Determination of dosing guidelines for stavudine (2',3'-didehydro-3'-deoxythymidine) in children with human immunodeficiency virus infection.

The results of the development of dosing guidelines for stavudine in human immunodeficiency virus (HIV)-infected children are summarized. Included in the integrated analyses were 21 and 33 HIV-infected pediatric and adult patients, respectively, from three phase I-II studies. Data for 21 children and 18 adults who received intravenous doses of 0.125 to 2 and 0.5 to 1 mg/kg of body weight, respectively, were used for the determination of dosing guidelines; exposure data for 16 children and 15 adults who received oral doses of 1 to 2 and 0.5 to 1 mg/kg/day, respectively, were used to validate the dosing recommendations for children. Significant relationships were observed between total body clearance (in milliliters per minute) in children and adults combined and demographic parameters of age, body weight, and body surface area (R(2) = 0.77 to 0.80; P = 0.0001). Models of approximated pediatric dose based on clearance values and direct adult exposure yielded a stavudine dosage of 2 mg/kg/day for children of < or =30 kg of body weight and 1 mg/kg/day (adult dose) for children of >30 kg of body weight.

Safety and antiretroviral effects of combined didanosine and stavudine therapy in HIV-infected individuals with CD4 counts of 200 to 500 cells/mm3.

The safety and antiretroviral effects of didanosine and stavudine in combination were evaluated in 86 people infected with HIV with CD4 counts between 200 and 500 cells/mm3 who had received <7 days of prior nucleoside analogue antiretroviral treatment. Patients were randomized to receive blinded treatments with one of five weight-adjusted, twice-daily regimens of didanosine and stavudine (100 + 10 mg, 100 + 20 mg, 100 + 40 mg, 200 + 20 mg, and 200 + 40 mg) for up to 1 year. Dosages were adjusted appropriately for patients weighing <60 kg and reduced in response to adverse effects. No clear dose-related differences among treatment groups were detected with regard to suppression of plasma HIV RNA level or reduction in infectious titers in peripheral blood mononuclear cells (PBMCs), improvement in CD4 count, or adverse effects. However, trends toward greater decreases in viral load and increases in CD4 count were detected when treatment groups containing the full recommended dosage of one or both agents (high-dose subgroup; arms 3, 4, and 5) were compared with the groups receiving lower dosages. At 28 weeks the mean log 10 HIV RNA decrease was 1.12 (n = 52) and at 52 weeks it was 0.97 (n = 32). Combination therapy was well tolerated, with no apparent dose-related adverse effects. Peripheral neuropathy occurred in 2 of 86 (2.3%) of patients. Didanosine and stavudine together appear to be a good nucleoside analogue foundation for aggressive triple- or quadruple-drug therapy. Full therapeutic doses of each of these two agents should be used to achieve optimal suppression of HIV replication.

The safety profile and antiviral activity of the combination of stavudine, didanosine, and nelfinavir in patients with HIV infection.

