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Treatment of central nervous system toxoplasmosis with pyrimethamine/sulfadiazine combination in 35 patients with the acquired immunodeficiency syndrome. Efficacy of long-term continuous therapy.

Thirty-five patients with the acquired immunodeficiency syndrome (AIDS) and central nervous system toxoplasmosis, seen over a 30-month period, were treated with the combination pyrimethamine/sulfadiazine. All patients had clinical and computed tomographic scan findings consistent with active neurotoxoplasmosis. Mean duration of total therapy was six months. During the first two months of therapy, four patients died of acute neurotoxoplasmosis and 31 showed improvement. Of the 24 patients evaluable for long-term therapy, 14 (58 percent) achieved complete resolution and 10 had late clinical (n = 7) and/or computed tomographic scan (n = 6) sequelae. Six patients experienced 10 relapses, which occurred within six weeks of treatment discontinuation in seven of 10. Reintroduction of the combination led to complete resolution of the relapse in eight cases. These clinical results were correlated with brain anatomic findings in the 15 autopsied cases. Side effects, noted in 25 of 35, were mainly hematologic toxicity (n = 21) and cutaneous rash (n = 12). However, the combination had to be definitively stopped in only two cases and sulfadiazine alone had to be withdrawn in eight other cases. These data suggest that pyrimethamine/sulfadiazine is highly efficacious in neurotoxoplasmosis and that life-long therapy is needed to prevent relapses in patients with AIDS.

Changes in blood Cd8+ lymphocyte activation status and plasma Hiv Rna levels during antiretroviral therapy

Objective:To analyse the relationship between CD8+ lymphocyte phenotype alterations and plasma HIV RNA levels in HIV-infected patients treated with the zidovudine–didanosine combination. Methods:A total of 30 HIV-infected patients who had never received antiretroviral therapy and who were starting treatment with a combination of zidovudine and didanosine were prospectively studied. Multiparameter flow cytometric analysis of CD8+ lymphocytes and plasma HIV RNA determination were performed on day 0, day 15 and monthly from months 1 to 6. Results:Patients were divided into three categories according to the time-course of plasma HIV RNA levels. In 14 patients, an early and sustained fall in plasma HIV RNA to below the detection limit (500 copies/ml) was observed; in 10 patients, the fall was transient; in six patients, plasma HIV RNA was always detectable (non-responders). The mean CD4+ lymphocyte gain was 120 × 106/l at month 6 in sustained and transient responders, and 55 × 106/l in non-responders. A significant fall in the proportion of CD8+ lymphocytes with an activated phenotype was observed only in the two groups of responders, and was higher in the sustained responders (CD38+HLA-DR+, −56.8%; CD38+CD45RO+, −54.0%; HLA-DR+CD45RO+, −48.4%; CD38+CD28−, −47.3%). Conclusion:A fall in the proportion of activated CD8+ lymphocytes is associated with the disappearance of HIV RNA from plasma during antiretroviral therapy. Undetectable plasma HIV RNA is not associated with a return to normal CD8+ lymphocyte activation status after 6 months of treatment, suggesting that viral replication persists in lymphoid tissues.

T cell changes after combined nucleoside analogue therapy in HIV primary infection.

OBJECTIVE To characterize the immune changes after treatment of acute HIV-1 infection with triple nucleoside analogue therapy. DESIGN Immunological and virological parameters were monitored from day 0 to weeks 36-44 in eight patients [median CD4 cells = 451 cells/microl (range: 149-624), viral load = 4.8 log10 copies/ml (range: 6.5-3.3)] who started at time of primary HIV infection (PHI) a therapy including zidovudine (ZDV), didanosine (ddl), and lamivudine (3TC). METHODS Lymphoid subsets were evaluated on peripheral blood lymphocytes by four-colour flow cytometry using a panel of mAbs directed against differentiation and activation markers. RESULTS We observed a median -2.1 (range: -1; -3.3) log10 copies/ml viral load decrease and a median +158 cells/microl (range: +7 to +316) CD4 cell count increase at week 4 reaching normal CD4 cell count values of 761 CD4 cells/microl (range: 389-1153) at weeks 36-44. Virus undetectability was obtained at week 24 for all subjects. A rapid CD4 T cell amplification involved both memory and naive CD4 T cells. This was associated with a very rapid and significant decrease in activation markers [human leukocyte antigen-DR (HLA-DR), CD38] on both CD4 and CD8 T cell subsets together with a CD8+CD28+ cell increase as early as week 4. CONCLUSIONS These results show that early therapy with nucleoside analogues can correct the immunological abnormalities observed in CD4 and CD8 T cell subsets at the time of PHI. This early kinetics in T cell recovery appears to be faster than in established disease.

Clinical and echocardiographic observations in pulmonary valve endocarditis.

