Exenatide improves weight loss insulin sensitivity and ß-cell function following administration to a type 2 diabetic HIV patient on antiretroviral therapy.

The use of retroviral drugs in the treatment of infection by human immunodeficiency virus (HIV) is associated, especially for first generations, with side effects such as lipodystrophy, fatty liver and insulin resistance, which may trigger secondary diabetes or worsen existing diabetes. The use of Glucagon-Like Peptide-1 in obese patients with type 2 diabetes on HIV retroviral as an alternative to insulin therapy is not documented; we report the case of a 47-year-old treated with exenatide when insulin was discontinued. During the first year of treatment, exenatide, in combination with metformin and repaglinide, led to a weight loss of 14 kg and fat mass and waist circumference were respectively reduced from 31 to 25.5% and from 114 to 103 cm. Homeostatic model assessment (HOMA) was used to calculate ß-cell secretion which increased from 50 to 78% and insulin sensitivity which increased from 28 to 51%, reflecting a decrease in HbA(1c) by 1.9%. Exenatide may be a new therapeutic option for HIV-infected type 2 diabetes patients undergoing retroviral therapy.

ABCB1 allele polymorphism is associated with virological efficacy in naïve HIV-infected patients on HAART containing nonboosted PIs but not boosted PIs.

OBJECTIVE: To assess the effect of the multidrug resistance-1 single nucleotide polymorphism (ABCB1 SNP) C3435T in exon 26 on the virological responses to first-line protease inhibitor (PI)-containing HAART regimens. METHOD: A cohort of 182 HIV-infected patients with a PI-containing HAART regimen initiated from 1997 to 2004 was enrolled. Time to the first indetectable viral load (VL) was determined in patients with the CC, CT, or TT genotype. RESULTS: There were 37%, 44%, and 19% of patients who had the CC, CT and TT genotypes, respectively. The median estimated times to VL indetectability in the CC, CT, and TT groups were respectively 5.9, 3.9, and 4.8 months (p= .06). In patients on a non-boosted PI regimen, ABCB1 genotype was associated with time to VL indetectability that was shorter in patients with the CT than CC genotype (CT vs. CC, hazard ratio [HR]=0.62, p= .02; TT vs. CC, HR= 0.72, p= .21). This association was not found in patients with first-generation boosted PI-containing regimens and especially not with second-generation boosted PI-containing regimens. CONCLUSION: Our results show that the ABCB1 SNP in exon 26 is associated with virological efficacy in HIV-infected patients treated with non-boosted PI-containing regimens but not with those containing boosted PIs, particularly of the second generation.

[Demographic, clinical, immunovirological and therapeutic features of 8714 HIV infected French patients included in the Nadis Hospital Cohorte in 2006]. / Caractéristiques démographiques, cliniques, immunovirologiques et thérapeutiques de 8714 patients infectés par le VIH de la cohorte Nadis en 2006.

OBJECTIVES: The authors had for aim to describe demographic, immunovirilogical and therapeutic characteristics of HIV infected patients enrolled in a French clinical cohort. STUDY DESIGN: A cross-sectional analysis was performed on 30 September 2006, among patients followed in seven French University Medical Centers using the Nadis computerized medical file. RESULTS: Among 8714 patients enrolled (median age 43 years: 15-86, sex ratio 2.37), sexual transmission was the most frequent route of infection (heterosexual: 39.3%, homosexual: 34.8%). HIV and hepatitis C (HCV) or B (HBV) co-infection rates were at 19.2 and 5.8%, respectively. The number of patients who had a triple infection with HIV-HBV-HCV were 1.7%. CDC aids classification was A: 56.7%, B: 19.6%, C: 23.7%. We observed a higher proportion of female patients and an increase of the median age. The number of patients receiving antiretroviral therapy (ARV) at the study date were 81.7%, 11.7% were ARV-naive and 6,6% on a treatment interruption. Under ARV, the median CD4 count was 478cells per millimetre cube (1 to 2166) and 84.8% of patients had an undetectable viral load (VL). Among these patients, 10% had a CD4 cell count inferior or equal to 200 per millimetre cube. Patients followed in centers that participated in this study were different regarding sex, transmission routes, and HBV or HCV co-infection rates, but not regarding the proportion of patients with undetectable VL. ARV combination included more frequently protease inhibitors than nonnucleosidic reverse transcriptase (50% versus 26.2%). CONCLUSION: Among the 8714 HIV-infected patients on ARV, 85% had a VL inferior or equal to 400 per millilitre, 10% of whom had CD4 cell counts inferior or equal to 200 per millimetre cube. The proportion of patients on ARV with undetectable VL was comparable in centers who participated in this study.

