D. Sicard

Acquired hemophilia due to factor VIII inhibitors in 34 patients

BACKGROUND Acquired hemophilia is a rare disease caused by the development of auto-antibodies against factor VIII. SUBJECTS AND METHODS We studied the characteristics and outcomes of 34 patients (19 women and 15 men) with acquired hemophilia from 1980 to 1997. RESULTS The mean age of the patients was 61 years (range, 22-93 years). An underlying disease was observed in 18 (53%) patients: 5 patients had cancer, 4 an autoimmune disorder, 2 a dermatologic disorder, 3 asthma, 3 were postpartum, and 1 had an adverse reaction to ampicillin. Factor VIII level was <5% in 30 (90%) patients; factor VIII antibodies were elevated (>10 Bethesda units) in 23 (69%) patients. Bleeding requiring transfusions was reported in 25 (75%) patients. Human factor VIII was given to 14 patients and porcine factor VIII to 5. Six patients received prothrombin complex concentrates and one desmopressin. Several immunosuppressive treatments were used, mainly corticosteroids, cyclophosphamide, and intravenous immunoglobulin. Bleeding stopped in all but one patient within 2 weeks. Most patients achieved complete remission, although two relapses were observed subsequently. CONCLUSION This large study helps to clarify the presentation and clinical course of acquired hemophilia. Prospective studies are needed to determine the efficacy of treatment.

Exacerbations of Clinical Symptoms in Human Immunodeficiency Virus Type 1—Infected Patients with Multicentric Castleman's Disease Are Associated with a High Increase in Kaposi's Sarcoma Herpesvirus DNA Load in Peripheral Blood Mononuclear Cells

The epidemiologic link between multicentric Castlemans disease (MCD) and Kaposis sarcoma (KS) and the high frequency of KS herpesvirus (KSHV) detection in both diseases raise the question of a role of this new virus in the pathogenesis of MCD. To explore this hypothesis, the KSHV DNA load was investigated in peripheral blood mononuclear cells of 3 human immunodeficiency virus (HIV)-infected patients with MCD at different points during the clinical course. Clinical parameters, such as fever and the presence of lymphadenopathy, were systematically assessed. Hemogram and C-reactive protein level determinations were performed as standard procedures. KSHV DNA load was investigated by means of semiquantitative polymerase chain reaction assay using peripheral blood mononuclear cells of the patients. A correlation between the variation in clinical and biologic parameters related to MCD and KSHV DNA load was found, suggesting a close relationship between KSHV and MCD in HIV-1-infected patients.

Combination of HIV-1-Specific CD4 Th1 Cell Responses and IgG2 Antibodies Is the Best Predictor for Persistence of Long-Term Nonprogression

BACKGROUND Strong T cell and antibody responses to human immunodeficiency virus (HIV), low virus production, and some genetic traits have been individually associated with nonprogression of HIV infection, but the best correlate with protection against disease progression remains unknown. METHODS We prospectively followed 66 untreated long-term nonprogressors and analyzed relationships between HIV-1-specific CD4 T helper (Th) 1 and CD8 T cell responses and HIV-1-specific antibodies, HIV-1 RNA and proviral DNA loads, host genes, and CD4 Th1 cell counts at entry into the study and 4 years later. RESULTS HIV-1 p24-specific CD4 Th1 cell proliferation, interferon (IFN)- gamma production, and IFN- gamma -producing cell frequencies at entry significantly and negatively correlated with HIV-1 RNA and proviral DNA loads and were independent of CD4 Th1 cell counts and host genes. HIV-1 Gag-specific IFN- gamma -producing CD8 T cell frequencies correlated with HIV-1 proviral DNA loads but not with RNA loads. Only high frequencies of HIV-1 p24-specific CD4 Th1 cells combined with HIV-1 gp41-specific IgG2 antibodies significantly predicted persistence of high CD4 Th1 cell counts. CONCLUSION HIV-1-specific CD4 Th1 responses combined with IgG2 antibodies and IFN- gamma -producing CD4 Th1 cells are better predictors of long-term nonprogression than are virus parameters, host genes, or HIV-1-specific CD4 Th1 or CD8 T cell proliferation.

HIV type 1-specific IgG2 antibodies: markers of helper T cell type 1 response and prognostic marker of long-term nonprogression.

