Influence of HLA-C environment on the spontaneous clearance of hepatitis C in European HIV-HCV co-infected individuals.

Natural killer (NK) cell functions are regulated by diverse inhibitory and activating receptors, including killer cell immunoglobulin-like receptors (KIR), which interact with human leukocyte antigen (HLA) class I molecules. Some KIR/HLA genetic combinations were reported associated with spontaneous clearance (SC) of hepatitis C virus (HCV) but with discordant results, possibly reflecting KIR and/or HLA gene polymorphism according to populations. KIR/HLA genetic combinations associated with both an exhaustive NK and T cell repertoire were investigated in a cohort of HIV-HCV co-infected individuals with either SC (n = 68) or chronic infection (CI, n = 163) compared to uninfected blood donors [controls (Ctrl), n = 100]. Multivariate analysis showed that the HLA C2C2 environment was associated with SC only in European HIV-HCV co-infected individuals [odds ratio (OR) = 4·30, 95% confidence interval = 1·57-12·25, P = 0·005]. KIR2D+ NK cell repertoire and potential of degranulation of KIR2DL1/S1+ NK cells were similar in the SC European cohort compared to uninfected individuals. In contrast, decreased frequencies of KIR2DS1+ and KIR2DL2+ NK cells were detected in the CI group of Europeans compared to SC and a decreased frequency of KIR2DL1/S1+ NK cells compared to controls. Regarding T cells, higher frequencies of DNAX accessory molecule-1 (DNAM-1)+ and CD57+ T cells were observed in SC in comparison to controls. Interestingly, SC subjects emphasized increased frequencies of KIR2DL2/L3/S2+ T cells compared to CI subjects. Our study underlines that the C2 environment may activate efficient KIR2DL1+ NK cells in a viral context and maintain a KIR2DL2/L3/S2+ mature T cell response in the absence of KIR2DL2 engagement with its cognate ligands in SC group of HCV-HIV co-infected European patients.

Prototyping Trastuzumab Docetaxel Immunoliposomes with a New FCM-Based Method to Quantify Optimal Antibody Density on Nanoparticles.

Developing targeted nanoparticles is a rising strategy to improve drug delivery in oncology. Antibodies are the most commonly used targeting agents. However, determination of their optimal number at the surface remains a challenging issue, mainly due to the difficulties in measuring precisely surface coating levels when prototyping nanoparticles. We developed an original quantitative assay to measure the exact number of coated antibodies per nanoparticle. Using flow cytometry optimized for submicron particle analysis and beads covered with known amounts of human IgG-kappa mimicking various amounts of antibodies, this new method was tested as part of the prototyping of docetaxel liposomes coated with trastuzumab against Her2+ breast cancer. This quantification method allowed to discriminate various batches of immunoliposomes depending on their trastuzumab density on nanoparticle surface (i.e., 330 (Immunoliposome-1), 480 (Immunoliposome-2) and 690 (Immunoliposome-3), p = 0.004, One-way ANOVA). Here we showed that optimal number of grafted antibodies on nanoparticles should be finely tuned and highest density of targeting agent is not necessarily associated with highest efficacy. Overall, this new method should help to better prototype third generation nanoparticles.

Switching from abacavir/lamivudine plus nevirapine to abacavir/lamivudine/dolutegravir in virologically controlled HIV-infected adults (SWAD study).