[CCR5 antagonists: a new class of antiretrovirals]. / Les inhibiteurs de CCR5: une nouvelle classe d'antirétroviraux.

Inhibition of CCR5 co-receptor which is also a chemokine receptor, is a new way for inhibition of HIV-1 replication. Small antagonist molecules exert non competitive inhibition of the HIV co-receptor CCR5, which is essential for HIV entry. The CCR5 antagonists aplaviroc (GlaxoSmithKine), vicriviroc (Schering-Plough), and maraviroc (Pfizer) have reached phases III of clinical development. The development of aplaviroc was stopped because of its hepatotoxicity in some of the HIV-infected patients. In ACTG 5211 and MOTIVATE trials, treatment-experienced subjects who added respectively vicriviroc and maraviroc demonstrated substantially greater reductions in plasma HIV-1 RNA levels than those who received the placebo ; maraviroc currently having obtained European authorization. The place of this new class in the strategies of initial, switch or rescue treatment remains to be clarified. The limitations of the use of these small molecules depend on their mechanism of action : obligation for monitoring the evolution of coreceptor usage, risk of failure by emergence of pre-existing strains with CXCR4 (X4) tropism or by resistant strains with CCR5 tropism, potential risks related to blocking of the physiological functions of this chemokine receptor.

Variations in serum IL-7 and 90K/Mac-2 binding protein (Mac-2 BP) levels analysed in cohorts of HIV-1 patients and correlated with clinical changes following antiretroviral therapy.

Serum levels of interleukin-7 (IL-7), a non-redundant cytokine that plays a crucial role in lymphopoiesis, are known to be elevated in HIV-1-infected subjects. To examine further the association between levels of IL-7, CD4+ cell counts and viraemia, we analysed these parameters in a large cohort of HIV-1 patients along with serum levels of 90K, a marker of disease severity but with no established involvement in lymphopoiesis. While IL-7 levels were only found to correlate with CD4+ cell counts, 90K levels presented strong correlations with both CD4+ cell numbers and with plasma viral loads (VLs). These correlations were maintained in patients naive to treatment with antiretrovirals (n = 38) but were abolished when the analysis was restricted to the group receiving highly active antiretroviral therapy (HAART, n = 82). Moreover, although 90K levels were significantly reduced in patients on HAART, IL-7 levels continued to be elevated despite successful treatment. The influence of HAART on the variations in these serum parameters was further assessed in a longitudinal study on 32 subjects. The HAART-induced decrease in VLs and increase in CD4+ counts were found to correlate with a reduced serum level of 90K and IL-7, respectively. Nevertheless, following a median period of 33 months of immunological and virological successful HAART, serum levels of IL-7 continued to be significantly elevated compared with those detected in healthy controls. These findings suggest that immunotherapy with IL-7, aimed to replenish T-cell stock in HAART-treated subjects, may have a limited impact on the process of immune reconstitution.

[Availability of antiretroviral agents in the city: a 1-year assessment in the Lille metropolitan area]. / Double dispensation des antirétroviraux en ville: bilan à un an dans l'agglomération lilloise.

