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COMPARATIVE TRIAL OF TWO DOSAGES OF ZALCITABINE IN ZIDOVUDINE-EXPERIENCED CHILDREN WITH ADVANCED HUMAN IMMUNODEFICIENCY VIRUS DISEASE

1997; Lippincott Williams & Wilkins; Volume: 16; Issue: 6 Linguagem: Inglês

10.1097/00006454-199706000-00015

1532-0987

Stephen A. Spector, Suzette Blanchard, Diane W. Wara, James M. Oleske, Kenneth McIntosh, David S. Hodes, Wayne M. Dankner, Miklos Salgo, James McNamara,

Pneumocystis jirovecii pneumonia detection and treatment

Human immunodeficiency virus infection type 1 is an increasing problem among children throughout the world.1,2 Although a multicenter clinical trial has demonstrated the efficacy of zidovudine in decreasing the transmission of HIV from an infected mother to her infant,3 there remains an urgent need for improved treatment of those children who are or will become infected with HIV. The current study was performed to evaluate the safety and efficacy of zalcitabine (dideoxycytidine, ddC) in HIV-infected children who had failed or were intolerant of zidovudine. Methods.Study design. The protocol was reviewed and approved by local institutional review boards, and a parent or guardian of all children participating gave written informed consent. All children were HIV-infected and ages 3 months to 18 years. For participation in the study children were required to have symptomatic HIV infection and to have experienced zidovudine intolerance, signs of disease progression after 6 months of zidovudine therapy or both zidovudine intolerance and signs of disease progression after 6 months of zidovudine therapy. (Complete entry criteria are available on request.) The study was designed as a multicenter, open label trial stratified by a combination of disease progression and prior zidovudine experience. The strata were defined as follows: zidovudine-intolerant; disease progression after 6 months of zidovudine therapy; and both zidovudine-intolerant and disease progression. Patients were to be randomized within strata in equal proportions to the two dosages of zalcitabine (0.005 mg/kg or 0.01 mg/kg given every 8 h). Study drug was supplied as a raspberry-flavored syrup in a sorbitol base at a concentration of 0.1 mg/ml. Study participants were evaluated at baseline and every 2 weeks for the first 2 visits and then every 4 weeks for up to 96 weeks. HIV p24 antigen and T cell subset determinations were performed at baseline and every 12 weeks on treatment. Quantitation of plasma HIV RNA was unavailable at the time this study was completed. Neuropsychologic testing was performed at baseline and at every 24 weeks on study. End points. The primary objectives of the study were to evaluate and compare the safety and tolerance of two dosages of zalcitabine taken orally by evaluation of adverse events, laboratory and clinically determined toxicities, with specific emphasis on peripheral neuropathy. The secondary objectives were to evaluate and compare the efficacy of the two dosages of zalcitabine with regard to patient outcome including survival, changes in neurologic examination or neuropsychologic function, time to first occurrence of opportunistic infection, life-threatening infection and neoplasms, growth status as measured by changes in weight z score, change in CD4+ lymphocyte counts and change in quantitative p24 antigen. Statistical analysis. The sample size of 170 children provided ∼80% power to detect a difference of 20% (between 0.15 and 0.35) in rates of severe toxicities or worse with a 5% level of significance (two-sided). The study was reviewed by a Data and Safety Monitoring Board on three occasions that included the final analysis. (A full summary of the statistical analysis performed is available on request.) Results.Study population. The 170 evaluable subjects were enrolled at 52 sites and included in the analyses. Fifty-nine percent of the participants were males, 33% were black and 35% were Hispanic. The median age for all subjects was 5.3 years. The baseline characteristics were similar in the high dosage and low dosage treatment arms (Table 1). The median time of follow-up was 65 weeks with a mean of 66.7 ± 1.2 weeks.TABLE 1: Selected baseline characteristics of study participants Adverse events and drug discontinuation. Of the 170 participants 127 (67 receiving high dosage zalcitabine and 60 receiving low dosage zalcitabine) experienced at least one reportable adverse event. The median time to the first reported adverse event was 113 days for the high dosage group