We assessed the safety profile, tolerability, and antiviral effect of 12 weeks of triple combination therapy with stavudine (d4T), didanosine (ddI), and nelfinavir in patients who had not previously received therapy with d4T, ddI, or a protease inhibitor. We also assessed the effect of the buffered tablet formulation of ddI on the pharmacokinetics of nelfinavir. The study had a single-arm, open-label design and enrolled patients aged > or =18 years who had HIV infection and > or =10,000 plasma HIV RNA copies/mL. Patients received the full recommended doses of oral d4T, ddI, and nelfinavir. Efficacy was assessed in terms of change from baseline in plasma HIV RNA and CD4+ cell counts, as well as in terms of the proportion of patients achieving HIV RNA levels <400 copies/mL. The first 10 patients enrolled in the study were included in a substudy to determine the effects of the buffered tablet formulation of ddI on the pharmacokinetic profile of nelfinavir. A dose of ddI was given 1 hour before nelfinavir, after which the maximum plasma concentration (Cmax), time to Cmax (Tmax), and area under the concentration-time curve (AUC) of nelfinavir were determined. A total of 22 patients entered the trial, of whom 1 (5%) had AIDS, 12 (55%) had symptomatic HIV infection, and 9 (41%) were asymptomatic. The median baseline CD4+ cell count was 315 cells/microL (range, 70-709 cells/microL), and the median plasma viral load was 4.8 log10 copies/mL (range, 4.0-5.6 log10 copies/mL). ddI had no clinically significant effects on the plasma pharmacokinetics of nelfinavir. At the end of 12 weeks of treatment, the mean (+/- SE) decrease in plasma viral load was 1.36+/-0.24 log10 copies/mL, and 8 of 16 patients (50%) achieved plasma HIV RNA levels <400 copies/mL; the mean (+/- SE) increase in CD4+ cell count was 111.4+/-31.7 cells/microL. Patients who were judged to be compliant with antiretroviral therapy (ie, who missed <7 days of all 3 study drugs during 12 weeks of treatment) experienced mean decreases in viral load exceeding 2.0 log10 copies/mL, and 6 of 7 patients achieved HIV RNA levels <400 copies/mL after 12 weeks of therapy. Although 95% of patients reported an adverse event of grade 1 or higher, only 1 patient experienced a grade 3 or 4 adverse event (maculopapular rash) related to nelfinavir. As reflected in the Cmax, Tmax, and AUC, administration of ddI 1 hour before nelfinavir did not influence the pharmacokinetic profile of the protease inhibitor. Triple drug therapy with d4T, ddI, and nelfinavir was well tolerated and associated with few clinically significant toxicities. This treatment resulted in substantial reductions in viral load and improvements in CD4+ cell count over 12 weeks.

A single-dose study to assess the penetration of stavudine into human cerebrospinal fluid in adults.

Penetration of stavudine into the cerebrospinal fluid (CSF) was studied in healthy humans. In this open, randomized study, a single oral dose of 40 mg of stavudine was given to 12 fasting volunteers > or = 18 years of age. Subjects were divided into three groups based on the time of CSF sampling (i.e., 0.75-1.25, 2-3, or 4-5 hours after dosing). Blood samples were collected over an 8-hour period after dosing and included a sample simultaneous with CSF collection to permit an estimate of CSF : plasma ratios. Stavudine concentrations in plasma and CSF were determined by a validated high-performance liquid chromatography method. Repeated measurements of vital signs, physical examination, and clinical laboratory tests indicated that the stavudine dose was well tolerated. CSF levels were not detected 0.75 to 1.25 hours after dosing. Thereafter, levels were detected in the CSF of five subjects; the mean concentration was 61 ng/ml. The mean CSF: plasma ratio increased with time, from 0.16 at 2 to 3 hours postdose in one subject to 0.40 at 4 to 5 hours postdose in four subjects. In conclusion, the mean stavudine concentration of 61 ng/ml achieved in the CSF of five subjects exceeds the ED50 of clinical isolates of HIV (230 nM, 52 ng/ml).

Combination therapy with stavudine and didanosine in children with advanced human immunodeficiency virus infection: pharmacokinetic properties, safety, and immunologic and virologic effects.

OBJECTIVES: To obtain preliminary information on the pharmacokinetic properties, tolerance, safety, and antiviral activity of combination therapy with stavudine and didanosine in children with advanced human immunodeficiency virus (HIV) infection. METHODS: Eight children (median age, 6.6 years; range, 2.8 to 12 years) with advanced HIV disease (median CD4 + lymphocyte count at baseline, 42 cells/ microL; range, 8 to 553 cells/microL) were treated with stavudine (2 mg/kg per day in two divided doses) and didanosine (180 mg/m2 per day in two divided doses) for 24 weeks. Seven children had histories of prior zidovudine therapy. All children had received stavudine alone for 19 to 33 months before the addition of didanosine to the treatment regimen. Children were assessed clinically and with laboratory studies at baseline, weekly through week 4 of combination therapy, and every 4 weeks thereafter. RESULTS: Analysis of stavudine and didanosine plasma half-life values, clearances, and area under the plasma concentration-versus-time curves revealed no obvious clinical pharmacokinetic interaction between the drugs through study week 12. Combination therapy was well tolerated, and there were no drug-associated clinical or laboratory adverse events. Signs and symptoms of peripheral neuropathy were not observed. All three children with baseline CD4 + lymphocyte counts greater than 50 cells/muL had greater than 20% increases in their counts within the first 12 weeks of therapy; CD4 + lymphocyte count increases were not observed in the other children. Plasma HIV RNA concentrations showed median declines of 0.88 log10 (range, -3.41 log10 to 0.31 log10) and 0.30 log10 (range, -0.63 log10 to 0.89 log10) at study weeks 12 and 24, respectively. CONCLUSIONS: Combination therapy with stavudine and didanosine was well tolerated and safe in this small group of children with advanced HIV disease. Plasma HIV RNA concentration declines suggest a favorable effect of therapy on virus load. These findings should be confirmed, and the regimen's clinical efficacy should be examined, in controlled studies of HIV-infected children with less-advanced disease.