OBJECTIVES: Dispensing antiretroviral drugs in private pharmacies has been allowed in France since October 1997. One year after this measure was implemented, we conducted a survey of patients and pharmacists in the Lille metropolitan area to assess its impact. METHOD: Structured interviews with a representative sample of private pharmacists and HIV infected patients in the Lille metropolitan area were carried out. RESULTS: 100 pharmacists were interviewed. Most worked in urban areas and their main clientele were from the neighbourhood. Most felt that HIV infection was a common disease and were interested in dispensing antiretroviral drugs as a public health service despite the marginal income from these sales. Two-thirds had received training on HIV infection and most knew the importance of adhering to the treatment. However, the number of antiretroviral drugs and the classes of these drugs that were available were not well known. Among the 97 patients followed by the Service of Infectious Diseases of the Tourcoing Hospital, 22% received their medications from the local private pharmacy, 62% got them from the hospital pharmacy and 16% got them from both places. However, 39% received at least one drug that was only available from the hospital pharmacy. The patients going to private pharmacies described an improved quality of life and mostly chose their regular pharmacist to get their medications. Most preferred to get their medications openly, as opposed to secretly. Many patients going to the hospital pharmacy made their choice based on better confidentiality. Private pharmacists also expressed the fear of lack of confidentiality. Private pharmacies were seen as friendlier with quicker service, but slightly less competent than the hospital pharmacy. Finally, the topic of adhering to this form of HIV treatment is rarely discussed in private pharmacies. CONCLUSIONS: Both the patients and private pharmacists appreciate the fact that these drugs can be dispensed in private pharmacies, but the impact of this measure is limited by the number of drugs that are only available at the hospital pharmacy. Private pharmacists do not often discuss the importance of adhering to the therapy and progress is needed in this area.

SS-56, a novel cellular target of autoantibody responses in Sjögren syndrome and systemic lupus erythematosus.

Certain autoimmune disorders, including Sjögren syndrome (SS) and systemic lupus erythematosus (SLE), are characterized by autoantibodies against the Ro/SSA and La/SSB cellular antigens. Although the implication of these autoantibodies in disease pathogenesis is still unclear, it is believed that the aberrant responses against autoantigens may extend to other proteins that are not yet well defined. In an attempt to analyze the regulated gene expression in lymphocytes by an HIV-suppressive immunomodulator, we have identified and cloned a novel gene encoding a 56-kDa protein, named SS-56, which is structurally related to the 52-kDa Ro/SSA antigen. The new protein showed primarily perinuclear cytoplasmic localization, and recombinant SS-56 was found to react in ELISA with sera from most patients with SS or SLE. Western blot analysis confirmed the autoantigenic nature of native SS-56 in extracts from HeLa cells. Interestingly, the incidence of antibodies to SS-56 was associated with visceral complications in SLE, and roughly half of the 17 SS or SLE patients with no detectable antibodies to SSA and SSB antigens presented measurable antibodies against recombinant SS-56. Thus, SS-56 represents a new member of the SS family of autoantigens and could become an additional and important diagnostic marker for SS and SLE.

Symptomatic hyperlactataemia: an emerging complication of antiretroviral therapy.

BACKGROUND: Fatal lactic acidosis is a serious complication of therapy with nucleoside analogues. OBJECTIVE: To examine symptomatic hyperlactataemia in HIV-infected adults treated with antiretroviral drugs. METHODS: In this prospective study, arterial blood lactate levels were measured in patients presenting with unexplained clinical symptoms. When these levels were high, functional respiratory tests (FRT) were carried out. Liver or muscle biopsies were further proposed. Incidences were calculated by comparison with the entire cohort of patients treated in the department. RESULTS: Fourteen HIV-infected adults treated with antiretroviral drugs were identified with symptomatic hyperlactataemia during a 2-year period follow-up study. The incidence of hyperlactataemia was 0.8% per year but reached 1.2% if only patients treated with a regimen including stavudine were considered. Clinical symptoms included abnormal fatigue, tachycardia, abdominal pain, weight loss, peripheral neuropathy, and more specifically exercise-induced dyspnoea occurring despite effective antiretroviral treatment. FRT showed a metabolic deviation towards anaerobiosis with a high lactate/pyruvate ratio. Ultrastructural mitochondrial abnormalities were seen in all four patients for whom this was examined. There was a marked decrease in complex IV activity in muscle biopsies from four of five patients, consistent with a mitochondrial dysfunction. Evolution was favourable in 13 patients, probably because of an early diagnosis. CONCLUSIONS: Potentially fatal adverse events occurring during antiretroviral treatment may be avoided by close monitoring of clinical signs and blood lactate levels. If other studies confirm that the cumulative long-term toxicity of antiretroviral drugs results from mitochondrial dysfunction, the incidence of hyperlactataemia and its clinical consequences may become more important.

[Cutaneous, hepatic and hematologic manifestations due to nevirapine: DRESS syndrome?]. / Manifestations cutanées, hépatiques et hématologiques liées à la névirapine: DRESS syndrome?