and 184 days for the low dosage group (relative risk, 1.3; 95% confidence interval, 0.91 to 1.84, P = 0.15) (Fig. 1A). There was also no difference in the two groups when the disease status stratification factor was included in the model (P = 0.17). The time to first reportable adverse event curves were further examined by stepwise regression methodology to define a Cox model. The variables under investigation were dosage group, disease stratification, baseline age categorized as <2 years of age and ≥2 years of age, baseline p24 antigen categorized as <25 pg/ml or ≥25 pg/ml and baseline CD4+ lymphocyte count categorized as <100 cells/mm3 or ≥100 cells/mm3. The analysis included the 119 patients who had measurements for p24 antigen and CD4+ lymphocytes at baseline. The significant variables in the model were treatment (P = 0.08) and baseline age (P = 0.017). The relative risk of an adverse event was 1.37 (95% confidence interval, 0.96 to 1.97) times higher in the high dosage group than the low dosage group, given the same baseline age category. The relative risk of an adverse event in the baseline age ≥2 years group was 0.59 (95% confidence interval, 0.27 to 0.72) times that of having an adverse event in the <2 years age group. A summary of hematologic and chemistry abnormalities, including the number of patients who experienced an event, the number of patients observed and the 1-year Kaplan-Meier rate are provided in Table 2.Fig. 1: Time to first reportable adverse event (A) and first AIDS-defining opportunistic infection, neoplasm, serious bacterial infection or death receiving either high dosage or low dosage zidovudine (B). Hatch line, low dosage; solid line, high dosage.TABLE 2: Frequency of hematologic toxicities and abnormal blood chemistries by dosage groups Peripheral neuropathy related to zalcitabine, defined as either documented or probable, occurred in a total of 8 (5%) study participants including 4 children receiving high dosage and 4 children receiving low dosage zalcitabine. The median time to development of peripheral neuropathy for these 8 children was 173 days (range, 30 to 384 days). No child experienced severe symptoms associated with the peripheral neuropathy and none had permanent sequelae secondary to zalcitabine peripheral neuropathy. Survival. Of the 170 study participants 25 children had died in the high dosage group and 27 in the low dosage group (relative risk, 0.94; 95% confidence interval, 0.54 to 1.6; P = 0.8). The cause of death was considered by investigators to be primarily HIV disease-related. Factors impacting on survival were examined with a Cox regression model including treatment, disease stratification, baseline age, baseline p24 antigen and baseline CD4+ lymphocyte counts. Only baseline CD4+ lymphocyte count was an important determinant in this model (P = 0.002). The relative risk of death in children with CD4+ lymphocyte counts ≥100 cells/mm3 was 0.28 times (95% confirmed interval 0.12 to 0.63) that of children with baseline CD4+ lymphocytes 100 cells/mm3 was 0.42 (95% confidence interval, 0.25 to 0.7) times that in the baseline CD4+ group (<100 cells/mm3). The relative risk of an event was 1.63 (95% confidence interval, 1.05 to 2.57) times greater in the p24 antigen positive group than for those with p24 antigen <25 pg/ml at baseline given the same CD4+ lymphocyte category. No significant differences between the two dosage groups were observed for neurodevelopment (P = 0.85). Impact of ddC treatment on p24 antigen. Of the 170 study participants 65 had a positive p24 antigen determination at baseline, and of those the response outcome of a 50% decrease from baseline could be defined in 56 (high dosage, 29; low dosage, 27) participants. Thirty-two (high dosage, 15; low dosage, 17) of the 56 (57%) participants available for the analysis, experienced a ≥50% decline in p24 antigen from baseline. Using a Wilcoxon rank sum test there was no difference in the percent change from baseline between the two dosage groups at Weeks 12 (P = 0.24), 24 (P = 0.33) or 36 (P = 0.83). Pooling the data for the two dosage groups, there was a significant decrease in p24 antigen at Week 12 (Wilcoxon signed rank; P = 0.02, n = 58); however, the decrease at Weeks 24 and 36 was not statistically significant (Week 24; P = 0.94, n = 52; Week 36; P = 0.59, n = 39). Impact of zalcitabine on weight. The effect of treatment on weight was analyzed for all 170 patients using data through the first 294 days on study. A random effects model was used to test whether changes