A phase I/II evaluation of stavudine (d4T) in children with human immunodeficiency virus infection.

OBJECTIVES: To determine the pharmacokinetic properties, tolerance, safety, and preliminary activity of stavudine in human immunodeficiency virus (HIV)-infected children. DESIGN: Phase I/II, open and dose-ranging (0.125 to 4 mg/kg/day in two divided doses). PATIENTS: Thirty-seven HIV-infected children (median age, 5.5 years; range, 7 months to 15 years) with a median CD4+ lymphocyte count at baseline of 242 cells/microL (range 2 to 2290 cells/microL). Thirty children had symptomatic HIV disease at entry; seven had HIV-related immunosuppression alone. Twenty-nine subjects had a history of prior zidovudine (ZDV) therapy. RESULTS: As compared with adults receiving the same weight-adjusted doses, the children we studied had lower maximum observed stavudine plasma concentrations (CMAX) and area under the plasma concentration versus time curves (AUC), and more rapid stavudine elimination. The absolute oral bioavailability of the drug ranged from 61% to 78%. There was no plasma accumulation of the drug between day 1 and week 12. Week 12 cerebrospinal fluid stavudine concentrations in seven subjects, obtained approximately 2 to 3 hours after oral doses, ranged from 16% to 97% of concomitant plasma concentrations. Stavudine was well-tolerated and there were no dose-related clinical or laboratory adverse events. One subject with baseline neurologic abnormalities experienced a transient episode of apparent pain or discomfort in her fingers, possibly related to stavudine. All other adverse events were attributed to underlying disease. Stavudine activity, measured indirectly by CD4+ lymphocyte count and serum p24 antigen concentration changes, was observed in some subjects. Progression of HIV disease and survival correlated with prior ZDV therapy, HIV disease classification, baseline CD4+ lymphocyte count, and weight growth velocity. CONCLUSIONS: Stavudine appears to hold promise for the treatment of HIV infection in children. Its pharmacokinetic properties are consistent and predictable, and it appears to be remarkably well-tolerated and safe. Although our study was not designed to assess the drug's efficacy, preliminary clinical and laboratory evidence of activity was observed.

Design and implementation of the stavudine parallel-track program.

In a randomized, double-blind, large, simple trial, the safety and efficacy of two weight-adjusted dose levels of stavudine were evaluated in patients with advanced human immunodeficiency virus (HIV) infection. All patients were refractory to or intolerant of both zidovudine and didanosine. Patients weighing > or = 60 kg received 20 or 40 mg of stavudine twice daily. The dose was reduced to 15 or 30 mg for patients weighing 40-59 kg and to 10 or 20 mg for those weighing < 40 kg. The primary efficacy end points were survival and time to clinical progression of HIV disease. The primary safety end point was time to dose-limiting neuropathy. A total of 8127 patients were enrolled as of 31 July 1993. Although many patients who might have benefitted from stavudine were reached by the parallel-track program, a review of demographic data revealed disproportionate representation by white men from large metropolitan areas on both coasts.

Stavudine in patients with AIDS and AIDS-related complex: AIDS clinical trials group 089.

