Pediatric HIV Treatment Guidelines Update

1. Pediatric HIV Treatment Guidelines Update Ana M. Puga, MD Comprehensive Family AIDS Program Children’s Diagnostic & Treatment Center Fort Lauderdale, FL Faculty, Florida/Caribbean AETC

2. Disclosures of Financial Relationships This speaker has the following significant financial relationships with commercial entities to disclose: • Speaker’s Bureau: Abbott, Boehringer-Ingelheim, Gilead This speaker will discuss off-label use or investigational product during the program: • Unlabeled use of drugs in pediatrics if pertinent to discussion for all ARVs This slide set has been peer-reviewed to ensure that there are no conflicts of interest represented in the presentation.

3. Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection • August 16, 2010 guidelines updated August 11, 2011 • For full set of guidelines, visit the AIDSinfo website at http://aidsinfo.nih.gov/guidelines

5. What’s New in the Pediatric Guidelines? • When to Start Antiretroviral Therapy (ART) • Recommendations for naïve infants < 12 months and those older than 1 year • What to Start; pediatric trial updates • Monitoring updates for blips and lab evaluations • Toxicity management table updated

6. What’s New in the Pediatric Guidelines? • Treatment Failure with focus on adherence assessment/management • Resistance Testing section expanded • Pediatric Antiretroviral Drug Information section reorganized and updated

7. At what ages should an exposed infant be tested for HIV? • Birth, 1m, 2m, 3m • 2m, 4m, 6m, 18m • 14 days, 1m, 4m • Birth, 1m 4m, 6m • Birth, 14 days, 3m, 6m

8. ART Initiation: Infants <12 Months • Youngest children are at high risk of rapid disease progression. • Clinical and laboratory markers are poor indicators of risk of rapid progression in infants. • RCT and observational data suggest early ART reduces risk of HIV progression and death. • Limited information on appropriate ARV dosing. August 2011 AETC National Resource Center, www.aidsetc.org

9. Indications for Initiation of ART in Children <12 Months of Age August 2011 AETC National Resource Center, www.aidsetc.org

10. ART: Age ≥12 Months • Children with AIDS or significant symptoms are at high risk of disease progression and death; in them, treatment should be initiated regardless of immunologic or virologic status(AI) August 2011 AETC National Resource Center, www.aidsetc.org

11. ART: Age ≥12 Months (2) • Asymptomatic or mildly symptomatic children are at lower risk of disease progression; CD4 count and VL may be useful in determining need for ART. • Younger age at initiation of therapy has been associated with improved immune response and rapid growth reconstitution. • Higher CD4 count or % is associated with better immune response to ART. August 2011 AETC National Resource Center, www.aidsetc.org

12. ART: Age ≥12 Months (3) • For asymptomatic children, ART now recommended at higher CD4 count or %, though few data available to define optimal CD4 threshold for starting ART. • At lower CD4 levels, recommendation to treat is stronger (and supporting data are more substantial) August 2011 AETC National Resource Center, www.aidsetc.org

13. ART: Age ≥12 Months (4) • Factors to consider in deciding when to initiate therapy in asymptomatic children >12 mos • Increasing HIV RNA levels (e.g., approaching 100,000 copies/mL) • CD4 count or percentage values approaching age-related threshold for treatment • Development of clinical symptoms • Ability of caregiver and child to adhere to regimen August 2011 AETC National Resource Center, www.aidsetc.org

14. At what age can you use the CD4 cut off used for adults to start HAART in asymptomatic children? • 6 • 5 • 12 • 4 • 13

15. What is the CD4 cut off used in adults? • 350 • 200 • 500 • 450 • 600

16. Indications for Initiation of ART in Children ≥1 - <5 Years of Age August 2011 AETC National Resource Center, www.aidsetc.org

17. Indications for Initiation of ART in Children >5 Years of Age August 2011 AETC National Resource Center, www.aidsetc.org

18. Initial Combination Therapyfor ARV-Naïve Children • Initial therapy should include at least 3 ARVs, from at least 2 drug classes, to include: • Either an NNRTI or a PI (boosted or unboosted), plus • A dual-NRTI backbone (AI) August 2011 AETC National Resource Center, www.aidsetc.org

19. Which ARV was most recently FDA approved for children? • Rilpivirine • Efavirenz • Raltegravir • Etravirine • Tenofovir

20. Current ARV Medications • = FDA approved for pediatric treatment August 2011 AETC National Resource Center, www.aidsetc.org