INTRODUCTION: The metabolic pathways of dolutegravir suggest a potential predator effect of nevirapine on dolutegravir pharmacokinetics and switching from a nevirapine- to a dolutegravir-containing regimen could lead to a lower and suboptimal exposure to dolutegravir several weeks after the switch in case of persistent inducer effect. PATIENTS AND METHOD: Prospective, pilot, single-arm, open-label, non-comparative, bicentric study to evaluate the pharmacokinetics, virologic outcomes, safety, and patient satisfaction of switching from abacavir/lamivudine and nevirapine to a single tablet of abacavir/lamivudine/dolutegravir. The primary endpoint was the maintenance of virologic suppression (HIV-1 RNA<50 copies/mL) at week 12. Secondary endpoints were virologic suppression at week 48, safety and tolerability, patient satisfaction, and pharmacokinetic interaction between nevirapine and dolutegravir. Fifty-three adults on stable abacavir/lamivudine and nevirapine regimen for a median duration of 6years and virologically suppressed for 9.6years were included. RESULTS: Dolutegravir reached steady state by week 4/week 12 when expected by day 5/day 10. All subjects maintained plasma HIV-RNA˂50 copies/mL at week 12 and week 48. Abacavir/lamivudine/dolutegravir was well-tolerated, with two cases of serious adverse events deemed unrelated to study drugs (coronary syndrome in both cases), and one discontinuation for renal impairment at week 24 with a slight improvement after dolutegravir discontinuation. Level of treatment satisfaction remained high after the switch. CONCLUSION: The transient predator effect of nevirapine on dolutegravir had no clinical consequences after switching from nevirapine to dolutegravir, neither on safety nor maintenance of virologic suppression. It also had no consequences on patient satisfaction.

Emerging resistance mutations in PI-naive patients failing an atazanavir-based regimen (ANRS multicentre observational study).

Background: Atazanavir is a PI widely used as a third agent in combination ART. We aimed to determine the prevalence and the patterns of resistance in PI-naive patients failing on an atazanavir-based regimen. Methods: We analysed patients failing on an atazanavir-containing regimen used as a first line of PI therapy. We compared the sequences of reverse transcriptase and protease before the introduction of atazanavir and at failure [two consecutive viral loads (VLs) >50 copies/mL]. Resistance was defined according to the 2014 Agence Nationale de Recherche sur le SIDA et les Hépatites Virales (ANRS) algorithm. Results: Among the 113 patients, atazanavir was used in the first regimen in 71 (62.8%) patients and in the first line of a PI-based regimen in 42 (37.2%). Atazanavir was boosted with ritonavir in 95 (84.1%) patients and combined with tenofovir/emtricitabine or lamivudine (n = 81) and abacavir/lamivudine or emtricitabine (n = 22). At failure, median VL was 3.05 log10 copies/mL and the median CD4+ T cell count was 436 cells/mm3. The median time on atazanavir was 21.2 months. At failure, viruses were considered resistant to atazanavir in four patients (3.5%) with the selection of the following major atazanavir-associated mutations: I50L (n = 1), I84V (n = 2) and N88S (n = 1). Other emergent PI mutations were L10V, G16E, K20I/R, L33F, M36I/L, M46I/L, G48V, F53L, I54L, D60E, I62V, A71T/V, V82I/T, L90M and I93L/M. Emergent NRTI substitutions were detected in 21 patients: M41L (n = 2), D67N (n = 3), K70R (n = 1), L74I/V (n = 3), M184V/I (n = 16), L210W (n = 1), T215Y/F (n = 3) and K219Q/E (n = 2). Conclusions: Resistance to atazanavir is rare in patients failing the first line of an atazanavir-based regimen according to the ANRS. Emergent NRTI resistance-associated mutations were reported in 18% of patients.

Interest of proviral HIV-1 DNA genotypic resistance testing in virologically suppressed patients candidate for maintenance therapy.

Switch of antiretroviral therapy in virologically suppressed HIV-infected patients is frequent, to prevent toxicities, for simplification or convenience reasons. Pretherapeutic genotypic resistance testing on RNA can be lacking in some patients, which could enhance the risk of virologic failure, if resistance-associated mutations of the new regimen are not taken into account. Proviral DNA resistance testing in 69 virologically suppressed patients on antiretroviral treatment with no history of virological failure were pair-wised compared with pre-ART plasma RNA resistance testing. The median time between plasma (RNA testing) and whole blood (proviral DNA testing) was 47 months (IQR 29-63). A stop codon was evidenced in 23% (16/69) of proviral DNA sequences; these strains were considered as defective, non-replicative, and not taken into consideration. Within the non defective strains, concordance rate between plasma RNA and non-defective proviral DNA was high both on protease (194/220 concordant resistance-associated mutations=88%) and reverse transcriptase (28/37 concordant resistance-associated mutations=76%) genes. This study supports that proviral DNA testing might be an informative tool before switching antiretrovirals in virologically suppressed patients with no history of virological failure, but the interpretation should be restricted to non-defective viruses.

