Jean-Marie Ragnaud

Evaluation of cardiovascular risk factors in HIV-1 infected patients using carotid intima-media thickness measurement.

BACKGROUND. Highly active antiretroviral therapies (HAART) in HIV-infected patients are often associated with lipodystrophy syndrome and metabolic disorders. Atherogenic lipid profile could expose these patients to atheromatous cardiovascular disease. We describe carotid artery intima-media thickness (IMT), a surrogate marker of atherosclerosis, according to HIV status, antiretroviral treatment, lipodystrophy and conventional cardiovascular risk factors. METHOD. In a multicenter prospective cohort study we have surveyed HIV-infected subjects with a carotid IMT measurement by B-mode ultrasonography. We collected information on lipodystrophy clinical manifestations, age, gender, body mass index (BMI), smoking habits, alcohol intake, systolic blood pressure, HIV transmission category, AIDS stage, type and duration of HAART, CD4 + cell count, plasma HIV-1 RNA, glucose, insulin, total cholesterol and homocysteine. RESULTS. Four hundred and twenty-three HIV-infected patients were studied. The median carotid IMT measurement was 0.54 mm (range: 0.50-0.60). Lipodystrophy syndrome was diagnosed in 161 HIV-infected patients (38.1%). In univariate linear regression, IMT was significantly higher (P < 0.05) with older age, male gender, higher body mass index, higher waist-to-hip ratio, increased systolic blood pressure, total cholesterol, glucose disorders and homocysteine, regular smoking and alcohol consumption, lipo dystrophy and HAART. In a multivariate analysis, the effect of lipodystrophy and HAART disappeared after adjustment for other cardiovascular risk factors. CONCLUSIONS. It was concluded that only conventional cardiovascular risk factors are independently associated with increased IMT in HIV-infected patients.

Human Immunodeficiency Virus Type 1 Genotypic and Pharmacokinetic Determinants of the Virological Response to Lopinavir-Ritonavir-Containing Therapy in Protease Inhibitor-Experienced Patients

ABSTRACT The response to regimens including lopinavir-ritonavir (LPV/r) in patients who have received multiple protease (PR) inhibitors (PI) can be analyzed in terms of human immunodeficiency virus type 1 (HIV-1) genotypic and pharmacokinetic (pK) determinants. We studied these factors and the evolution of HIV-1 resistance in response to LPV/r in a prospective study of patients receiving LPV/r under a temporary authorization in Bordeaux, France. HIV-1 PR and reverse transcriptase sequences were determined at baseline LPV/r for all the patients and at month 3 (M3) and M6 in the absence of response to treatment. pK measurements were determined at M1 and M3. Virological failure (VF) was defined as a plasma viral load ≥400 copies/ml at M3. A multivariate analysis of the predictors of VF, including clinical and biological characteristics and the treatment history of the patients, was performed. The PR gene sequence at M0, including individual mutations or a previously defined LPV mutation score (D. J. Kempf, J. D. Isaacson, M. S. King, S. C. Brun, Y. Xu, K. Real, B. M. Bernstein, A. J. Japour, E. Sun, and R. A. Rode, J. Virol. 75:7262-7269, 2001), and the individual exposure to LPV were also included covariates. Sixty-eight patients were enrolled. Thirty-four percent had a virological response at M3. An LPV mutation score of >5 mutations, the presence of the PR I54V mutation at baseline, a high number of previous PIs, prior therapy with ritonavir or indinavir, absence of coprescription of efavirenz, and a lower exposure to LPV or lower LPV trough concentrations were independently associated with VF on LPV/r. Additional PI resistance mutations, including primary mutation I50V, could be selected in patients failing on LPV/r. Genotypic and pK parameters should be used to optimize the virological response to LPV/r in PI-experienced patients and to avoid further viral evolution.

Highly Active Antiretroviral Treatment Initiated Early in the Course of Symptomatic Primary HIV-1 Infection: Results of the ANRS 053 Trial

Highly active antiretroviral treatment (HAART) was given early to 64 patients with symptomatic primary human immunodeficiency virus (HIV)-1 infection. At the time of analysis, patients had been followed up for 9-21 months. No patient had died or developed an AIDS-defining event. Survival analysis showed that by month 21 the proportion of patients with plasma HIV-1 RNA <50 copies/mL was 72% (95% confidence interval, 58%-95%) in intention-to-treat analysis. After 18 months of treatment, 50% of the patients with undetectable plasma HIV-1 RNA also had undetectable HIV-1 RNA in peripheral blood mononuclear cells (PBMC). Only 1 of 3 patients had undetectable HIV-1 RNA in lymphoid tissue, while all patients had quantifiable HIV-1 DNA both in PBMC and lymphoid tissue. The median CD4 lymphocyte increase from baseline was 230 cells/microL. These preliminary results support the use of HAART in patients with primary HIV-1 infection.