21. Advantages Lower risk of dyslipidemia and fat maldistribution than seen with PIs PI sparing More palatable Lower pill burden Disadvantages Risk of virologic failure if exposed to single-dose NVP as part of PMTCT Single mutation can confer high-level resistance; cross-resistance between EFV and NVP Risk of serious or life-threatening rash and hepatitis (rare) Potential for multiple drug interactions NNRTI-Based Regimens August 2011 AETC National Resource Center, www.aidsetc.org

22. Advantages NNRTI-sparing Efficacy well documented Resistance requires multiple mutations Targets HIV at 2 steps of viral replication Disadvantages Metabolic complications Potential for multiple drug interactions Higher pill burden Poor palatability of liquid formulations PI-Based Regimens August 2011 AETC National Resource Center, www.aidsetc.org

23. Initial Treatment: Preferred Regimens 1 LPV/r should not be given to neonates before a postmenstrual age (first day of the mother’s last menstrual period to birth plus time elapsed after birth) of 42 weeks and a postnatal age of at least 14 days. ² EFV is currently available only in capsule and tablet form and should be used only in children age >3years who weigh >10 kg. Not recommended for adolescent females who are sexually active and may become pregnant unless adequate contraception can be ensured. August 2011 AETC National Resource Center, www.aidsetc.org

24. Initial Treatment: Alternative Regimens 3NVP should not be used in postpubertal girls with CD4 count >250, unless the benefit clearly outweighs the risk August 2011 AETC National Resource Center, www.aidsetc.org

25. Initial Treatment: Regimens for Use in Special Circumstances * Test for HLA-B*5701 before initiation of ABC; do not give ABC to children who are HLA-B*5701 positive. (AII*). August 2011 AETC National Resource Center, www.aidsetc.org

26. Initial Treatment: 2-NRTI Backbone Options * Test for HLA-B*5701 before initiation of ABC; do not give ABC to children who are HLA-B*5701 positive. (AII*). August 2011 AETC National Resource Center, www.aidsetc.org

27. Initial ARV Therapy: Components Not Recommended August 2011 AETC National Resource Center, www.aidsetc.org

28. Initial ARV Therapy: Components Not Recommended (2) August 2011 AETC National Resource Center, www.aidsetc.org

29. ARV Components Never Recommended as Part of an ARV Regimen for Children August 2011 AETC National Resource Center, www.aidsetc.org

30. ARV Components Never Recommended as Part of an ARV Regimen for Children August 2011 AETC National Resource Center, www.aidsetc.org

31. ARV Regimens Never Recommended for Children August 2011 AETC National Resource Center, www.aidsetc.org

32. How often should you monitor labs in HIV infected children? • Every 2 months • Every 4-6 months • Every 1-2 months • Every 3-4 months • Every 6-12 months

33. Monitoring of Children on ART • Baseline (before ART) • Clinical history, CBC and diff, chemistries (incl. electrolytes, creatinine, calcium, phosphorus, hepatic transaminases), glucose, lipid panel and u/a. • Urinalysis- NEW at baseline and reevaluate every 6-12 months • Genotype August 2011 AETC National Resource Center, www.aidsetc.org

34. Monitoring of Children on ART(2) • Within 1-2 weeks of starting new ARV regimen • Screen for side effects, assess adherence (AIII) • Within 4-8 weeks (AIII) • Screen for side effects, evaluate virologic response (AIII) • CD4/%, HIV RNA, CBC, chemistries (incl. renal panel and liver function tests) • For stable patients, follow up at least every 3-4 months (AII*) • Monitor adherence, toxicity, efficacy (AII*) • More frequent evaluation may be needed following initiation or change in therapy (AIII) * For children receiving nevirapine, serum transaminase levels should be measured every 2 weeks for the first 4 weeks of therapy, then monthly for 3 months, followed by every 3 to 4 months. August 2011 AETC National Resource Center, www.aidsetc.org

35. Monitoring Viral Loads • Panel noted that temporary viral load elevations between the level of detection and 1,000 copies/ml are often detected in children and are blips. • “Blips”: Isolated episode of viremia <1000 copies/mL followed by return to viral suppression. Common and not generally reflective of virologic failure.

