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Oral didanosine treatment appears to improve CD4 cell counts over the long term in some children with HIV infection. Didanosine is also known as DDI. CD4 cells are component of the immune system and are measured to evaluate immune system functioning. A group of 103 children with HIV infection, ranging in age from 6 months to 18 years, underwent didanosine therapy. Children had symptomatic HIV infection or a CD4 count of less than 500. Median length of therapy was 23 months. The CD4 count increased in 32% of patients after six months of therapy. Forty-one percent of these children improved CD4 counts for three years. The probability of survival for the 51 children with CD4 counts greater than 100 at the beginning of the study was 80% versus 39% for children with CD4 counts below that level. Treatment was discontinued in 11 children because of side effects and in 34 because of disease progression despite treatment., Background. Didanosine has demonstrated promising antiviral activity and a tolerable toxicity profile in short term studies. We describe a cohort of HIV-infected children who were treated for a prolonged period of time with didanosine. Methods. Children (6 months to 18 years of age) with symptomatic HIV infection or an absolute CD4 count < 0.5 x [10.sup.9] cells/L, received oral didanosine at doses between 20 mg/[m.sup.2] to 180 mg/[m.sup.2] every 8 hours. Clinical, immunological, and virological parameters were assessed at least every 2 months. The pharmacokinetics of didanosine were evaluated in 85 patients. Results. Previously untreated children (n = 51) and children who had received prior antiretroviral therapy (n = 52) were enrolled in the study (median time on study 22.6 months, range 2 to 48). The long-term administration of didanosine was well tolerated and no new toxicities were observed. The absolute CD4 count increased by [greater than or equal to] .05 x [10.sup.9] cells/L in 28 of 87 (32%) of patients after 6 months of therapy. Responses were also sustained in 41% of these children after 3 years of therapy. Children entering the study with a CD4 count > 0.1 x [10.sup.9] cells/L (n = 51) had a marked survival advantage (P = .00002) with an estimated survival probability after 3 years of 80% compared to 39% for children with lower CD4 counts. Although the area under the curve of didanosine increased proportionally with the dose, there was considerable interpatient variability at each dose level. There was no apparent relationship between surrogate markers of clinical outcome and plasma drug concentration. Conclusions. Didanosine was well tolerated with chronic administration, and toxicities were uncommon and usually reversible. In 41% of patients, the CD4 count increased and was maintained at the higher level even after years of treatment. Pediatrics 1994;94:724-731; HIV, didanosine, survival, toxicities, CD4 counts, pharmacokinetics, child.

Combined therapy with zidovudine (AZT) and didanosine (ddI) may benefit children with HIV infections more than either drug alone. Researchers administered varied doses of combined therapy and evaluated the outcome of 49 children who were previously untreated and 12 who had prior AZT-related toxicity. The patients tolerated AZT and ddI well at all dose levels and showed no evidence of new or enhanced toxicity. Fifty-one children gained weight while on the combined therapy program. After 24 weeks, the midpoint CD4 cell count increased from 331 to 556 cells per millimeter cubed for all patients. Among the previously untreated group, cell counts increased from 386 to 726 cells per millimeter cubed. CD4 cells are immune cells that are depleted as HIV infection progresses to advanced immune deficiency disease. Of 36 samples tested for HIV, only eight were positive after combination treatment, compared to 24 at the beginning of the study., Objective. Zidovudine and didanosine are both beneficial for the treatment of human immunodeficiency virus (HIV) infection in children. Because disease progression and toxicity often limit their long-term use as single agents, new approaches to using nucleoside analogues are necessary to improve current antiretroviral therapy. Design. We conducted a phase I-Il study to evaluate the tolerance, pharmacokinetics, and antiviral activity of the combination of zidovudine and didanosine in children with HIV infection. Sixty-eight children who were either previously untreated or who had manifested hematologic toxicity on full-dose zidovudine were enrolled. Eight dose combinations were studied in the previously untreated children, with doses of zidovudine ranging from 90 to 180 mg/[m.sup.2] every 6 hours and doses of didanosine ranging from 90 to 180 mg/[m.sup.2] every 12 hours. Results. Fifty-four previously untreated HIV-infected children were enrolled in this part of the study, of whom 49 remained in the study for a minimum of 24 weeks. For children with previous zidovudine-related hematologic toxicity, three dose levels with zidovudine at 60 mg/[m.sup.2] every 6 hours orally and didanosine ranging from 90 to 180 mg/[m.sup.2] every 12 hours orally were used. A total of 14 children were enrolled in this part of the study, and 12 remained on therapy for at least 24 weeks. No evidence of new or enhanced toxicity was observed in either group. After 24 weeks, the median CD4 cell count for all patients increased from 331 to 556 cells/[mm.sup.3] (P = .01). For the previously untreated group, the median increase in CD4 counts was from 386 to 726 cells/[mm.sup.3] (P = .003). The median p24 antigen concentration (in those with a detectable level at baseline) decreased from 95 to

