Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection

1. Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection

2. About this Presentation These slides were developed using the November 2004 Pediatric Guidelines. The intended audience is clinicians involved in the care of patients with HIV. The user is cautioned that, due to the rapidly changing field of HIV care, this information could become out of date quickly. Finally, it is intended that these slides be used as prepared, without changes in either content or attribution. Users are asked to honor this intent. -AETC NRC http://www.aids-etc.org

3. Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection Developed by the Working Group on Antiretroviral Therapy and Medical Management of HIV-Infected Children François-Xavier Bagnoud Center, UMDNJ, the Health Resources and Services Administration (HRSA); and the National Institutes of Health (NIH)

4. Antiretroviral (ARV) Therapy in Adults and Children • Similar pathogenesis of HIV infection • General virologic and immunologic principals for antiretroviral therapy apply • Unique considerations in infants, children, and adolescents

5. Special Considerations in Pediatric ARV Therapy • Diagnostic issues • Pharmacokinetic changes • Natural history differences in virologic and immunologic markers • Adherence issues

6. Changing Pharmacokinetics • Age-related differences between children & adults • Body composition • Renal excretion • Liver metabolism • Gastrointestinal function • Drug distribution, metabolism and clearance • Drug dosing and toxicities Lead to potential differences in:

7. Diagnostic Issues • Early identification means all pregnant women must be offered HIV testing • Perinatal infection = primary infection • Early diagnosis = starting therapy during primary/early infection

8. Diagnostic Issues in Infants • HIV is diagnosed by 2 positive HIV virologic tests performed on blood samples 2 separate dates • Use DNA PCR or HIV culture for diagnosing at: • Birth (<48 hours) • 14 days (optimal) • 1–2 months • 3–6 months

9. Diagnostic Issues in Infants • HIV is reasonably excluded with: • 2 or more negative virologic tests • One at age >1 month • One at age >4months • 2 or more negative HIV IgGs at >6 months

10. Pediatric HIV ClassificationAge-Specific CD4+ Immunologic Categories

11. Pediatric HIV Classification Clinical Categories • Category E: Perinatally Exposed • Category N: Not Symptomatic • Category A: Mildly Symptomatic • Category B: Moderately Symptomatic • Category C: Severely Symptomatic

12. Immunologic Parameters in Children • Absolute CD4+ counts in healthy children are much higher than in adults • Normal absolute CD4+ counts slowly decline to adult levels by age 6 • If using CD4+ count for ARV decision, use appropriate levels • CD4 percent varies less with age and may be a better immunologic parameter to follow in children <6 years

13. Likelihood of Developing AIDS Within 12 MonthsBy Age and CD4+ Percentage in Children Receiving No Therapy or ZDV Monotherapy Figure 1 % with AIDS CD4 % Age of Child

14. Likelihood of Death Within 12 MonthsBy Age and CD4+ Percentage in Children Receiving No Therapy or ZDV Monotherapy Figure 2 % Mortality CD4 % Age of Child

15. Immunologic Parameters in Children • Obtain baseline CD4 assays when child is clinically stable • Confirm CD4 changes with a second test before making therapy changes

16. HIV RNA and Children:Clinical Considerations • HIV RNA and CD4 assays are independently predictive of risk of disease progression • Both help determine when to start and when to change ARV therapy • For HIV RNA, 5-fold change in infants or 3-fold change in children is biologically and clinically significant

17. HIV RNA and Children:Clinical Considerations • Low levels at birth rise to >100,000 copies/mL to several million copies within the first 1–2 months of life • Very slow decline over several years to reach “set point”

18. HIV RNA and Children:Clinical Considerations • Children >12 months with HIV RNA >100,000 copies/mL are at higher risk for disease progression and death • Predictive value of HIV RNA in infants <12 months old less than older children • In infants, HIV RNA levels are much higher and overlap with rapid and non-rapid progressors • CD4+ counts/percentages may be more useful in evaluating risk in infants <12 months than HIV RNA; in older children both parameters are useful

19. Likelihood of Developing AIDS Within 12 MonthsBy Age and HIV-1 RNA Log10 Copy Number in Children Receiving No Therapy or ZDV Monotherapy Figure 3 % with AIDS HIV-1 Log10 RNA Age of Child

20. Likelihood of Death Within 12 MonthsBy Age and HIV-1 Log10 RNA Copy Number in Children Receiving No Therapy or ZDV Monotherapy Figure 4 % Mortality HIV-1 Log10 RNA Age of Child

21. HIV RNA in Children:Clinical Considerations • Moderate predictive value of specific HIV RNA levels for disease progression/death in individual child • HIV RNA levels difficult to interpret in first year of life • CD4+ and HIV RNA level provide complimentary and independent information about prognosis • Assess HIV RNA every 3-4 months

22. HIV RNA and Children:Clinical Considerations • Obtain 2 baseline HIV RNA tests when child is clinically stable • Confirm HIV RNA changes with a second test before making therapy changes • Consult pediatric HIV specialist when interpreting HIV RNA for clinical decision-making

23. Antiretroviral Treatment Guidelines for Children with HIV Infection

24. Decision Factors about ARV Initiation in Children • Disease severity and risk of progression—presence/hx of serious illness, CD4+ count, HIV RNA • Availability of appropriate, palatable drugs

25. Decision Factors about ARV Initiation in Children • Complexity of regimen and potential adverse effects • Effect of initial choice on later therapeutic options

26. Decision Factors about ARV Initiation in Children • Presence of comorbidities (e.g. TB, Hep B or C, or chronic renal/liver disease) • Potential ARV interaction with child’s other meds • Ability of the child and caregiver to adhere to the regimen