Combined nerve and muscle biopsy in the diagnosis of vasculitic neuropathy. A 16‐year retrospective study of 202 cases

Abstract  We reviewed 202 biopsies performed on patients with suspected vasculitic neuropathy, of which 24 Churg‐Strauss cases are studied separately. Specimens from the superficial peroneal nerve and peroneus brevis muscle were taken simultaneously by one incision. Without taking into account constitutional signs, systemic involvement was present in 131 patients, whereas the remaining 47 corresponded to non‐systemic patients with lesions limited to peripheral nervous system and adjoining muscles. Diagnosis of panarteritis nodosa or microscopic polyangiitis, according to the size of involved vessels, was attested by an infiltration of vessel walls by inflammatory cells associated with fibrinoid necrosis or sclerosis. Microvasculitis was diagnosed when inflammatory infiltration concerned small vessels with few or no smooth‐muscle fibers and without any necrosis. Microvasculitis was present in 11 of 46 non‐systemic cases, and this predominance is statistically significant. Isolated perivascular cell infiltrates in the epineurium were considered not significant but allowed the diagnosis of ‘probable vasculitis’ if associated with at least one of the following features: regenerating small vessels, endoneurial purpura, asymmetric nerve fiber loss, and/or asymmetric acute axonal degeneration. Necrotizing vasculitis was visible in 60 cases: in nerve (16 cases), in muscle (19 cases), and both (25 cases). Microvasculitis was present in 25 cases: in nerve (19 cases), muscle (four cases), or both (two cases). Moreover, granulomatous vasculitis was found in the nerve of one non‐systemic patient presenting also sarcoid granulomas in muscle. There were 24 ‘probable vasculitis’ and 68 negative cases. Muscle biopsy improved the yield of definite vasculitis by 27%.

Occult Hepatitis B Virus Infection in HIV-Infected Patients with Isolated Antibodies to Hepatitis B Core Antigen: Aquitaine Cohort, 2002–2003

We prospectively assessed the prevalence of occult hepatitis B virus (HBV) infection by investigating HBV replication in 160 human immunodeficiency virus (HIV)-infected patients with isolated antibodies to hepatitis B core antigen. This prevalence was 0.6% (1 case/160 patients; 95% confidence interval, 0%-3.4%). A second serum sample was collected later from 52 of the patients. HBV DNA was once again undetectable in all patients, except for the sole patient who had previously been found to be HBV DNA positive.

Kinetics of appearance of neutralizing antibodies in 12 patients with primary or recent HIV-1 infection and relationship with plasma and cellular viral loads

HIV-1 primary infection is characterized by a short high titer viremia, which rapidly declines as the immune response emerges. The role of autologous neutralizing antibodies in the decline of viral replication was evaluated in 12 patients with primary or recent HIV-1 infection. Neutralizing antibodies detected for each patient could not generally be observed before several months after isolation of the first obtained HIV isolate. The plasma viral load, as measured by quantitation of the HIV-1 RNA, underwent a global decrease during the first 6 months of the infection, but this decrease did not seem to be associated with the emergence of neutralizing antibodies. The proviral load in peripheral blood mononuclear cells, which was studied by quantitative DNA polymerase chain reaction, exhibited fluctuations and was not as well curtailed as the plasma viremia in the majority of patients.

Detection of JC virus DNA in the peripheral blood leukocytes of HIV-infected patients.

ObjectivesTo assess whether JC virus (JCV) DNA is frequently harboured by peripheral blood leukocytes (PBL) in HIV-positive patients, before the onset of progressive multifocal leukoencephalopathy (PML). DesignThe polyomavirus JCV induces PMI in immunocompromised persons and particularly AIDS patients. Leukocytes may play a central part in the onset of PML, but their precise role in JCV latency and reactivation still remains hypothetical. The controversial presence of JCV DNA in PBL has been, until now, investigated only among small groups of patients. We therefore studied 157 HIV-positive persons and compared them with 65 HIV-negative immunocompromised patients. MethodsDNA was extracted from PBL. The presence of JCV DNA was demonstrated by the polymerase chain reaction (PCR) alone or combined with a molecular hybridization assay. ResultsThe presence of JCV DNA was ascertained by PCR and hybridization in 28.9% of 135 HIV-infected persons at all stages of HIV infection and only 16.4% of 61 HIV-negative immunocompromised patients. No correlation could be drawn between the detection of JCV DNA and the clinical or biological status of the HIV-positive patients. ConclusionsJCV DNA is detectable in the PBL of 28.9% of HIV-infected persons, even in the early stages of infection. JCV is more seldomly amplified in I HV-negative immunocompromised patients. Further work is in progress to determine the prognostic value of the presence of JCV DNA in the blood of HIV-positive patients.

