Disseminated toxoplasmosis in non-allografted patients with hematologic malignancies: report of two cases and literature review.

Toxoplasmosis can be a severe opportunistic infection in patients with acquired immunodeficiency syndrome (AIDS), and also among solid organ transplant and allogeneic hematopoietic stem cell transplant (HSCT) patients. Patients with low-grade or chronic hematologic malignancies are treated with increasing immunosuppressive regimens and, therefore, represent an emerging population at risk for opportunistic diseases. We report here two cases of disseminated toxoplasmosis occurring in non-allografted hematologic patients with chronic lymphoproliferations. A review of 44 cases from the literature reveals that toxoplasmosis occurs increasingly in indolent B cell lymphoproliferative disorders. Aggressive lymphoproliferations, adenosine analogs, autologous HSCT, and the absence of chemoprophylaxis are the main risk factors for opportunistic toxoplasmosis. The central nervous system is the main organ involved. Fever is only present in half of all cases. Latent Toxoplasma cysts reactivation (LTCR) is the most common, but primary infection occurs in about 20% of cases. Global mortality is over 50%.

Comparative effectiveness of continuing a virologically effective first-line boosted protease inhibitor combination or of switching to a three-drug regimen containing either efavirenz, nevirapine or abacavir.

OBJECTIVES: To compare virological effectiveness in patients who continued on a virologically successful first-line boosted protease inhibitor (PI)-containing combination antiretroviral therapy (cART) regimen or who switched to a PI-free cART including efavirenz, nevirapine or abacavir. METHODS: From the French Hospital Database on HIV, we selected 439 patients with undetectable viral load (VL) on a first-line boosted PI-containing cART regimen who switched to a PI-free combination including efavirenz, nevirapine or abacavir. Each of these patients was matched with three patients who continued to take their first-line cART regimen, on the basis of gender, age, CD4 cell count, VL, date of cART initiation and the duration of VL undetectability. Time to virological failure (VF) was analysed with Kaplan-Meier curves and Cox models. RESULTS: The 12 month probabilities of VF were 3.7% and 5.7% in non-switch and switch patients, respectively, and 3.9%, 7.2% and 9.0% in patients switching to efavirenz-, nevirapine- and abacavir-containing cART, respectively. After adjustment, only patients switching to abacavir-containing cART had a higher risk of VF than non-switch patients (adjusted hazard ratio, 1.99; 95% confidence interval, 1.05-3.79). CONCLUSIONS: Switching from a virologically successful first-line boosted PI-containing cART regimen to a non-nucleoside reverse transcriptase inhibitor-containing cART regimen containing either efavirenz or nevirapine is virologically safe, while switching to abacavir-containing cART should be avoided.

Simplification and first validation of a short battery of patient questionnaires for clinical management of HIV-infected patients: The HIV-SQUAD (Symptom Quality of life Adherence) Questionnaire.

PURPOSE: Questionnaires assessing patient-reported outcomes in HIV are either too long or not HIV-specific. Our aim was to develop and validate a simplified HIV patient questionnaire. METHOD: 607 HIV patients treated with a combination of antiretroviral (ARV) drugs were enrolled in an observational, longitudinal study. Questionnaires covering health-related quality of life (HRQoL), satisfaction, tolerability, and adherence were administered at baseline (BL) and Month 3 (M3). The items were selected according to their content and discriminant properties. The simplified questionnaire was then administered at Month 12 (M12). Psychometric properties of physical wellbeing, psychological well-being, and global HRQoL scores were assessed. RESULTS: The simplified questionnaire included 12 HRQoL items, 13 side-effects items, and one visual analog scale (VAS) measuring adherence. The principal component analysis (PCA) confirmed the validity of the global HRQoL score. The multivariate analysis showed acceptable-to-good internal consistency of the three scores. Convergent and discriminant validity were excellent for the physical score. The global score showed significant differences according to time since diagnosis, hepatitis coinfection, CD4 count, and viral load. CONCLUSION: This questionnaire deals with the major aspects of HIV patient perceptions. The global HRQoL score is well correlated to the surrogate markers of HIV. Such a questionnaire may represent a new tool for the therapeutic management of HIV-infected patients. Further steps are required to complete these results.

Zidovudine inhibits functional extracellular monocytic interleukin-1.

Zidovudine (AZT) penetrates human monocytes to exert its antiretroviral activity at the level of reverse transcriptase in infected cells. Stimulation of normal human monocytes with lipopolysaccharide (LPS) results in the transcription of interleukin-1 (IL-1) genes, the intracellular accumulation of IL-1 alpha and IL-1 beta precursors, and the subsequent extracellular release of functional IL-1 beta. The present study demonstrates that zidovudine inhibits the extracellular release of IL-1 activity without affecting the generation of intracellular IL-1 or the amount of released IL-1 beta protein. Similar results were observed with monocytes from normal individuals and monocytes from patients with AIDS. Since IL-1 may upregulate the expression of HIV genes in infected cells, the inhibitory effect of zidovudine on the release of functional IL-1 may be relevant for the beneficial effect of the drug in HIV infection.