36. Toxicities and their management • New sections added to table 17 on CNS toxicity, gastrointestinal effects, nephrotoxicity and peripheral nervous system toxicity • CNS: LPV/r EFV, RAL, TPV • GI: Nausea/vomiting, diarrhea, pancreatitis • Renal: IDV, ATV, TDF • Peripheral Nervous System : d4T, ddI

37. Overview of Treatment Failure (2) • Evaluate the cause of treatment failure, especially adherence (the #1 cause of treatment failure) • Not all ART failures require immediate change in therapy (AII) • Manage treatment failure in collaboration with pediatric HIV specialist (AI*) • Bridging regimens August 2011 AETC National Resource Center, www.aidsetc.org

38. Virologic Failure • Incomplete virologic response to therapy or viral rebound after achieving virologic suppression • Incomplete response to therapy: • <1.0 log10 decline in HIV RNA from baseline after 8-12 weeks of ART; or • HIV RNA >200 copies/mL after 6 months of ART; or • Repeated HIV RNA above the level of detection after 12 months of therapy using most sensitive assay August 2011 AETC National Resource Center, www.aidsetc.org

39. 13 yr. old in clinic has viral load of 1975 copies/ml after 5 years of undetectable viral loads. What would you do next? • Discuss adherence and follow up in 1 month. • Discuss adherence, adjust doses, test for resistance and follow up in 2-4 weeks. • Discuss adherence, adjust doses and follow up in 3 months. • Change medications and discuss adherence.

40. Resistance Testing • Recommended : • Before initiation of ART for all treatment-naive children (AII) (genotype preferred) (AIII) • Before changing ART in patients with treatment failure (AI*) • In setting of viral failure, ensure patient is on current regimen or within 4 weeks of discontinuation (AII*) August 2011 AETC National Resource Center, www.aidsetc.org

41. Resistance Testing • Use phenotype (usually in addition to genotype) for known or suspected complex drug resistance (BIII) • Absence of detectable resistance to a drug does not insure its success • Current assays are not sensitive enough to exclude the presence of resistant virus • ARVs history and previous resistance tests should be reviewed when choosing new ART after virologic failure (AII) August 2011 AETC National Resource Center, www.aidsetc.org

42. Tropism (Viral Coreceptor) Assays • Detects presence of CCR5 and CXCR4 coreceptors • Standard test is phenotypic assay, requires HIV RNA >1,000 copies/mL • Genotypic assay available; few clinical data • Should be performed before starting patient on CCR5 antagonist (CCR5 antagonists not effective in patients with CXCR4 virus) (AI*) • Consider for patients who have virologic failure on a CCR5 inhibitor (AI*) August 2011 AETC National Resource Center, www.aidsetc.org

43. Pediatric Antiretroviral Drug Information • Abacavir: Once daily dosing 16mg/kg/day max 600mg; in clinically stable undetectable children • Lamivudine: Once daily (300mg daily) for youth ≥16 yrs who weigh ≥ 50kg • Stavudine: Use only 30mg dose in adolescents • Tenofovir: Bone Mineral Density effects and renal function effects updated in children

44. Pediatric Antiretroviral Drug Information • Efavirenz: Interpatient variabiltiy due to CYP450 genes, TDM discussed. • Nevirapine: Extended release not approved for <18 yr. • Rilpivirine: No pediatric data.

45. Pediatric Antiretroviral Drug Information • Darunavir: Once daily only for naïve 12-18 yrs if >40kg Dose at (800/100 mg). • Lopinavir/ritonavir: Cardiovascular toxicity in preterm infants- use only after postmenstrual age of 42 weeks and a postnatal age of at least 14 days. • Saquinavir: Pretherapy ECG recommended due to prolonged PR and QT; do not use if has prolonged QT or on meds that effect QT.

46. References • Most slides in this presentation were prepared by Mary Jo Hoyt, MSN; Carolyn K Burr, EdD, RN; and Susa Coffey, MD for the AETC National Resource Center in August 2011. • Panel on Antiretroviral Therapy and Medical Management of HIV-Infected Children. Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection, August 11, 2011; Available at http://aidsinfo.nih.gov/contentfiles/lvguidelines/PediatricGuidelines.pdf (Accessed 10-14-2012).

47. Perinatal HIV Treatment Guidelines Update Ana M. Puga, MD Comprehensive Family AIDS Program Children’s Diagnostic & Treatment Center Fort Lauderdale, FL

48. DHHS Guidelines • September 2011 guidelines updated July 31, 2012, including supplement update on Safety & Toxicity of Individual Antiretroviral Agents in Pregnancy • For full set of guidelines, visit the AIDSinfo website at http://aidsinfo.nih.gov/guidelines

49. When do you test a pregnant woman for HIV? • When she starts prenatal care. • When she has an STI. • When she gets sick. • At entry into Prenatal Care and at 28-32 weeks or at delivery if not done in third trimester • Every trimester.

50. What’s New in the Perinatal Guidelines? • New Clinical Trial results • More info on Preconception Counseling, including drug interactions and contraceptives • Antepartum care expanded, including management of naïve pregnant women and those already on ARVs • New ARVs recommended in preferred category and category changes for other ARVs