BACKGROUND: Manifestations similar to DRESS syndrome (drug rash with eosinophilia and systemic symptoms) may be induced by nevirapine. CASE REPORTS: Three patients developed skin rash and general signs of liver dysfunction during the first 5 weeks after starting nevirapine. Laboratory tests showed elevated eosinophil counts and signs of inflammation simulating severe infection. DISCUSSION: The incidence of DRESS syndrome is probably underestimated. No standard treatment has been proposed. In our 3 patients, parenteral corticosteroid therapy was successful, leading to a rapidly favorable clinical course although liver tests took longer to return to normal.

Ex vivo interferon-gamma response to human immunodefiency virus-1 derived peptides in human immunodeficiency virus-1 infected patients.

The pattern of human immunodeficiency virus (HIV)-1 antigen-activated production of interferon (IFN)-gamma by immunocompetent cells of HIV-1 infected patients has been studied using a simplified assay combining a small volume (25 microliter) of whole blood stimulation with various HIV-1 antigens, and cytokine measurement in the same wells of microtitre plates (enzyme-linked immunotrapping assay, ELITA). The levels of IFN-gamma were higher using this assay than in the supernatant from stimulated whole blood cultures, therefore ELITA was used in the rest of the study. Specific immune responses to HIV-1 proteins (gp120, p24) and synthetic peptides derived from these proteins and from gp41 were detected in patients, but not in healthy controls. Decreased levels of IFN-gamma were observed in CDC class B (n = 5) and C (n = 4), compared with CDC class A (n = 5), following HIV-1 antigen-specific challenge. The positive response of cells from different patients to overlapping peptides of p25 (amino acids 329-344 and 335-351) was suggestive of a new epitope of HIV-1 gag recognized by T cells in the overlap region. In conclusion, the difference in in vitro antigen-specific T-cell responses of HIV-1-infected patients was shown using the ELITA method. Our results raise the possibility of using this method in screening specific antigens in HIV-1 infection.

[Edmond Sergent (1876-1969) and the Pasteur Institute of Algeria]. / Edmond Sergent (1876-1969) et l'Institut Pasteur d'Algérie.

Edmond Sergent, supported by a distinguished team of colleagues, directed the Pasteur Institute of Algeria for over 60 years, from 1900 to 1963. As a student of Emile Roux, Sergent had received a Pasteurian training. His institute devoted extensive study to malaria. Sergent defined the concept of prevention and extended it to other pathologies. For many years, the Institute persevered in carrying out successful antimalarial campaigns such that Algeria was freed of the disease. In 1916-1917, Sergent and his brother were called upon to organise anti-malarial efforts for the Armée d'Orient. By way of systematic and energetic curative and prophylactic measures, they were able to eradicate the disease. In 1908, the Sergent brothers were the first to discover the role of the louse in the transmission of another disease, relapsing fever. The Pasteur Institute team also discovered the sand fly vector which transmits the parasite causing leishmaniasis. The Sergents found a new form of oculonasal myiasis, called "Thimni". In addition, they led effective campaigns against tuberculosis based on BCG vaccination administered throughout Algeria. The Pasteur Institute of Algeria conducted important research in plant and animal diseases. For example, they detected a trypanosome agent causing dromedary "debab", as well as its vector, the horsefly. They also studied in depth bovine piroplasmosis, which causes widespread and destructive disease, and demonstrated the role of the tick in promoting transmission generally. Their work in botany included the discovery that a Fusarium-type fungus was the causal agent for "baïoudh", the main disease of date palms. They also demonstrated the basic role of the fruit fly in alcoholic grape fermentation.

Specific immune response to human immunodeficiency virus (HIV)-1 in patients assessed through the production of interferon-gamma and interleukin-4 in HIV-1 p24-activated whole blood cultures: relationship with the viral load in plasma.