High doses of dideoxyinosine (ddI) may cause pancreatitis in children with HIV infection. ddI is a drug used to treat HIV infection in patients who are resistant to zidovudine (AZT). Among 95 HIV-positive children between three months and 18 years old who had been treated with ddI for an average of 56 weeks, 7% developed pancreatitis. Their symptoms resolved when they stopped taking the drug. All the episodes of pancreatitis occurred in patients treated with 360 milligrams or more of ddI per square meter per day. The risk of pancreatitis recurrence is high in patients who resume treatment with a high dose of ddI. Treatment with a reduced dose lowers this risk significantly., To define predictive or contributory risk factors for pancreatitis in human immunodeficiency virus-infected children receiving dideoxyinosine (ddI), the authors evaluated 95 children, 3 months to 18 years of age, who had received ddI at 66 to 540 mg/[m.sup.2] per day for a mean of 56 weeks. Pancreatitis developed in 7 patients (7%) but resolved in all upon withdrawal of ddI. Neither age, sex, nor CD4 count at study entry was predictive of pancreatitis, but pancreatitis appeared more likely to develop in hemophiliacs than in other patients (4 of 23 vs 3 of 72). Pancreatitis developed only in patients who received ddI at the highest dose levels (7 of 60 patients who received ddI at a dose [is greater than or equal to] 360 mg/[m.sup.2] per day vs 0 of 35 patients who received [is less than or equal to]270 mg/[m.sup.2] per day). Patients in whom pancreatitis developed had received a higher mean daily dose of ddI than patients with normal amylase and lipase levels throughout the study (348 mg/[m.sup.2] vs 282 mg/[m.sup.2]), but no relationship with the cumulative dose or the duration of ddI therapy was observed. Although a statistically significant relationship between ddI plasma concentration (area under the curve) and pancreatitis was not conclusively demonstrated, as the number of patients in whom pancreatitis actually developed was small, such a relationship may have been obscured. The mean interval from initiation of ddI to onset of symptoms of pancreatitis (25 weeks) was significantly shorter than the overage duration of ddI therapy (56 weeks), and, consequently, patients in whom pancreatitis developed had been exposed to a lower cumulative dose of ddI than those with normal amylase and lipase levels (64.5 g/[m.sup.2] vs 119.06 g/[m.sup.2]). Although baseline amylase values did not correlate with the development of pancreatitis, elevation of baseline aspartate aminotransferase and alanine aminotransferase levels was significantly associated with the later development of pancreatitis. Pediatrics 1993,91:747-751, pancreatitis, dideoxyinosine, human immunodeficiency virus, antiretroviral therapy.

The safety, tolerability, pharmacokinetic profile, and preliminary activity of lamivudine (2′deoxy-3′-thiacytidine), a novel cytidine nucleoside analogue with antiretroviral activity, in human immunodeficiency virus (HIV)-infected children beyond the neonatal period were studied. Ninety children received dosages of 1–20 mg/kg/day. Pharmacokinetic evaluation demonstrated serum and cerebrospinal fluid concentrations that increased proportionally to dose. As of January 1994, 11 children had been withdrawn from study for disease progression and 10 because of possible lamivudine-related toxicity, and 6 had died. CD4 and CD8 cell counts remained stable over 24 weeks in therapy-naive children and decreased slightly in previously treated children. Quantitative immune complex-dissociated p24 antigen and HIV RNA were decreased significantly at 12 and 24 weeks. In vitro resistance to lamivudine was documented in sequential virus isolates from some patients by 12 weeks. Lamivudine was well-tolerated and exhibited virologic activity in children, although future use in children is likely to be in combination antiretroviral regimens. [ABSTRACT FROM PUBLISHER]

Adolescents should be enrolled in ethically appropriate and scientifically rigorous HIV biomedical prevention research involving vaccines, pre-exposure prophylaxis, or microbicides. There is general agreement that children should only be enrolled in a clinical trial if the scientific objectives cannot be met either through enrolling adult subjects who can provide informed consent personally or through conducting research using animal models. In addition, the risks to which children are exposed in a clinical trial without the possibility of direct therapeutic benefit must be low. Children also should not be placed at a disadvantage after being enrolled in a clinical trial by, for example, being exposed to an unnecessarily risky intervention or by failing to receive a comparable treatment that would prevent significant morbidity or mortality. In light of this shared framework, we discuss the timing of enrolling adolescents in HIV prevention trials; some general study design considerations that may be necessary for adequate labeling of products for an adolescent indication; the use of data obtained from international studies for licensure applications in the United States; the role of parental permission and adolescent assent to research participation; and the inclusion of pregnant adolescents in HIV biomedical prevention research.