Usefulness of an HIV DNA resistance genotypic test in patients who are candidates for a switch to the rilpivirine/emtricitabine/tenofovir disoproxil fumarate combination.

OBJECTIVES: In the context of a rilpivirine/emtricitabine/tenofovir disoproxil fumarate switch in HIV-1-infected patients with at least 1 year of virological success, we determined whether proviral DNA is an alternative to plasma HIV RNA for resistance genotyping. METHODS: Resistance-associated mutations (RAMs) in DNA after at least 1 year of virological success [viral load (VL) <50 copies/mL] were compared with those identified in the last plasma RNA genotype available. Rilpivirine/emtricitabine/tenofovir disoproxil fumarate RAMs studied were K65R, L100I, K101E/P, E138A/G/K/R/Q, V179L, Y181C/I/V, M184V/I, Y188L, H221Y, F227C and M230I/L in the RT. We studied patients without virological failure (VF) and with at least 1 VF (two consecutive VLs >50 copies/mL). Kappa's coefficient was used to measure agreement between the DNA and RNA genotypes. RESULTS: In patients without VF (n = 130) and with VF (n = 114), RNA and DNA showed resistance to at least one drug of the rilpivirine/emtricitabine/tenofovir disoproxil fumarate combination in 8% and 9% and in 60% and 45%, respectively. For rilpivirine RAMs, correlation between RNA and DNA was higher in patients without VF than in patients with VF (kappa = 0.60 versus 0.19, P = 0.026). Overall, the prevalence of RAMs was lower in DNA than in RNA. CONCLUSIONS: Incomplete information provided by the DNA genotypic test is more notable in patients with VF, suggesting that all resistance mutations associated with prior VF have not been archived in the proviral DNA or decreased to a level below the threshold of detection. In the case where no historical plasma genotypic test is available, DNA testing might be useful to rule out switching to rilpivirine/emtricitabine/tenofovir disoproxil fumarate.

[Congenital anophthalmos. Control of osteogenesis with an expanding intraorbital prosthesis]. / Anophtalmie congénitale. Contrôle de l'ostéogenèse par prothèse expansive intraorbitaire.

Both congenital anophthalmia and severe microphthalmia lead to micro-orbit with early appearance of craniofacial hemiatrophy. There is simultaneous lack of development of the lids (which remain small but complete) and of the conjunctival sac. Use of esthetic ocular prosthesis is thus impossible. The conjunctival sac can be dilated with conformators of increasing size but this technique has no effect on the orbit. The results of repeated plastic surgery are unsatisfactory. Stimulation of ocular growth by an expandable prosthesis in early infancy would appear to be the most logical and effective therapy. The authors propose a "new" technique for the expansion of the orbital cavity of the congenital anophthalmia. They have deviced a silicone prosthesis which is progressively expanded in size. The device has now been in use for over eighteen months with really encouraging results (17 cases).

[The chondromucosal graft. Its use in the correction of entropion caused by tarsoconjunctival cicatrix, trichiasis and distichiasis]. / La greffe chondro-muqueuse. Son intéret dans la correction de l'entropion par cicatrice tarso-conjonctivale, du trichiasis et du distichiasis.

The use of chondromucosal grafts is the classical treatment for reconstruction of the eyelids, whereas these grafts are less employed for correction of tarso-conjunctival scars due to either disease or surgery. The ideal nasal graft is the triangular cartilage, as its mucosa is more delicate and more adhesive than that of the septum, and it separation and positioning do not involve any problems if certain rules are followed. The technique appears attractive to us, as it is simple to perform, there is a lack of postoperative complications and it is logical (replacing a pathological tissue or a missing tissue by an identical one, keeping the lids framework). It appears to be not enough employed in trachomatous entropion (both eyelids being generally affected). However, the technique is useful: during first intention surgery (whether associated or not with tarsectomy); in all cases of recurrence, where it appears to be the only worthwhile treatment (trachomatous eyelids already operated upon by another method, tarsectomy alone).