We studied the in vitro HIV-1 antigen-stimulated production of IFN-gamma and IL-4 in HIV-1-infected patients and its relationship with viral replication as assessed through the plasma level of HIV-1 RNA. The levels of IFN-gamma and IL-4 were higher in supernatants of stimulated whole blood cultures than in stimulated peripheral blood mononuclear cell cultures, therefore whole blood cultures were used in the rest of the study. Specific IFN-gamma and IL-4 responses to HIV-1 p24 antigen were observed in HIV-1-infected patients but not in healthy controls (n = 23). A lower proportion of individuals with a positive IFN-gamma response to HIV-1 p24 was observed in patients at a declining clinical stage: 62% in asymptomatic patients (CDC group A, n = 16) versus 19% in symptomatic patients (CDC groups B and C, n = 21; P = 0.007, chi2 testing), whereas the proportion of individuals with a positive IL-4 response to HIV-1 p24 was almost similar in both groups of patients (25% versus 23.8%). Increased IL-4 production by HIV-1 p24-activated immunocompetent cells of patients and a predominant IL-4 response to HIV-1 p24 (with IL-4/IFN-gamma > 1) were positively correlated with an increased viral load. In contrast, there was no correlation between the mitogen-stimulated production of IL-4 and IFN-gamma and the viral load in plasma. The CD8 T cells from whole blood of patients, but not from controls played a significant role in the HIV-1 p24-activated production of IFN-gamma and IL-4. In conclusion, HIV-1-antigen-stimulated whole blood appears to be a valuable tool to study the production of IL-4 in HIV-1-infected patients. The cytokine profile pattern in response to epitopes of HIV-1 gag p24 may play an important role in the host immune response to HIV-1.

Tolerance, compliance and psychological consequences of post-exposure prophylaxis in health-care workers.

Our objectives were to evaluate tolerance and compliance of post-exposure triple therapy in health-care workers (HCWs) by retrospective observational study. Structured telephone interview of HCWs identified through data from antiretroviral prescribing centres. Twenty HCWs who received triple prophylaxis were identified over one year. Sixteen agreed to participate in the study. All but one source patient had documented HIV infection. Half HCWs were not aware of post-exposure therapy. Most HCWs received a zidovudine, lamivudine and indinavir combination. All completed at least 4 weeks of therapy. Only 50% received their first dosage less than 4 h after exposure. Nearly all experienced adverse events, mostly digestive (nausea and abdominal pain n=15) or psychological (anxiety and depression n=15), none resulting in therapy discontinuation. Most events occurred 2 to 7 days after therapy initiation. Most modified their sexual life with abstinence or condom use. Compliance was excellent. Half HCWs did not miss any tablet, 4 forgot one dosing a month and 4 one dosing a week. Follow up is over 6 months in all but one HCW. No HIV seroconversion has been observed to date. In France, post-exposure triple antiretroviral therapy is widely available 24 h a day in every emergency room but further training and development of HCWs is needed to decrease consulting time and increase referral to specialized physicians. Notable moderate adverse events, both physical and psychological are noted, however, compliance is excellent.

Production of interleukin-4, interferon (IFN)-gamma and IFN-alpha in human immunodeficiency virus-1 infection: an imbalance of type 1 and type 2 cytokines may reduce the synthesis of IFN-alpha.

Interferon-alpha (IFN-alpha) is an important molecule in the antiviral response, but cells from HIV-1-infected individuals show a reduced ability to secrete IFN-alpha. We investigated an association between an imbalance of type 1/type2 cytokines and the production of IFN-alpha in HIV-1 infection. We used whole blood culture to study the cytokine production profile, interferon-gamma (IFN-gamma) and interleukin-4 (IL-4), in response to HIV-1 antigens and to study the Sendai Virus and HSV-1-induced-production of IFN-alpha in seven HIV-1-infected patients. An impaired synthesis of IFN-alpha was obtained in patients with a predominant IL-4 production (IL-4 > IFN-gamma), and we found a positive correlation between the ex vivo production of IFN-alpha and the IFN-gamma/IL-4 ratio but not with the HIV RNA copy number in plasma. We investigated the role of T-cell-derived cytokines in the in vitro production of IFN-alpha by PBMC from eight healthy donors, activated with Sendai Virus or HSV-1. Whereas type 2 cytokines (IL-4, IL-13) inhibited virus-induced IFN-alpha synthesis, on the contrary, type 1 cytokines (IL-2, IFN-gamma) enhanced it. A disarray in the T-cell-derived cytokine response may play a role in the defect of IFN-alpha production in HIV-1-infected individuals. Further investigations are needed to explore this hypothesis.

RANTES production in HIV-1 antigen-stimulated whole blood culture: relationship with type 1 immune response and plasma viral load in individuals infected with HIV-1.

