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28 References: 1. XVI International AIDS Conference, 2006 Abstract no. ThPE Bergshoeff A, Burger D, Farrelly L e t al. Pharmacokinetics of once daily vs. twice daily lamivudine and abacavir in HIV-Infected Children: PENTA th Conference on Retroviruses and Opportunistic Infections, Poster number Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection October 26, 2006 Page 29 Supplement I: Pediatric Antiretroviral Drug Information 4. PENTA guidelines. HIV Medicine 2004: 5: AIDS 2003; 17: AIDS 2008, 22: Lancet 364, (2004). 8. NACO guidelines for HIV care and treatment in infants and children, November Antiretroviral therapy of HIV infection in infants and children in resource-limited settings: towards universal access: WHO

29 Appendix 1 Estimation of Body Surface Area in Infants and Children* Weight (kg) Surface area (m 2 ) Weight (kg) Surface area (m 2 ) Weight (kg) Surface area (m 2 )

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31 Caution (for children less than 10 kg body weight) For children < 10 kg body weight, dosing by body surface area represents a change in usual clinical practice, this will result in an increase in calculated dose. The implications of this change in clinical practice are not known in terms of drug toxicity. Recommendations: Starting doses: For infants < 6 months of age: 50% of calculated dose by body surface area. For infants 6 months 1 year of age: 75% of calculated dose by body surface area For infants over 1 year of age: 100% of calculated dose by body surface area These doses may be adjusted according to clinical circumstances Individual investigators (protocols) should have clear recommendations for dosing in infants *From the United Kingdom Children s Cancer Study Group (UKCCSG) Chemotherapy Standardisation Group. 71

32 Appendix 2 Weight band Equivalent BSA for each weight band a Recommended dose (mg) range using 300mg/m 2b Recommended dose (mg) range using 400mg/m 2b Actual nevirapine dose (mg) 3-< < < < < < a From the UKCCSG (Appendix 1) b PENTA Guidelines recommend dosing at mg/m 2 for children aged 1 month to Tanner stage 3 72

33 Appendix 3 Dosing recommendations for chronic treatment of children are somewhat controversial. Body surface area has traditionally been used to guide NVP dosing for infants and young children, with dosing recommended at 120 to 200 mg per meter 2 of body surface area every 12 hours, at a maximum of 200 mg per dose. Younger children (e.g., age < 8 years) may require the higher range of dosage (i.e., 200 mg per meter 2 of body surface area twice daily) [17, 19]. The drug label also includes dosing recommendations based on mg/kg dosing, with 7 mg/kg every 12 hours recommended for children aged < 8 years and 4 mg/kg every 12 hours recommended for children aged > 8 years, with a maximum dose of 200 mg. NVP apparent clearance adjusted for body weight is approximately two-fold greater in children under age 8 years; however, these clearance changes are gradual and the mg/kg dosing recommendations result in an abrupt 43% decrease in dose size when the 8 th birthday is reached. Thus, many clinicians prefer the mg per meter 2 of body surface area dosing that was used in clinical trials, particularly for children around the eighth birthday. Ref: Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection October 26, 2006 Page 29 Supplement I: Pediatric Antiretroviral Drug Information 73

34 Appendix 4 74

35 Ref: HIV Medicine 2004: 5: Appendix 5 Superior virologic responses with higher nevirapine doses Verweel et al studied the safety and clinical, virological and immunological responses in 74 HIV- 1-infected children 96 weeks after starting a nevirapine-containing regimen. Nevirapine was dosed at the discretion of the paediatrician, according to the manufacturer s guidelines (an initial dose of 120 mg/m 2 /day, increased if no rash occurred after 2 weeks to a maintenance dose of 300 mg/m 2 /day for children < 8 years and 240 mg/m 2 /day for children > 8 years. Children were categorized into high, recommended or low dosage. If the dose was greater than 300 mg/m 2 /day before week 24 they were classified as high. If at all timepoints the dose was less than 240 mg/m 2 /day they were classified as low. The rest were classified as recommended. The median age was 5.2 years and median baseline viral load was 5.1 log copies/ml. In children using nevirapine and NRTI who were maintained on a high (> 300 mg/m 2 per day) dosage of nevirapine, significantly more patients had an undetectable viral load at weeks 24 (P = 0.012) and 96 (P = 0.007) compared with patients on recommended dosages ( mg/m 2 per day; P = and P = 0.007, respectively) and compared with patients on lower dosages (< 240 mg/m 2 per day; P = and P = 0.007, respectively). At week 48 a trend towards more patients with an undetectable viral load was seen for patients receiving a high dosage of nevirapine compared with patients on recommended (P = 0.066) or lower (P = 0.071) dosages. If the dosage was increased for children on a recommended or lower dosages to more than 300 mg/m 2 per day when the viral load was already undetectable, the viral load continued to be undetectable up to at least week 96. When the viral load was not undetectable or rebounded, three out of four patients reached undetectable levels if the dosage was increased before 24 weeks of treatment. 75

36 Proportion of patients with undetectable viral load (%) w eeks 24 w eeks 48 w eeks 96 w eeks Time after Nevirapine initiation in w eeks low dosage recommended dosage high dosage Figure: Proportion of patients achieving undetectable viral load levels (< 400 copes/ml) on high (> 300 mg/m 2 /day), recommended ( mg/m 2 /day) and low (< 240 mg/m 2 /day) dosage of nevirapine, intention-to-treat analysis, missing equals failure, last value carried forward. Ref: AIDS 2003; 17: