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Updated Pediatric ARV Guidelines

Updates to the Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection were released on Thursday, November 1, 2012. Please send your comments to ContactUs@aidsinfo.nih.gov by November 15, 2012.

Corrections were made to the guideline. For a description of the changes, please see the correction notice.

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Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection

Protease Inhibitors (PIs)

Tiprinavir

(Last updated:11/1/2012; last reviewed:11/1/2012)

Tipranavir (TPV, APTIVUS)
For additional information see Drugs@FDA: http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm
Formulations
Oral solution: 100 mg TPV/mL with 116 International Units (IU) vitamin E/mL
Capsules: 250 mg
Dosage Recommendations

TPV must be used with ritonavir (RTV) boosting. The RTV boosting dose used for TPV is higher than that used for other protease inhibitors (PIs).

Pediatric dose (aged <2 years):

  • Not approved for use in children aged <2 years.

Pediatric dose (2–18 years of age):
Not recommended for treatment-naive patients.

  • Body surface area dosing:
    TPV 375 mg/m2 + RTV 150 mg/m2, both twice daily.
  • Maximum dose:
    TPV 500 mg + RTV 200 mg, both twice daily.
  • Weight-based dosing:
    TPV 14 mg/kg + RTV 6 mg/kg, both twice daily.
  • Maximum dose:
    TPV 500 mg + RTV 200 mg, both twice daily.

Adult dose:
Not recommended for treatment-naive patients.

  • TPV 500 mg (two 250-mg capsules) + RTV 200 mg, both twice daily.






Selected Adverse Events
  • Rare cases of fatal and non-fatal intracranial hemorrhage
  • Skin rash
  • Nausea, vomiting, diarrhea
  • Hepatotoxicity
  • Hyperlipidemia
  • Hyperglycemia
  • Fat maldistribution
  • Possible increased bleeding episodes in patients with hemophilia 
Special Instructions
  • Administer TPV and RTV together with food.
  • TPV oral solution contains 116 IU vitamin E/mL, which is significantly higher than the reference daily intake for vitamin E. Patients taking the oral solution should avoid taking any form of supplemental vitamin E that contains more vitamin E than found in a standard multivitamin.
  • TPV contains a sulfonamide moiety and should be used with caution in patients with sulfonamide allergy.
  • Store TPV oral solution at room temperature 25°C (77°F); do not refrigerate or freeze. Oral solution must be used within 60 days after the bottle is first opened.
  • Store unopened bottles of oral TPV capsules in a refrigerator at 2° to 8°C (36°–46°F). Once bottle is opened, capsules can be kept at room temperature (maximum of 77°F or 25°C) if used within 60 days.
  • Use TPV with caution in patients who may be at risk of increased bleeding from trauma, surgery, or other medical conditions or who are receiving medications known to increase the risk of bleeding, such as antiplatelet agents, anticoagulants, or high doses of supplemental vitamin E.
  • Use of TPV is contraindicated in patients with moderate or severe hepatic impairment.
Metabolism
  • Cytochrome P450 3A4 (CYP3A4) inducer and substrate.
  • Dosing in patients with renal impairment: No dose adjustment required.
  • Dosing in patients with hepatic impairment: No dose adjustment required for mild hepatic impairment; use contraindicated for moderate-to-severe hepatic impairment.

Drug Interactions (see also the Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents):

  • Tipranavir has the potential for multiple drug interactions.
  • Before tipranavir is administrated, a patient’s medication profile should be carefully reviewed for potential drug interactions.
  • Tipranavir should be used with caution in patients who are receiving medications known to increase the risk of bleeding, such as antiplatelet agents, anticoagulants, or high doses of supplemental vitamin E.

Major Toxicities:

  • More common: Diarrhea, nausea, fatigue, headache, rash (more frequent in children than in adults), and vomiting. Elevated transaminases, cholesterol, and triglycerides.
  • Less common (more severe): Lipodystrophy. Hepatotoxicity: clinical hepatitis and hepatic decompensation, including some fatalities. Patients with chronic hepatitis B or hepatitis C coinfection or elevations in transaminases are at increased risk of developing further transaminase elevations or hepatic decompensation (approximately 2.5-fold risk). Epistaxis.
  • Rare: New-onset diabetes mellitus, hyperglycemia, ketoacidosis, exacerbation of pre-existing diabetes mellitus, spontaneous bleeding in hemophiliacs. Increased risk of intracranial hemorrhage. Tipranavir should be used with caution in patients who may be at risk of increased bleeding from trauma, surgery, or other medical conditions.

Resistance: The International Antiviral Society-USA (IAS-USA) maintains a list of updated resistance mutations (see http://www.iasusa.org/resistance_mutations/index.html) and the Stanford University HIV Drug Resistance Database offers a discussion of each mutation (see http://hivdb.stanford.edu/pages/GRIP/TPV.html).

Pediatric Use: Tipranavir is Food and Drug Administration (FDA) approved for use in children aged ≥2 years who are treatment-experienced and infected with HIV strains resistant to more than one protease inhibitor (PI).1 The use of tipranavir is limited by the high pill burden imposed on patients taking tipranavir capsules, including the burden of taking a higher dose of boosting ritonavir than is required with other PIs. This increased dose of ritonavir is associated with greater potential for drug interactions and increased toxicity. In addition, tipranavir is associated with serious adverse events that limit its use to patients with few treatment options. However, tipranavir is approved for use in children as young as age 2 years and is available in a liquid formulation.

FDA approval of tipranavir was based on a multicenter, pediatric study of the safety, efficacy, and pharmacokinetics (PKs) of tipranavir/ritonavir in HIV-infected children (PACTG 1051/BI-1182.14).2 This study enrolled treatment-experienced children (with the exception of 3 treatment-naive patients) ages 2 to 18 years (median age 11.7 years) with baseline HIV RNA ≥1,500 copies/mL. Children in 3 age strata were randomized to 2 different doses of tipranavir/ritonavir: tipranavir/ritonavir 290 mg/115 mg per m2 body surface area (low dose, 58 patients) or 375 mg/150 mg/m2 body surface area (high dose, 57 patients) twice daily, plus optimized background therapy. All children initially received the oral solution but patients who were aged 12 years or older and receiving the maximum adult dose of 500 mg tipranavir/200 mg ritonavir twice daily were eligible to switch to tipranavir capsules after Week 4. At baseline, resistance to all commercially available PIs was present in greater than 50% of patient isolates, and the tipranavir/ritonavir mutation scores increased with age.2 At 48 weeks, 39.7% of patients receiving the low dose and 45.6% of those receiving the high dose had viral loads <400 copies/mL. The groups did not differ in percentage of patients who achieved viral loads <50 copies/mL. The proportion of patients with HIV RNA levels <400 copies/mL tended to be greater in the youngest patients (70%) who had less baseline resistance. Tipranavir treatment was associated with a mean increase in CD4 T lymphocyte count of 100 cells/mm3 and 59 cells/mm3 in low- and high-dose groups, respectively. Overall, adverse effects were similar between treatment groups. Twenty-five percent of children experienced a drug-related serious adverse event, and 9% of patients discontinued study drugs because of adverse events. The most common adverse events were gastrointestinal disturbances; 37% of participants had vomiting and 24% had diarrhea. Moderate or severe laboratory toxicity (primarily increase in gamma glutamyl transpeptidase and creatine phosphokinase) was seen in 11% of children. Four patients (all in the low-dose group) developed AIDS-defining illnesses through 48 weeks. A Kaplan-Meier analysis comparing AIDS-defining events in the low-dose versus high-dose group reached statistical significance (P = 0.04). In a multivariate model, three variables (listed in order) predicted virologic outcome: greater genotypic inhibitory quotient (GIQ), greater adherence, and baseline viral load <100,000 copies/mL. GIQ is calculated by dividing the tipranavir trough concentration by the number of tipranavir resistance-conferring mutations genotyped from a patient’s HIV strain. The GIQ was consistently greater in the high-dose group. Based on these findings and the increased number of AIDS-defining events in the low-dose group, high-dose tipranavir/ritonavir has been recommended.

PKs of the liquid formulation at steady state were assessed.3 In children ages 2 to <12 years, at a dosage of tipranavir/ritonavir 290/115 mg/m2 body surface area, tipranavir trough concentrations were consistent with those achieved in adults receiving standard tipranavir/ritonavir 500 mg/200 mg dosing. However, children ages 12 to 18 years required a higher dose (375/150 mg/m2 body surface area, 30% higher than the directly scaled adult dose) to achieve drug exposure similar to that in adults receiving the standard tipranavir/ritonavir dose. Population PK analysis demonstrated that tipranavir clearance can be affected by body weight and that volume of distribution can be affected by age.3 Based on these studies, the final dose of tipranavir/ritonavir 375/150 mg/m2 body surface area twice daily is recommended.

Vitamin E is an excipient in the tipranavir oral solution, with a concentration of 116 IU of vitamin E and 100 mg tipranavir/mL of solution. The recommended dose of tipranavir (14 mg/kg body weight) results in a vitamin E dose of 16 IU/kg body weight per day, significantly higher than the reference daily intake for vitamin E (10 IU) and close to the upper limit of tolerability for children. In PACTG 1051, bleeding events were reported more commonly in children receiving tipranavir oral capsules (14.3%) than in children taking tipranavir oral solution (5.75%).2 Overall, the incidence of bleeding episodes (primarily epistaxis) in pediatric patients observed in clinical trials was 7.5%.4

References

  1. Courter JD, Teevan CJ, Li MH, Girotto JE, Salazar JC. Role of tipranavir in treatment of patients with multidrug-resistant HIV. Ther Clin Risk Manag. 2010;6:431-441. Available at http://www.ncbi.nlm.nih.gov/pubmed/20957134.
  2. Salazar JC, Cahn P, Yogev R, et al. Efficacy, safety and tolerability of tipranavir coadministered with ritonavir in HIV-1-infected children and adolescents. AIDS. Sep 12 2008;22(14):1789-1798. Available at http://www.ncbi.nlm.nih.gov/pubmed/18753862.
  3. Sabo J, Cahn P, Della Negra M, al e. Population pharmacokinetic (PK) assessment of systemic steady-state tipranavir (TPV) concentrations for HIV+ pediatric patients administered tipranavir/ritonavir (TPV/r) 290/115 mg/m2 and 375/150 mg/m2 BID (BI 1192.14 and PACTG 1051 study team). 13th Conference on Retroviruses and Opportunistic Infections (CROI); February 5-9, 2006; Denver, CO.
  4. Boehringer Ingelheim. Aptivus Prescribing Information. 2012. Available at http://bidocs.boehringer-ingelheim.com/BIWebAccess/ViewServlet.ser?docBase=renetnt&folderPath=/Prescribing+Information/PIs/Aptivus/10003515+US+01.pdf. Accessed on September 11, 2012.