The helper T type 1 (Th1) function of CD4(+) T lymphocytes is presumed to be of key importance in host defense against HIV-1. As the production of different antibody isotypes is dependent on this helper T function, we investigated whether HIV-1-specific responses of a particular IgG isotype could be a reliable marker of long-term HIV-1 control. Assessment of the IgG subclass distribution in the plasma of HIV-1-infected patients enrolled in the French prospective Asymptomatic Long-Term (ALT) cohort showed that IgG2 directed against HIV-1 Env gp41 and Gag proteins was associated with low viral load, high CD4(+) lymphocyte count, and weak neutralizing activity. By contrast, levels of anti-Env and anti-Pol IgG1 as well as the magnitude of neutralizing activity were correlated with the viral load and thus merely reflect the level of HIV replication. Furthermore, IgG2 directed against Gag proteins was significantly associated with HIV-1 p24-specific Th1 cell production of interferon gamma and interleukin 2. In multivariate analysis, only two variables, anti-gp41 IgG2 and plasma HIV-1 RNA, were found to be independent prognostic factors of remaining long-term nonprogressive over time. By providing new insight into the nature of an HIV-specific antibody response associated with the control of virus replication, these findings have implications for the design of HIV vaccines.

Neurological complications of varicella-zoster virus infection in adults with human immunodeficiency virus infection.

This multicentre retrospective study describes the clinical features and prognostic significance of Varicella-zoster virus (VZV)-associated neurological complications. The study was performed in patients with human immunodeficiency virus (HIV) infection, hospitalized for VZV neurological complications, confirmed in every case by positive VZV polymerase chain reaction (PCR) in cerebrospinal fluid (CSF). Between 1990 and 1995, 34 HIV-infected patients were included in the study. At diagnosis, 59% had AIDS, with a median CD4 count of 11 x 10(9)/l. A past history of zoster was noted in 35% of cases. A concomitant herpes zoster rash and/or acute retinal necrosis were noted in 71% and 12% of patients, respectively. The predominant neurological manifestations were encephalitis (13), myelitis (8), radiculitis (7) and meningitis (6). The mean CSF white blood cell count was 126/mm3 and the mean CSF protein concentration was 2.3 g/l. Interferon-alpha level was increased in 36% of patients. VZV was isolated from CSF cultures in 2/6 cases. Magnetic resonance imaging was abnormal, demonstrating encephalitis lesions. After intravenous antiviral therapy, complete recovery was obtained in 18 cases (53%), serious sequelae were observed in 10 cases (29%) and 6 patients died (18%). Severe symptoms and a low CD4 cell count appeared to be associated with death or sequelae. In conclusion, VZV should be considered as a possible cause of encephalitis, myelitis, radiculitis or meningitis in HIV-infected patients, especially in patients with a history of or concomitant herpes zoster or acute retinal necrosis. VZV-PCR in the CSF may allow rapid diagnosis and early specific antiviral treatment.ARNAUD DE LA BLANCHARDIERE, FLORE ROZENBERG, ERIC CAUMES, ODILE PICARD, FRANCOIS LIONNET, JOEL LIVARTOWSKI, JOEL COSTE, DIDIER SICARD, PIERRE LEBON and DOMINIQUE SALMON-CÈRON From the Department of Internal Medicine, CHU Cochin-AP.HP, Uni6ersité Paris, Department of Virology, Hôpital Saint-Vincent-de-Paul, Department of Infectious Diseases, Hôpital de la Pitié-Salpétriére, Department of Internal Medicine, Hôpital Saint-Antoine, Paris, Department of Hematology, Centre Hospitalier Général, Argenteuil, Department of Internal Medicine, Hôpital Antoine-Béclère, Clamart, and the Department of Biostatistics, Hôpital Cochin, Paris, France

HIV Combination Therapy: Immune Restitution Causing Cryptococcal Lymphadenitis Dramatically Improved by Anti-inflammatory Therapy

Two patients with AIDS developed microscopically verified focal cryptococcal lymphadenitis while treated with highly active anti-retroviral therapy for 8 and 15 months. Both were treated with fluconazole as a secondary prophylaxis for prior cryptococcal meningitis. Cryptococcus neoformans did not grow. Amphotericin was ineffective. Anti-inflammatory drugs had a dramatic effect.