[Conjunctival sac of anophthalmic orbits]. / Le sac conjonctival de l'orbite anophtalme.

Reconstruction of the conjunctival sac is never a simple procedure. It is a question of positioning a prosthesis in the orbital cavity which will have no anatomic support, as the eye has been enucleated, reduced to a stump (microphthalmos) or has been replaced by an implant that has just been expelled. All described techniques consist in enlarging the existing conjunctival sac, and then positioning a mucosal or dermo-epidermical graft in the orbital cavity maintained by a conformer. In order to limit the effects of the inevitable retraction during the first weeks following surgery, operative enlargement beyond the needs of the conjunctival sac is essential. The conformer should be supported by tarsorraphy until the phenomenon of retraction has reached an end (4 to 6 months). The problem of the "orbital cavity" must be understood so that indications for surgical remodelling of the conjunctival sac can be established. This is simple after enucleation, but more complex in the case of a microphthalmos, an injury, or an exenteration of the orbit where remodelling represents only the last operative stage after bone remodelling, or lids remodelling and sometimes transposition of the temporalis muscle in the socket.

[Eyelid burns]. / La paupière du brûlé.

Reconstruction of eyelids following burns has two fold objective: functional and esthetic. Except in the must severe forms (carbonization) eyelids' burns usually involve only superficial lesions. Surgery, by means of a skin graft only, may be required after initial medical treatment. The choice of a graft among those considered standard, (full-thickness skin graft for the lower lid, thinner graft for the upper lid) should be guided by anatomophysiological considerations. Treatment in each case varies according to the anatomic type and the stage of evolution of the burn; whether the orbicularis muscle has been affected or not, should determine the choice of the graft. Certain points of this surgical technique have to be emphasized: the need for respecting esthetic unity; for careful dissection sparing the orbicularis; for fixation of the graft on the medial canthus, and lastly, the necessity of performing surgery of upper and lower lids in two stages so that the lid is "in surocclusion" during each operative procedure. Treatment of eyelids' burns as described above, is well established. It is very different from that for total facial burns, which requires total operative strategy.

Computed tomography of the optic nerve: part I. Normal results.

In vivo visualization of the optic nerve (ON) by computed tomography (CT) has important clinical applications, both realized and potential. An accurate CT analysis of the ON is, however, hampered by a number of technical limitations. Sinuosity and gaze-shift-related motility of the ON tend to increase the difficulties of demonstrating in a consistently satisfactory fashion this anatomical structure. Nevertheless, if rigid imaging criteria are followed, adequate visualization of the ON may be attained in the majority of patients. Simultaneous visualization of the ON and the eyeball permits establishment of a neuroocular index for clinical use.

Computed tomography of the optic nerve: part II. Size and shape modifications in papilledema.

Increase in the caliber and course tortuosity of the optic nerve (ON) can be demonstrated by computed tomography (CT) in cases of papilledema due to intracranial tumors, hydrocephalus, pseudotumor cerebri, and other conditions causing increased intracranial pressure. The enlargement of the ON in these conditions is generally bilateral, although one of the nerves, usually of the side of the tumoral pathology, may be thicker. Enlargement on the ON may also be demonstrated by CT in papilledema due to optic neuritis. Occasionally, the thickened ON also display increased attenuation coefficient values.

[Action potential changes induced by a polyflavane on normal or hypoxic guinea pig myocardial strips]. / Modifications du potentiel d'action provoquées par un polyflavane sur le lambeau myocardique normal ou hypoxié de cobaye

On normal isolated or stimulated Guinea-Pig myocardial strips, a polyflavane extracted from Poterium spinosum (Rosaceae) increased the duration of the action potential plateau phase. Such a modification was also elicited on hypoxic strips; in this case it did not depend on the glucose concentration in the medium; it could be related to an effect on the slow calcium-sodium channel.