JC Virus Remains Latent in Peripheral Blood B Lymphocytes but Replicates Actively in Urine from AIDS Patients

JC virus (JCV) is thought to reach the central nervous system by a vascular route. To determine whether JCV is conveyed in peripheral blood as latent or reactivated virus, blood leukocytes, plasma, and urine from 50 AIDS patients and plasma and B lymphocytes from 60 AIDS patients were investigated. Peripheral blood from 88 human immunodeficiency virus-negative blood donors was studied. Nested polymerase chain reaction assays allowed the identification of JCV T DNA and VP1 mRNAs. The latter indicate viral replication. Blood harbored JCV DNA in 31.8% of AIDS patients (only 2.3% of blood donors; P > .001) and urine in 56%. VP1 mRNAs were detected in blood of 1 AIDS patient. Notably, 38% of DNA-positive urine samples and 10 cerebrospinal fluid samples (CSF) from AIDS patients with progressive multifocal leukoencephalopathy contained JCV mRNAs. Thus, JCV was significantly more frequent in blood from AIDS patients than from controls, but, in most instances, it was latent, whereas active replication was detected in urine and CSF.

Immune Thrombocytopenic Purpura after Recombinant Hepatitis B Vaccine: Retrospective Study of Seven Cases

Recombinant hepatitis B vaccine is usually well tolerated. Clinical and laboratory test manifestations with immunologic mechanisms have nonetheless been described following use of this vaccine. We retrospectively report 7 cases of thrombocytopenia occurring within 3 months (7 weeks on the average) of 1 or following injections of recombinant hepatitis B vaccine. Four boys and 3 girls, average age 12 y, were involved. Three had a history of immune thrombocytopenic purpura. Four had haemorrhagic manifestations. The haemogram showed thrombocytopenia (24 x 10(9)/l on the average) without alterations of the other lines. Infectious and immune aetiologies were excluded in all cases. The course varied after treatment by corticosteroids, high-dose intravenous immunoglobulin, or both. After describing the different manifestations subsequent to recombinant hepatitis B vaccination, we discuss post-vaccinal thrombocytopenias (vaccines in question, mechanisms) and the reality of this entity.

Prevalence of and Factors Associated With Hepatic Steatosis in Patients Coinfected With Hepatitis C Virus and HIV: Agence Nationale pour la Recherche contre le SIDA et les h??patites virales CO3 Aquitaine Cohort

Background:Hepatic steatosis is a common feature in liver biopsies from patients with chronic hepatitis C and is associated with fibrosis progression. Patients with HIV infection and hepatitis C virus (HCV) coinfection have more rapid progression of liver fibrosis than patients with HCV infection alone. The prevalence and factors associated with hepatic steatosis are not well defined in HCV-HIV-coinfected patients. Methods:Steatosis was assessed among 148 HCV-HIV-coinfected patients of the Aquitaine Cohort. Steatosis was graded as follows: none, mild (1%-10% of hepatocytes), moderate (11%-30%), severe (31%-60%), and massive (more than 60%). Epidemiologic, clinical, biologic, and therapeutic data were retrieved from the cohort database to investigate the risk factors. Results:Steatosis was present in 67% of patients (95% confidence interval [CI]: 59% to 74%) and was at least moderate in 30% (95% CI: 23% to 38%). Steatosis was macrovesicular or mixed (macro- and microvesicular) in 40.5% and 52.8% of patients, respectively. Necroinflammatory activity was the only factor independent of steatosis (adjusted odds ratio = 5.3, 95% CI: 1.6 to 17.9). When necroinflammatory activity was removed from the model, HCV genotype 3 and body mass index (BMI) were significantly associated with steatosis. Conclusions:Liver inflammation, HCV genotype 3, and BMI are associated with steatosis, a common finding in HCV-HIV-coinfected patients.