HIV infection is associated with the spontaneous production of interleukin-1 (IL-1) in vivo and with an abnormal release of IL-1 alpha in vitro.

Interleukin-1 (IL-1) is not constitutively produced by normal human monocytes. We have investigated the production of cell-associated IL-1 in uncultured unstimulated adherent monocytes from HIV-infected patients, which reflects ongoing generation of IL-1 by the cells in vivo. High levels of cell-associated IL-1 activity and of cell-associated IL-1 alpha and IL-1 beta antigens were found in monocytes from HIV-infected patients as compared with those found in monocytes from normal individuals. Amounts of cell-associated IL-1 were high in patients with AIDS and in patients from Centers for Disease Control groups II and III. Serum-free culture for 24 h of monocytes from HIV-infected individuals in the absence of lipopolysaccharides (LPS) resulted in spontaneous release of IL-1 activity from the cells whereas no release occurred upon culture of normal cells. Stimulation of monocytes with LPS induced the release of IL-1 alpha and IL-1 beta from cells of infected patients. Only IL-1 beta was released from cells of normal individuals. Thus, circulating monocytes from HIV-infected patients are triggered to produce IL-1 in vivo. The present study also indicates that HIV infection is associated with an acquired defect in the intracellular processes regulating IL-1 secretion.

Discrepant responses to triple combination antiretroviral therapy in advanced HIV disease.

OBJECTIVES: To determine the clinical, virological and immunological outcome in a cohort of unselected patients receiving triple combination therapy for more than 1 year. METHODS: Prospective follow-up of a cohort of 162 unselected, protease inhibitor-naive, antiretroviral-experienced patients with advanced HIV disease, treated with indinavir combined with two nucleoside analogues. RESULTS: The mean CD4 cell count and plasma HIV RNA level in the study group at baseline were 69+/-5 x 10(6)/l and 4.75+/-0.07 log10 copies/ml, respectively. Five per cent of patients died prematurely or were lost to follow-up. Fifty-seven per cent of patients responded to therapy, as assessed by a sustained increase in CD4 cell counts above 50 x 10(6)/l and a decrease in plasma HIV RNA greater than 1 log10 copies/ml, throughout 12.1 months of follow-up. Seventeen per cent of patients were immunological and virological non-responders. Twenty-one per cent of patients exhibited discrepant virological and immunological responses to treatment, of whom one-half failed to exhibit significant increases in CD4 cells despite a virological response to therapy and one-half exhibited increased CD4 cell counts in the absence of significant decrease in plasma viral load. The incidence of AIDS-defining events in the latter group of patients was similar to that of responder patients, whereas their incidence was higher in patients who failed to exhibit a virological and immunological response and those who failed to increase CD4 cells despite a significant decrease in viral load. CONCLUSION: Our observations of discrepant immunological and virological responses to treatment raise the issue of the significance of persistent elevated levels of plasma HIV RNA and of the relevance of measurements of plasma viral load for assessing the efficacy of antiretroviral therapy in patients whose CD4 cell counts increase despite the absence of significant decrease in plasma HIV viral load.

Sequential occurrence of thyroid autoantibodies and Graves' disease after immune restoration in severely immunocompromised human immunodeficiency virus-1-infected patients.

We analyzed the kinetics of CD4 cells, human immunodeficiency virus (HIV) viral load, and autoantibodies in acquired immune deficiency syndrome patients with Graves' disease (GD) after immune restoration on highly active antiretroviral therapy (HAART; retrospective study). Five patients (median age, 41 yr) were diagnosed with GD after 20 (range, 14-22) months on HAART on the basis of clinical and biological hyperthyroidism, diffuse hyperfixation of thyroid scan, and the presence of anti-TSH receptor (anti-TSHR) antibodies (Ab). GD was diagnosed several months after the plasma HIV ribonucleic acid load became undetectable, when the CD4+ cell count had risen from 14 (range, 0-62) to 340 (range, 163-460) x 10(6) cells/L. Antithyroid peroxidase (anti-TPO) and anti-TSHRAb appeared 14 (range, 9-18) and 14 (range, 11-20) months after starting HAART and 12 (range, 6-15) and 11 (range, 9-17) months after the increase in CD4+ cells. In 3 patients, TPOAb preceded TSHRAb by 3-10 months. No other autoantibodies were detected. Thyroid antibodies were absent in a group of 55 HIV-1-positive patients with comparable response to HAART and no symptoms of hyperthyroidism (cross-sectional study). Thyroid-specific autoimmunity can occur upon immune restoration with HAART. Our observations suggest a relationship between thymus-dependent immune reconstitution after immunosuppression and autoimmunity and may provide insight into the pathophysiology of GD.

The sequential occurrence of pol 215 and pol 41 zidovudine resistance mutations is associated in an additive fashion with low CD4 cell counts and high plasma and cellular HIV viral load.