in weight z-score were different in the two dosage groups. No significant difference between the two treatment groups was observed (P = 0.6). However, there was a difference in the slopes of the disease status strata overtime on study (P = 0.03). The slopes for the disease strata were 0.28, −0.36 and −0.39 standard deviations per year, for intolerant, progressed, and intolerant/progressed strata, respectively. Impact of zalcitabine on CD4+ lymphocyte counts. The median CD4+ lymphocyte count was 51/mm3 at baseline for the 156 study participants with available data (high dosage, 60/mm3; low dosage, 48/mm3). CD4+ lymphocyte data were available for 167 study participants and all data from the first 294 days on study were used in the analyses. A significant difference in the slopes of the 2 treatments (P = 0.04) favoring the low dosage treatment group was observed. The decline in CD4+ lymphocyte count in the high dosage group was 1.27 times that of the low dosage group. This difference represents a difference in CD4+ cell decline of ∼5% per month. However, in absolute numbers the median CD4+ lymphocyte count after 36 weeks of therapy declined from 60/mm3 to 22/mm3 for the high dosage group vs. 48/mm3 to 39/mm3 for the low dosage group. There was also a significant difference in the slopes of the strata (P = 0.05). The slopes of the intolerant and progressed strata were different from the intolerant/progressed stratum but not from each other (high dosage: intolerant, 0.14; progressed, −0.29; intolerant/progressed, −0.85; low dosage: intolerant, 0.13; progressed, −0.02, intolerant/progressed, −0.58). Discussion. The current study has demonstrated that zalcitabine is generally well-tolerated by children with advanced HIV-related disease who have been intolerant or have experienced disease progression while receiving zidovudine. Furthermore there appears to be no clear advantage to patients receiving zalcitabine at 0.01 mg/kg over the 0.005-mg/kg dosage. However, the current study was not sufficiently powered to demonstrate a clinical benefit of one treatment group over the other. Additionally a study by Chadwick et al.4 suggested that children receiving the 0.01-mg/kg/dose of zalcitabine have lower serum concentrations of drug than would be expected. Thus for most children an initial dosage of zalcitabine of 0.01 mg/kg/dose would appear most reasonable and will usually be well-tolerated. However, if there is a need to reduce the dosage of zalcitabine, lowering the treatment dosage to 0.005 mg/kg appears likely to be efficacious. Additionally the findings of this study suggest that zalcitabine may be a useful drug for children with advanced HIV disease. As increasing information regarding antiretroviral therapies has become available, it appears that combination therapy is of benefit in early as well as late treatment of HIV-infected persons.5 The toxicity profile of zalcitabine in children would appear to be compatible with combining zalcitabine with other antiretrovirals. The studies in adults demonstrating the efficacy of zalcitabine used as a single agent6-8 or in combination with zidovudine9,10 further support the use of zalcitabine in HIV-infected children. Moreover a recent study completed by the Pediatric AIDS Clinical Trial Group (ACTG 190) as well as an earlier Phase I study of zalcitabine alternating with zidovudine have demonstrated that zalcitabine combined or alternating with zidovudine is well-tolerated by children.11,12 Thus zalcitabine is tolerated by children and should be considered when developing antiretroviral combinations for the treatment of children infected with HIV. Acknowledgments. Sponsored by the Pediatric AIDS Clinical Trials Group funded through the National Institute of Allergy and Infectious Diseases and the National Institute of Child Health and Human Development. Stephen A. Spector, M.D. Suzette Blanchard, Ph.D. Diane W. Wara, M.D. James M. Oleske, M.D. Kenneth McIntosh, M.D. David Hodes, M.D. Wayne M. Dankner, M.D. Miklos Salgo, M.D. James McNamara, M.D. The Pediatric AIDS Clinical Trials Group University of California, San Diego; La Jolla, CA (SAS, WMD) Harvard School of Public Health; Boston, MA (SB) University of California; San Francisco, CA (DWW) New Jersey Medical School and Children's Hospital of New Jersey; Newark, NJ (JMO) Boston Children's Hospital; Boston, MA (KM) Mt. Sinai Medical Center; New York, NY (DH) Hoffman La-Roche, Inc. Nutley, NJ (MS) National Institute of Allergy and Infectious Diseases; Division of AIDS; Bethesda, MD (JM)