In a phase I trial of stavudine in AIDS or AIDS-related complex (ARC), antiviral effects and safety were assessed in 41 patients treated with dosages of 0.5-12.0 mg/kg/day. Among evaluable patients, 10% increases in CD4 lymphocyte counts were sustained in 24 (60%) of 40 during treatment; an NAUC response (normalized area under the CD4 cell count-versus-time curve > 1.0) was observed in 31 (91%) of 34 at 10 weeks and in 20 (80%) of 25 at 24 weeks; 15 (83%) of 18 had decreases in p24 antigenemia; and 24 (60%) of 40 gained > or = 2.5 kg body weight. Median CD4 lymphocyte levels remained above baseline for 6 months in patients receiving > 0.5 mg/kg/day. Median serum p24 antigen levels remained below baseline for > or = 1 year in patients with p24 antigen responses. The principal toxicity was peripheral neuropathy, which generally resolved after drug discontinuation but limited the dosage to < or = 2.0 mg/kg/day. Additional trials assessing the effect of stavudine on overall morbidity and mortality are ongoing.

Dose-related activity of stavudine in patients infected with human immunodeficiency virus.

In a multicenter, randomized, open-label, dose-ranging study to determine the relative effects of three dose levels of stavudine on CD4 lymphocyte count, weight gain, and hematologic variables in patients infected with human immunodeficiency virus (HIV), 152 patients with CD4 lymphocyte counts < or = 600/mm3 received stavudine at 0.1 mg/kg/day (n = 51), 0.5 mg/kg/day (n = 53), or 2.0 mg/kg/day (n = 48). The study was designed to evaluate the activity of stavudine after 10 weeks of therapy and permitted extended dosing and follow-up for long-term safety. A significant dose effect on increases in CD4 lymphocyte counts and declines in HIV titer in peripheral blood mononuclear cells was observed. Stavudine was well-tolerated; the only dose-related, dose-limiting adverse event was peripheral neuropathy, which usually was reversible. In this trial, the most favorable therapeutic index was seen at 0.5 mg/kg/day.

Analysis of potential risk factors associated with the development of pancreatitis in phase I patients with AIDS or AIDS-related complex receiving didanosine.

Phase I dose-escalating trials of didanosine revealed dose-limiting toxicities, including pancreatitis, and established a total daily dose of 12.5 mg/kg/day as the maximum tolerated dose. Clinical and pharmacokinetic data of 61 patients from two trials were analyzed to further evaluate the risk of pancreatitis: 1 (6.3%) of 16 patients who received < 500 mg/day didanosine, 2 (13.3%) of 15 who received 500-750 mg/day, and 15 (50%) of 30 who received > 750 mg/day developed pancreatitis (P < .001). A relationship between risk of pancreatitis and steady-state plasma concentrations of didanosine and age was also observed, suggesting that knowledge of didanosine pharmacokinetics provided additional information regarding risk of toxicity. Further confirmation of these findings will be necessary to determine if the risk factors for pancreatitis remain the same at lower doses currently used.

Didanosine compared with continuation of zidovudine in HIV-infected patients with signs of clinical deterioration while receiving zidovudine. A randomized, double-blind clinical trial. The Bristol-Myers Squibb AI454-010 Study Group.

OBJECTIVE: To determine the benefits of switching to didanosine compared with continuing zidovudine among patients infected with human immunodeficiency virus (HIV) who have previously used zidovudine and have signs of clinical deterioration. DESIGN: Randomized, double-blind, two-armed, parallel, comparative clinical trial with a blinded, compassionate crossover provision at 12 weeks. SETTING: Outpatient clinics at 19 tertiary care medical centers. PATIENTS: 312 patients infected with HIV who had received zidovudine for 6 months or more, had CD4 cell counts of 300/mm3 or less, and had signs of clinical deterioration within 12 weeks before study entry. INTERVENTION: Peroral didanosine tablets (600 mg/d adjusted for weight, "high dose") or zidovudine capsules (600 mg/d). MEASUREMENTS: Primary study end points were death, a new acquired immunodeficiency syndrome (AIDS)--defining event, or the combination of two new or recurrent HIV-related diagnoses with a 50% decrease in CD4 cells. RESULTS: Switching to didanosine was associated with fewer end points than continuing zidovudine (relative risk [RR] for zidovudine:didanosine = 1.5; 95% Cl, 1.1 to 2.0). This benefit was consistent across subgroups of patients with either AIDS-related complex or AIDS and was most apparent among those with a CD4 count at entry of 100/mm3 or more (RR = 2.2; Cl, 1.1 to 4.4). CONCLUSIONS: This study shows a positive treatment effect for switching from zidovudine to didanosine among patients with either AIDS-related complex or AIDS and validates the common practice of using clinical signs or a decrease in the CD4 count as an indication for changing therapy.