We report on a cross-sectional study of virological and immunological surrogate markers of HIV infection in 115 patients for whom a determination of the pol 215 and pol 41 zidovudine (ZDV) resistance mutations had been described between January 1995 and February 1996. The patients received ZDV alone or a combination of ZDV and zalcitabine or didanosine. A total of 55, 15 and 45 patients exhibited a wild (W), a mixed (MIX) or a mutant (M) genotype at codon pol 215, respectively; 85, 10 and 20 patients exhibited a W, a MIX or a M genotype at codon pol 41, respectively. Patients exhibiting the pol 215 M genotype had lower CD4 cells, higher plasma viral load and higher proviral burden than patients exhibiting the pol 215 W genotype. Patients who had variants exhibiting both pol 215 M and pol 41 M or MIX genotypes had significantly worsened surrogate marker values than patients having variants only carrying the pol 215 M genotype. These observations demonstrate that the two mutations additively associate with pejorative surrogate markers.

Monitoring plasma levels of ganciclovir in AIDS patients receiving oral ganciclovir as maintenance therapy for CMV retinitis.

OBJECTIVES: To investigate whether low ganciclovir serum levels in patients on maintenance oral ganciclovir therapy are associated with recurrence of CMV retinitis. METHODS: A prospective study of the plasma concentration of ganciclovir after initiation of maintenance oral ganciclovir therapy in 14 AIDS patients who had recovered from acute cytomegalovirus (CMV) retinitis. RESULTS: Five of the 14 patients exhibited a mean time to recurrence of 37 days. The mean trough plasma concentration of ganciclovir in these patients after 1 month of oral ganciclovir therapy, was 0.40 +/- 0.30 mg/L. Nine patients had a mean time of progression of 263 days. The mean trough plasma concentration of ganciclovir in the latter patients was 0.80 +/- 0.60 mg/L. CONCLUSIONS: Patients exhibiting trough plasma levels of ganciclovir below 0.6 mg/L may be at higher risk of progression than patients who exhibited levels above 0.6 mg/L.

[Lactic acidosis and hepatic mitochondrial changes during a treatment with zidovudine]. / Acidose lactique et altérations mitochondriales hépatiques au cours d'un traitement par zidovudine.

Adverse effects of zidovudine, which mainly result in myopathies and hematological disorders, could be due to multitissular mitochondrial toxicity of the drug. During zidovudine treatment, most cases of lactic acidosis have been attributed to mitochondrial myopathy. We report a case of hepatocellular failure with lactic acidosis in a 33 year-old patient with the human immunodeficiency virus infection and treated with zidovudine for 8 months. Liver biopsy showed massive macrovacuolar steatosis and ultrastructural mitochondrial abnormalities similar to those previously described in the skeletal muscle. This is the second reported case of lactic acidosis and hepatocellular failure which is probably related to hepatic mitochondrial dysfunction caused by zidovudine.

[Spinal cord toxoplasmosis and AIDS]. / Toxoplasmose médullaire et SIDA.

Toxoplasmosis is the most common brain parasitic infection in acquired immunodeficiency syndrome (AIDS). Spinal cord localisations are still rare (2 cases with cerebral involvement, 2 cases without). A case of both spinal cord and cerebral involvement is reported. MR imaging was performed because of sensory level (L1). A focal conus medullaris enlargement was seen, iso intense on T1 weighted images. This lesion was hyperintense on T2 weighted sequence, and was homogeneously enhanced after Gadolinium on T1 weighted images. A medullary oedema was noted. A toxoplasmosis treatment was initiated, without corticotherapy. MR imaging performed one month later (D30), while important clinical improvements were seen, pointed out normal thickness of conus medullaris, without enhancement after Gadolinium. Disease lesions in AIDS with focal spinal cord processes are reviewed, and diagnostic work-up is discussed. Spinal cord single lesion, associated or not with brain involvements should be treated as a toxoplasmic infection, with MR imaging follow up. This work up should avoid medullary biopsy, still required in case of treatment failure. Cerebral involvements, with multiples lesions, can mask medullary localisation.

[Therapeutic strategies for HIV infection: early response to antiretroviral treatment, predictive factor for the longer term response]. / Réponse précoce au traitement antirétroviral, un facteur prédictif de la réponse à plus long terme.

Despite the wide armamentarium available against the human immunodeficiency virus, the efficacy of therapeutic molecules is reduced by the selection of resistant viral strains. Several data argue in favour of an early control of viral replication ever since the first treatment: the intensity of the initial viral replication, as well as results of studies on antiretroviral drugs given as first line treatment and on the early inhibitory response of viral replication. Although an early control is essential for long-term antiviral success, the optimal time limit for the virologic response still needs to be established early knowledge of the virologic response could prove useful in the evaluation of new and more successful therapeutic combinations. Nevertheless, the impact of an earlier control of viral replication on long-term treatment efficacy and on the prevention of resistance emergence deserves further investigation.