaneous injections of PEG-IFN-alpha-2b were started at a dose of 1.5 microg/kg. Nine months later, two successive necrotizing cutaneous lesions developed at the site of injection. The cutaneous ulcerations slowly healed under local therapy without interruption or dose modification of the PEG-IFN. We review the literature on previously reported cases of cutaneous necrosis following standard or pegylated IFN-alpha injection and discuss the different pathophysiological mechanisms that might be involved.

Antiviral Agents↗