Acyclovir treatment of varicella in otherwise healthy adolescents. The Collaborative Acyclovir Varicella Study Group.

STUDY OBJECTIVE: To determine whether orally administered acyclovir is of therapeutic benefit for varicella in otherwise healthy adolescents, and to compare the severity of the disease in adolescents with that in younger children. DESIGN: Multicenter, randomized, placebo-controlled, double-blind trial. SETTING: Patients' homes and university hospital clinics. PATIENTS: Sixty-eight adolescents between 13 and 18 years of age with varicella entered the study. Of the 62 adolescents with laboratory-confirmed varicella who were included in the final analysis, 31 received acyclovir and 31 received placebo. INTERVENTIONS: Placebo or an 800 mg acyclovir tablet was given orally four times daily for 5 days, beginning within 24 hours of onset of rash. MEASUREMENTS AND MAIN RESULTS: Acyclovir recipients had significant reductions in times to cessation of new lesion formation (p less than 0.001), maximum number of lesions (p = 0.019), and defervescence (p = 0.045). Mean constitutional illness score was significantly reduced on day 4 (0.5 vs 1.5, p = 0.05), as was the mean number of residual hypopigmented lesions present on 28-day follow-up examination (22.7 vs 92.7, p = 0.018). Two complications, both bacterial superinfections, occurred in placebo recipients. Adverse experiences and varicella-zoster virus antibody titers measured 28 days after enrollment were similar in both treatment groups. Comparison of placebo recipients with children 2 to 12 years of age participating in a companion study indicated that varicella is more severe in adolescents: mean maximum total lesions (421 vs 347, p = 0.003), mean maximum constitutional illness score (3.1 vs 2.2, p = 0.032), and mean number of residual lesions (92.7 vs 33.2, p = 0.01) were all greater in the adolescent population. CONCLUSIONS: Oral acyclovir therapy is safe and effective for treatment of varicella in otherwise healthy adolescents; this may be an appropriate subgroup for treatment with antiviral drugs because the disease is more severe in them than in younger children.

A controlled trial of acyclovir for chickenpox in normal children.

BACKGROUND: Chickenpox, the primary infection caused by the varicella-zoster virus, affects more than 3 million children a year in the United States. Although usually self-limited, chickenpox can cause prolonged discomfort and is associated with infrequent but serious complications. METHODS: To evaluate the effectiveness of acyclovir for the treatment of chickenpox, we conducted a multicenter, double-blind, placebo-controlled study involving 815 healthy children 2 to 12 years old who contracted chickenpox. Treatment with acyclovir was begun within the first 24 hours of rash and was administered by the oral route in a dose of 20 mg per kilogram of body weight four times daily for five days. RESULTS: The children treated with acyclovir had fewer varicella lesions than those given placebo (mean number, 294 vs 347; P less than 0.001), and a smaller proportion of them had more than 500 lesions (21 percent, as compared with 38 percent with placebo; P less than 0.001). In over 95 percent of the recipients of acyclovir no new lesions formed after day 3, whereas new lesions were forming in 20 percent of the placebo recipients on day 6 or later. The recipients of acyclovir also had accelerated progression to the crusted and healed stages, less itching, and fewer residual lesions after 28 days. In the children treated with acyclovir the duration of fever and constitutional symptoms was limited to three to four days, whereas in 20 percent of the children given placebo illness lasted more than four days. There was no significant difference between groups in the distribution of 11 disease complications (10 bacterial skin infections and 1 case of transient cerebellar ataxia). Acyclovir was well tolerated, and there was no significant difference between groups in the titers of antibodies against varicella-zoster virus. CONCLUSIONS: Acyclovir is a safe treatment that reduces the duration and severity of chickenpox in normal children when therapy is initiated during the first 24 hours of rash. Whether treatment with acyclovir can reduce the rare, serious complications of chickenpox remains uncertain.