Host factors which control replication and clearance of human immunodeficiency virus (HIV) are poorly understood. RANTES (regulated on activation, normal T cell expressed and secreted) and other beta-chemokines may be HIV-1-suppressive factors but their role in the progression of HIV-1 infection is a subject of controversy. We investigated the relationship between production of RANTES and correlates of disease progression in 15 patients infected with HIV-1. We used whole blood culture to study the production of RANTES, interferon (IFN)-gamma, interleukin (IL)-4 and IL-13 in response to supernatant of T cells infected with HIV-1. A defect of RANTES production was associated with a predominant type 2 and decreased type 1 cytokine profile (IL-4 and/or IL- 13 > IFN-gamma). We obtained a positive correlation between RANTES and IFN-gamma (P = 0.004) and the ratio of type 1 and type 2 cytokines IFN-gamma/IL-4 (P = 0.04) and IFN-gamma/IL-13 (P = 0.003), and a negative correlation between RANTES production and HIV-1 RNA copy number in plasma (P = 0.01). The same pattern of correlation was observed between HIV-1 p24-stimulated production of RANTES and the plasma viral load (P = 0.02, n = 15). The measurement of RANTES produced by heparinized whole blood in response to HIV-1 antigens appears as a potentially valuable tool to assess the defect of type 1 immune response in individuals infected with HIV-1 and to define whether the absence of a RANTES response may play a role in the increased rate of HIV-1 replication.

An interferon-gamma (IFN-gamma) based whole blood assay to detect T cell response to antigens in HIV-1 infected patients.

Recently it has been reported that cytokine production by T cells in response to antigens may be more sensitive test than lymphoproliferation. T cell reactivities to antigens is usually performed on isolated PBMCs, however whole blood is being used frequently for cytokine production studies. A whole blood assay is described to measure T cell mediated immune responses to HIV-1 and recall antigens. The cultures were performed in 96-well plates in which only 25 microliters of whole blood was required. We studied the production of IFN gamma in short term culture (24 hours) of 1/10 diluted heparinized whole blood (HWB) from 22 HIV-1 (+) patients grouped according to the 1993 classification of the CDC. IFN gamma was measured with an immunoassay in supernatants of HWB cultured in parallel experiments in the presence of supernatant of HIV-1LAI infected CD4+ T cells, p24 HIV antigen, PPD, tetanus toxoid (TET) and PHA. We found no production of IFN gamma in response to HIV-1 antigens in 15 HIV-1 (-) subjects; whereas a specific IFN gamma production in the presence of HIV-1 antigen was obtained in all of the 9 group A patients, in 7 of 8 group B patients and in 2 of 5 group C patients. In response to recall antigens (TET, PPD), we obtained IFN gamma production in 6 of 9 group A patients, 5 of 8 group B patients and in 1 of 5 group C patients, the response to PHA decreased but remained preserved until late in the disease. The HWB assay is a quick and simple potentially valuable tool for assessing cellular immune function in HIV-1+ patients.

Telemedicine for AIDS patients accommodations.

People suffering from AIDS are subject to frequent hospitalisations. In some cases, they cannot go back home after hospitalisations, due to severe illness, family or sociologic problems. This is the reason why some therapeutic flats are at their disposal to make easier their medical follow-up after the hospital's discharge. In these Therapy Accommodation, they are treated by trained GP who often suffer from lack of information and lack of expertise in difficult cases. For this purpose we included these flats in the regional Telemedicine AIDS network to give these physicians free access to the computerised multimedia medical record of their patients and to provide them with synchronous co-operation facilities.

Dermatomyositis with follicular hyperkeratosis.

We report 2 cases of dermatomyositis with follicular hyperkeratosis (FHK) in children. They occurred in a 10-year-old Vietnamese girl and a 9-year-old Caucasian boy. The girl's FHK disappeared after 2 months of treatment. The boy presented, 15 months after the onset of his dermatomyositis, with a generalised FHK which lasted for 6 months. FHK can appear before, during or after dermatomyositis. It is more often generalized but can be localised. Erector pili myositis and ostial hyperkeratosis may be the explanation. The prognostic value of FHK in dermatomyositis is unknown. This manifestation, initially considered to be more frequent in the Far East, is not as rare in Western countries as the few reported cases suggest.