Decrease in HIV-1 seminal shedding in men receiving highly active antiretroviral therapy: an 18 month longitudinal study (ANRS EP012)

Thirty-nine HIV-1-infected men were prospectively tested for HIV seminal shedding after the initiation of highly active antiretroviral therapy. HIV RNA drastically decreased in the semen of all men, but low levels remained detectable in three men at month 18. Proviral HIV DNA became undetectable in the seminal cells of all men after 18 months. HIV-infected cells in the male genital compartment may come from the intermittent passage of blood lymphocytes, rather than constituing a major local reservoir.

Detection of HIV-1 in seminal plasma and seminal cells of HIV-1 seropositive men

It is of critical importance to precisely understand the modalities of HIV presence in semen, especially with regard to procreation. In this study, paired blood and semen samples from 31 human immunodeficiency virus type 1 (HIV-1)-positive men were assessed for cell-free HIV-RNA load in blood plasma (BP) and seminal plasma (SP), and for detection of HIV by culture, PCR and RT-PCR in semen cellular fractions separated by centrifugation on Percoll gradient. HIV-RNA was detected in 94% of BP and 84% of SP samples. For 11 men (35%), HIV-RNA load in SP was equal or superior to that observed in blood. HIV-DNA presence was demonstrated (either by PCR or culture positivity) in 39% of the non-spermatozoal cells (NSC)-enriched fractions, and in one Percoll-selected sperm pellet. HIV-RNA was detected in 17% (4/23) of the sperm pellets. This positivity was associated with an HIV-RNA load in SP equal or superior to the HIV-RNA load in blood, a high rate of HIV-DNA detection in the NSC fraction, and a low CD4+ cell count. In such conditions, a significant viral production inside the genital tract is more likely to be present, and a close association between HIV and gametes might occur. Assisted procreation with selected spermatozoa should be preceded by accurate assessments of viral presence in blood, SP and semen cellular fractions.

Safety and immunogenicity of a live recombinant canarypox virus expressing HIV type 1 gp120 MN tm/gag/protease LAI (ALVAC-HIV, vCP205) followed by a p24E-V3 MN synthetic peptide (CLTB-36) administered in healthy volunteers at low risk for HIV infection

A live recombinant canarypox vector expressing HIV-1 gp120 MN tm/gag/protease LAI (ALVAC-HIV, vCP205) alone or boosted by a p24E-V3 MN synthetic peptide (CLTB-36) was tested in healthy volunteers at low risk for HIV infection for their safety and immunogenicity. Both antigens were well tolerated. ALVACHIV (vCP205) induced low levels of neutralizing antibodies against HIV-1 MN in 33% of the volunteers. None of them had detectable neutralizing antibodies against a nonsyncytium-inducing HIV-1 clade B primary isolate (Bx08). After the fourth injection of vCP205, CTL activity was detected in 33% of the volunteers and was directed against Env, Gag, and Pol. This activity was mediated by both CD4+ and CD8+ lymphocytes. On the other hand, the CLTB-36 peptide was poorly immunogenic and induced no neutralizing antibodies or CTLs. Although the ALVAC-HIV (vCP205) and CLTB-36 prime-boost regimen was not optimal, further studies with ALVAC-HIV (vCP205) are warranted because of its clear induction of a cellular immune r...

Comparison of the Distribution of IgG and IgA Antibodies in Serum and Various Mucosal Fluids of HIV Type 1-Infected Subjects

We compared IgG and IgA distribution in serum, three different salivary samples, two different rectal secretion samples, cervicovaginal secretions, and seminal secretions from asymptomatic CDC stage II/III HIV-1-infected subjects (n = 44) and from HIV-1-seronegative volunteers (n = 52). In-house ELISAs were used to measure total IgG and total IgA levels, as well as HIV-specific anti-gp120 MN and anti-p24 LAI IgG and IgA. Human serum albumin was titrated in parallel to calculate the relative coefficient of excretion (RCE). In spite of substantial interindividual variability, total IgG concentrations in all fluids were found to be significantly greater in the HIV-1-infected group than in the seronegative subjects. Calculation of RCE values revealed three different types of mucosal secretion: secretions with no local Ig production, such as sperm; secretions with local production of IgA and transudative origin of IgG, such as salivary and rectal samples; and secretions with local production of both IgG and IgA, such as in cervicovaginal secretions. For all mucosal specimens from HIV-1-infected subjects, the response to HIV-1 was predominantly IgG, with highest titers observed in cervicovaginal secretions (although these were lower than serum levels). In contrast, the specific IgA response appeared weaker in the mucosa than in serum.