27. Early Therapy Controversies Starting ARVs in the asymptomatic patient: • Controls viral replication while genetic quasispecies are relatively homogeneous and before significant viral mutations occur • Could control development of heterogeneous viral strains/mutations • Potentially leads to less drug resistance • Could lower “viral setpoint”fewer viral strains • Slows immune system destruction preserving immune function and preventing clinical progression

28. Early Therapy Controversies Delaying ARV therapy until symptomatic: • Could reduce evolution of drug-resistant virus due to lack of drug selection pressure exerted by early ARV use • May support greater adherence when symptomatic • Reduces or delays adverse effects of ARVs

29. ARV Therapy for Infants <12 Months • Risk of disease progression is inversely correlated with age • Limited data on rapid v. slower disease • Limited clinical trial data on early aggressive therapy • Limited information on drug dosing • Potential ARV toxicities over the long term

30. ARV Therapy for Infants <12 Months The Working Group recommends: • Initiate treatment for any infant with clinical or immunologic symptoms • Consider treatment for infants who are asymptomatic with normal immune function

31. Indications for Initiation of ARV Therapy in Children <12 Months of Age

32. ARV Therapy for Children Age 12 Months and Older • Risk of disease progression is less in older children than in infants • Children with fewer clinical symptoms or only moderate immune suppression are at lower risk for progression than those with more advanced clinical symptoms/immune disease • In children >12 months, plasma HIV RNA may provide information about progression risk as an adjunct to clinical/immune parameters and can assist in making ARV decisions

33. ARV Therapy for Children Age 12 Months and Older The Working Group recommends: • Start treatment in children with AIDS or severe immune suppression • Consider treatment for children with • Mild-moderate clinical symptoms • Moderate immune suppression and/or • Confirmed plasma HIV RNA level >100,000 copies/mL

34. ARV Therapy for Children Age 12 Months and Older • Defer treatment in asymptomatic children with normal immune status with low risk of clinical disease (HIV RNA <100,000 copies/mL) when adherence factors favor postponing • Monitor virologic, clinical, and immunologic status

35. ARV Therapy for Children Age 12 Months and Older • Factors to consider in deciding when to initiate therapy • Increasing HIV RNA levels (>100,000 copies/mL) • Rapidly declining CD4+ count or percentage to values approaching severe suppression • Development of clinical symptoms • Ability of caregiver and child to adhere to regimen

36. Indications for Initiation of ARV Therapy in Children Age >1 Year

37. Choice of Initial ARV Therapy • Use ZDV monotherapy only for prophylaxis in indeterminate infant in first 6 weeks of life • Use combination ARV therapy with at least 3 drugs • Slows disease progression • Improves survival • Sustains virologic response better • Delays development of resistance

38. Choice of Initial ARV Therapy The goal of ARV therapy is: • Maximal suppression of viral replication to undetectable if possible for as long as possible • Preservation or restoration of immune function

39. Choice of Initial ARV Therapy The Working Group recommends: • Consideration of resistance testing before initiation of therapy in newly diagnosed infants <12 months • Particularly if mother has known or suspecteddrug-resistant virus

40. Recommendations on ARV Regimens for Initial Therapy Working Group criteria: • Data demonstrating durable viral suppression, immunologic and clinical improvement • Incidence and types of drug toxicity • Availability/palatability of formulations for children • Dosing frequency, food and fluid needs • Potential for drug interactions

41. Types of ARV Regimens for Children • PI-based (2 NRTIs + PI) • NNRTI-based (2 NRTIs + NNRTI) • NRTI-based (3 NRTIs)

42. Drug Regimen Categories for Initial Therapy • Strongly recommended • Recommended as an alternative • Offered in special circumstances • Not recommended • Insufficientdata for recommendation

43. Highly potent NNRTI-sparing Targets HIV at 2 steps Resistance requires multiple mutations High pill burden Potential for multiple drug interactions Poor palatability Metabolic complications PI-Based Regimens Advantages Disadvantages

44. Initial ARV Therapy:Recommended (PI-Based)

45. Effective Palatable Less dyslipidemia/fat maldistribution PI-sparing Lower pill burden Cross resistance among NNRTIs Rare, but serious life-threatening skin rashes Hepatic toxicity Multiple drug interactions NNRTI-Based Regimens Advantages Disadvantages

46. Initial ARV Therapy:Recommended (NNRTI-Based)

47. Spares other classes of drugs Minimal drug-drug interactions Limited NRTI cross resistance Palatable Lower pill burden May be less potent than other regimens Rare, but serious lactic acidosis/hepatic steatosis Potential for ABC hypersensitivity NRTI & NtRTIAdvantages Disadvantages

48. Initial ARV Therapy:Recommended (NRTI-Based)

49. Initial ARV Therapy: Not Recommended • Monotherapy—except ZDV prophylaxis for HIV exposed infants during the first 6 weeks of life • Certain 2 NRTI combinations • Antagonistic: ZDV/d4T • Overlapping Toxicities: d4T/ddC • Saquinavir: requires RTV boost to achieve adequate drug level; pediatric dose unknown

50. Initial ARV Therapy: Insufficient Data to Recommend • Two NRTIs +delavirdine • Dual PIs (except lopinavir/ritonavir) • NRTI + NNRTI + PI (except EFV + NFV + 1 or 2 NRTIs) • Regimens containing • Tenofovir • Enfuvirtide (T-20) • Emtricitabine (FTC) • Atazanavir • Fosamprenavir