Clinical and echocardiographic data from 12 patients with pulmonary valve endocarditis are described. Seven patients had isolated pulmonary endocarditis and in 5 patients other valves were infected (aortic, tricuspid, mitral or all 3). Two patients were heroin addicts and 4 had underlying heart disease (congenital heart disease in 3 and aortic regurgitation in 1 patient). The organisms involved were alpha streptococci in 3 patients (all with underlying heart disease), Staphylococcus aureus in 4, Streptococcus D bovis in 1 patient and Candida guillermondii in 1. M-mode and 2-dimensional echocardiography was performed in 10 patients and revealed vegetations in 8. Pulsed Doppler echocardiography was performed in 6 patients and revealed pulmonary regurgitation in all 6. Seven patients had pulmonary emboli. Four patients underwent surgery. Four patients died, including 1 after cardiac surgery. Five patients, including the patient infected with Candida guillermondii, recovered with antibiotic treatment.

Phase II study of liposomal encapsulated daunorubicin in the treatment of AIDS-associated mucocutaneous Kaposi's sarcoma

ObjectiveTo evaluate the efficacy and safety of liposomal encapsulated daunorubicin (DaunoXome) in the treatment of AIDS-associated mucocutaneous Kaposis sarcoma. DesignA Phase II, multicentre, European, non-comparative, open study to assess the use of DaunoXome in patients with no prior anthracycline chemotherapy for Kaposis sarcoma. The response rate, time to disease progression, and the incidence and severity of adverse events were documented. SettingHospital-based HIV units. PatientsThirty HIV-seropositive patients with mucocutaneous Kaposis sarcoma were enrolled and treated. InterventionsTreatment with DaunoXome at a dose of 40 mg/m2 intravenously once every 2 weeks. Treatment with antiretroviral agents and prophylaxis of opportunistic infections where indicated. ResultsOf the 30 evaluable patients, 22 patients (73%) achieved a partial response. Median time to treatment response was 30 days (range, 15–202). For patients with a partial response, median time to treatment failure was 153 days (range, 15–558). Patients received a median of 10 cycles (range, 1–44). Adverse events were minimal. The most common side effect was granulocytopenia in 16 patients (53%). ConclusionDaunoXome is an effective and well-tolerated treatment for AIDS-associated mucocutaneous Kaposis sarcoma and can be administered for prolonged periods. The myelosuppression can be managed by dose reductions and does not preclude the concurrent use of antiretroviral therapies.

Frequency of Cytokine-Producing T Cells in HIV-Infected Patients Treated with Stavudine, Didanosine, and Ritonavir

To assess prospectively the influence of the control of viral replication on the frequency of cytokine-producing T cells, and to correlate these changes with immune activation, we conducted a 15-month follow-up study of IFN-gamma- and IL-2-producing CD4+ and CD8+ T cells at a single-cell level in 12 previously untreated patients receiving highly active antiretroviral therapy (HAART). At baseline we observed a strikingly high proportion of IFN-gamma-producing CD8+ T cells. The treatment-induced decrease in the proportion of IFN-gamma-producing CD8+ T cells ran parallel to the decrease in HLA-DR+ and CD38+CD8+ T cell subsets and was associated with the reduction in HIV RNA level. IL-2-producing cells were mainly CD4+. As a consequence of CD4+ T cell loss, the number of IL-2-producing CD4+ T cells was lower in patients than in control subjects (52 vs. 171 cells/microl), but the proportion of these cells was unchanged (22.4 vs. 19.3). During therapy the proportion of CD4+ IL-2-producing cells was initially stable and then fell markedly at month 5, followed by a gradual return to previous values. The reduction in viral load was associated with the fall in the proportion of CD4+ activated subsets. Intracellular cytokine assays are a new approach to the assessment of T cell function in HIV infection. Our results suggest that the functional capacity of CD4+ T cells is probably less severely altered than previously thought on the basis of conventional assays. CD8+ T cells exhibit an increased capacity to produce IFN-gamma that is associated with an increase in activation marker expression. These alterations decrease partially and in parallel under treatment.

Dapsone as prophylaxis for disseminated Mycobacterium avium complex infection.

Disseminated infection due to the Mycobacterium avium complex (MAC) is the most common systemic bacterial infection among patients with AIDS in developed countries. Usually, the median CD4 cell count in patients with disseminated MAC infection is in the range 10-50/mm3 (1). Rifabutine is the only recommended drug, at the present time, for prophylaxis of disseminated MAC infection (1). Dapsone, a dihydropteroate synthase inhibitor, has been shown to be active in vitro against M. tuberculosis and MAC (2, 3). In addition, dapsone is recommended for prophylaxis of Pneumocystis carinii pneumonia and neurotoxoplasmosis in association with pyrimethamine (4). Thus, dapsone is a potential agent against “multiple opportunistic pathogen prophylaxis”.