A randomized, controlled, phase II trial comparing escalating doses of subcutaneous interleukin-2 plus antiretrovirals versus antiretrovirals alone in human immunodeficiency virus-infected patients with CD4+ cell counts >/=350/mm3.

A total of 73 patients with baseline CD4+ cell counts >/=350 cells/mm3 who were receiving combination antiretroviral therapy (ART) were randomized to receive subcutaneous interleukin-2 (IL-2; n=36) in addition to ART or to continue ART alone (n=37). Subcutaneous IL-2 was delivered at 1 of 3 doses (1.5 million international units ¿MIU, 4.5 MIU, and 7.5 MIU per dose) by twice-daily injection for 5 consecutive days every 8 weeks. After 24 weeks, the time-weighted mean change from baseline CD4+ cell count was 210 cells/mm3 for recipients of subcutaneous IL-2, compared with 29 cells/mm3 for recipients of ART alone (P<.001). There were no significant differences between treatment groups for measures of plasma human immunodeficiency virus RNA (P=.851). Subcutaneous IL-2 delivered at doses of 4.5 MIU and 7.5 MIU resulted in significant increases in CD4+ cell count (P=.006 and P<.001, respectively), compared with that seen in control patients. These changes were not significant in the 1.5 MIU dose group compared with that in the control patients (P=.105). Side effects that occurred from subcutaneous IL-2 administration were generally low grade, of short duration, and readily managed in an outpatient environment.

Zalcitabina / Zalcitabine

Revisao sucinta quimioterapico antiviral,contendo:emprego clinico,mecanismo de acao,farmacocinetica,efeitos adversos,precaucoes,contra-indicacoes,interacoes medicamentosas,associacoes farmacologicas e posologia.

High-level resistance to zidovudine but not to zalcitabine or didanosine in human immunodeficiency virus from children receiving antiretroviral therapy.

Human immunodeficiency virus type 1 (HIV-1) isolates from children receiving long-term therapy with an alternating regimen of zidovudine and zalcitabine, or with didanosine monotherapy, were evaluated for resistance to zidovudine, zalcitabine, and didanosine, and for mutations known to be associated with zidovudine or didanosine resistance. HIV-1 from four of six patients receiving zidovudine with zalcitabine developed high-level resistance to zidovudine. A mutation in the HIV-1 reverse transcriptase that is highly associated with zidovudine resistance was identified in all four zidovudine-resistant posttherapy isolates. In contrast, none of the HIV-1 isolates from the seven patients receiving didanosine developed high-level resistance to this agent, despite the identification of a didanosine-associated mutation in six of these posttherapy isolates, although small decreases in sensitivity to didanosine were observed. These results indicate that nucleoside analog-associated mutations in HIV-1 occur frequently in children receiving long-term antiretroviral therapy and that alternating combination therapy does not prevent the development of resistance to zidovudine. They also suggest that there may be differences in the degree of resistance conferred by mutations that result from therapy with different nucleoside analogs. These findings underscore the need for studies to define the clinical importance of these mutations, and for treatment strategies to overcome the emergence of viral resistance in vivo.

Didesoxicitidina y zidovudina secuenciales en infección avanzada por virus VIH-1: estudio fase II / Efficacy of sequential dideoxycytidine and zidovudine in stage IV HIV-1 infection: phase II study

Se estudiaron prospectivamente 17 pacientes infectados por VIH-1 tratados con ddC (0.375 mg tid durante 30 días), alternado con AZT (100 mg tid durante 30 días), por periodos de 8 a 32 semanas, medida de 17. Trece pacientes recibieron este tratamiento después de otros antirretrovirales, y cuatro lo recibieron desde el diagnóstico. Antes y después de AZT/ddC, la medida de células CD4 cambió de 184 a 164/uL (p NS), y la media de peso de 60 a 61 kg (p NS). Los parámetros hematológicos mejoraron en pacientes expuestos previamente a AZT. En uno de los cuatro casos desapareció la antigenemia P24 y en tres de nueve disminuyeron los niveles de beta-2-microglobulina sérica. En uno hubo neuropatía periférica sensorial reversible como efecto colateral de ddC y en ocho cedieron efectos adversos de AZT como intolerancia gástrica, cefalea y fiebre. La administración combinada secuencial de AZT/ddC fue bien tolerada y se disminuyó la toxicidad de AZT.

[Sequential dideoxycytidine and zidovudine in advanced HIV-1 infection. Phase II study]. / Didesoxicitdina y zidovudina secuenciales en infección avanzada por virus VIH-1. Estudio fase II.

Seventeen HIV-1-infected individuals were given AZT (100 mg tid) and ddC (0.375 mg tid) for consecutive periods of four weeks each and for total periods ranging from 8 to 32 weeks (median 17). Thirteen patients were offered AZT/ddC after having received other anti-retroviral combinations containing AZT, whereas in four it was used as front therapy. Before and after AZT/ddC, the median CD4 cell count changed from 184 to 164/uL (p NS), and the median body weight from 60 to 61 kg (p NS). Increases in hematological parameters were observed in patients previously exposed to AZT. In eight patients the side effects of AZT (gastrointestinal intolerance, cephalalgia and fever) disappeared when switched to ddC, whereas in one a reversible peripheral neuropathy ensued. The dosages of AZT/ddC used in this trial were well tolerated.

Dideoxycytidine alone and in an alternating schedule with zidovudine in children with symptomatic human immunodeficiency virus infection.

OBJECTIVE: To determine whether a short course of 2',3'-dideoxycytidine (ddC) could provide safe antiretroviral activity in children with symptomatic human immunodeficiency virus infection and whether it could be used with azidothymidine (AZT, zidovudine). The goal was to maintain uninterrupted antiretroviral therapy while sparing AZT-related myelosuppression and ddC-related neuropathy. METHODS: In a pilot study, we evaluated four dosage levels of ddC--0.015, 0.02, 0.03, and 0.04 mg/kg, given orally every 6 hours--in 15 children between 6 months and 13 years of age with Centers for Disease Control P2 (i.e., symptomatic) human immunodeficiency virus infection. Thirteen patients had not had any prior antiretroviral therapy; two patients had received and benefited from AZT, but dose-limiting neutropenia had developed. At each dosage level, ddC was given for 8 consecutive weeks and then stopped. After a 30-day rest, a schedule of ddC for 1 week was followed by 3 weeks of AZT therapy (180 mg/m2 every 6 hours); this alternating schedule was repeated for as long as tolerated. Age-appropriate psychometric testing was performed before the start of ddC therapy and after 8 weeks. RESULTS: During the 8 weeks of therapy with ddC alone, no neutropenia or anemia was observed; 6 of 9 patients had decreases in p24 antigen levels, and 8 of 15 had an increased CD4 cell count. At the 0.04 mg/kg level, a rash developed in three patients; mild mouth sores developed in 9 of 15 patients. On the alternating ddC/AZT schedule, no neuropathy was observed. CONCLUSIONS: 2',3'-Dideoxycytidine has antiretroviral activity in some children and appears to be safe for short intervals. Longer courses of ddC at lower dosage levels, and schedules integrating ddC into combination regimens, deserve to be explored.