1. November 2004 Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection

2. 11/04 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 The user is cautioned that, due to the rapidly changing field of HIV care, this information could become out of date quickly.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. 11/04 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. 11/04 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. 11/04 Special Considerations in Pediatric ARV Therapy  Diagnostic issues  Pharmacokinetic changes  Natural history differences in virologic and immunologic markers  Adherence issues

6. 11/04 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. 11/04 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. 11/04 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. 11/04 Diagnostic Issues in Infants  HIV is reasonably excluded with:  2 or more negative virologic tests  One at age >1 month  One at age >4 months  2 or more negative HIV IgGs at >6 months

10. 11/04 Pediatric HIV Classification Age-Specific CD4 + Immunologic Categories Age of Child <12 months1–5 years>6 years Immune Category Number/µL (%) Number/µL (%) Number/µL (%) Category 1 >1,500 (>25%) >1,000 (>25%) >500 (>25%) Category 2 750–1,499 (15–24%) 500–999 (15–24%) 200–499 (15–24%) Category 3 <750 (<15%) <500 (<15%) <200 (<15%)

11. 11/04 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. 11/04  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 Immunologic Parameters in Children

13. 11/04 Likelihood of Developing AIDS Within 12 Months By Age and CD4+ Percentage in Children Receiving No Therapy or ZDV Monotherapy % with AIDS Age of Child Figure 1 CD4 %

14. 11/04 Likelihood of Death Within 12 Months By Age and CD4+ Percentage in Children Receiving No Therapy or ZDV Monotherapy Age of Child % Mortality CD4 % Figure 2

15. 11/04  Obtain baseline CD4 assays when child is clinically stable  Confirm CD4 changes with a second test before making therapy changes Immunologic Parameters in Children

16. 11/04 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. 11/04 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. 11/04 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. 11/04 Likelihood of Developing AIDS Within 12 Months By Age and HIV-1 RNA Log 10 Copy Number in Children Receiving No Therapy or ZDV Monotherapy Age of Child % with AIDS HIV-1 Log 10 RNA Figure 3

20. 11/04 Likelihood of Death Within 12 Months By Age and HIV-1 Log 10 RNA Copy Number in Children Receiving No Therapy or ZDV Monotherapy HIV-1 Log 10 RNA Age of Child % Mortality Figure 4

21. 11/04 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. 11/04 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. November 2004 Antiretroviral Treatment Guidelines for Children with HIV Infection

24. 11/04 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. 11/04 Decision Factors about ARV Initiation in Children  Complexity of regimen and potential adverse effects  Effect of initial choice on later therapeutic options

26. 11/04 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. 11/04 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. 11/04 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. 11/04 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. 11/04 ARV Therapy for Infants <12 Months  Initiate treatment for any infant with clinical or immunologic symptoms  Consider treatment for infants who are asymptomatic with normal immune function The Working Group recommends:

31. 11/04 Indications for Initiation of ARV Therapy in Children <12 Months of Age Clinical Category CD4+ Cell Percentage Plasma HIV RNA Copy Number 1 Recommend Symptomatic (Clinical Category A, B, or C) OR <25% (Immune Category 2 or 3) Any ValueTreat Asymptomatic (Clinical Category N) AND >25% (Immune Category 1) Any Value Consider Treatment 2

32. 11/04 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. 11/04 ARV Therapy for Children Age 12 Months and Older  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 The Working Group recommends:

34. 11/04 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. 11/04 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. 11/04 Indications for Initiation of ARV Therapy in Children Age >1 Year Clinical Category CD4 + Cell Percentage Plasma HIV RNA Copy Number Recommendation AIDS (Clinical Category C) OR <15% (Immune Category 3) Any ValueTreat Mild-Moderate Symptoms (Clinical Category A or B) OR 15–25% (Immune Category 2) OR >100,000 copies/mL 2 Consider Treatment Asymptomatic (Clinical Category N) AND >25% (Immune Category 1) AN D <100,000 copies/mL 2 Many experts would defer therapy and closely monitor clinical, immune and viral parameters

37. 11/04 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. 11/04 Choice of Initial ARV Therapy  Maximal suppression of viral replication to undetectable if possible for as long as possible  Preservation or restoration of immune function The goal of ARV therapy is:

39. 11/04 Choice of Initial ARV Therapy  Consideration of resistance testing before initiation of therapy in newly diagnosed infants <12 months  Particularly if mother has known or suspected drug-resistant virus The Working Group recommends:

40. 11/04 Recommendations on ARV Regimens for Initial Therapy  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 Working Group criteria:

41. 11/04 Types of ARV Regimens for Children  PI-based (2 NRTIs + PI)  NNRTI-based (2 NRTIs + NNRTI)  NRTI-based (3 NRTIs)

42. 11/04 Drug Regimen Categories for Initial Therapy  Strongly recommended  Recommended as an alternative  Offered in special circumstances  Not recommended  Insufficient data for recommendation

43. 11/04 PI-Based Regimens Advantages Disadvantages  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

44. 11/04 Initial ARV Therapy: Recommended (PI-Based) Strongly recommended: 2 NRTIs 1 + lopinavir/ritonavir or nelfinavir or ritonavir Alternative recommendation: 2 NRTIs 1 + indinavir or amprenavir (children >4 years old) 2

45. 11/04 NNRTI-Based Regimens Advantages Disadvantages  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

46. 11/04 Initial ARV Therapy: Recommended (NNRTI-Based) Strongly Recommended:  Children >3 years: 2 NRTIs 1 + efavirenz 5  Children <3 years or who can’t swallow capsules: 2 NRTIs 1 + nevirapine 3 Alternative recommendation:  2 NRTIs + nevirapine in children >3 years old

47. 11/04 NRTI & NtRTI Advantages Disadvantages  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

48. 11/04 Initial ARV Therapy: Recommended (NRTI-Based) Strongly recommended: None Alternative recommendation: Zidovudine + lamivudine + abacavir Use only in special circumstances: 2 NRTIs 1

49. 11/04 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. 11/04 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

51. 11/04 Changing ARV Therapy  Failure based on virologic, immunologic, or clinical parameters  Toxicity or intolerance on the current therapy  Consider change if there is new data demonstrating that another regimen is superior to the current regimen

52. 11/04 Virologic Considerations for Changing ARV Therapy  Less than 1.0 log10 decrease in HIV RNA from baseline after 8-12 weeks  HIV RNA not suppressed to undetectable levels after 4-6 months  Repeated detection in HIV RNA levels after undetectable levels on ARVs  A reproducible increase in HIV RNA after substantial response

53. 11/04 Monitoring Virologic Response to Therapy Change  Assess virologic response within 4 weeks after initiating or changing therapy  Measure HIV RNA levels at least every 3 months  Resistance testing is recommended for persistent or increasing HIV RNA levels

54. 11/04  Change in immune classification  For children with <15% CD4 +, persistent decline of ≥5%  Rapid and substantive decrease in CD4 + count (ie, >30% decline in <6 months) Immunologic Considerations for Changing ARV Therapy

55. 11/04 Clinical Considerations for Changing ARV Therapy  Progressive neurodevelopmental deterioration  Growth failure despite adequate nutritional support  Disease progression

56. 11/04 Changing ARVs for Toxicity/Intolerance  Choose drugs from same class with different toxicity/side effect profiles  Change of a single drug is permissible if a single drug can be identified as a cause of toxicity  Do not reduce dose below lower end of therapeutic dose range for the particular drug

57. 11/04 Changing ARVs for Treatment Failure/Disease Progression  Assess and review adherence  Review patient medications  Perform resistance testing  Consider overlap in resistance  Change ARVs to contain at least 2 or 3 new ARVs  Consider clinical trial  Discuss quality of life issues

58. 11/04 Adherence is Critical  ARV most effective in initial therapy  Poor adherence may enhance drug resistance  Child and caregiver participation is crucial  Assess, discuss and address adherence issues before initiating therapy

59. 11/04 Adherence Issues in Children  Availability of drugs in palatable, liquid or mixable formulations  Difficulty of giving drugs that have food restrictions, because of children’s (particularly infant) eating schedules  Children’s dependence on caregivers for administration

60. 11/04 Adherence Issues in Children  Families’ reluctance to disclose HIV diagnosis may limit medication administration at daycare/school  Children’s developmental level influences ability and willingness to take medications

61. 11/04 Adherence Issues in Adolescents  Denial and fear of their HIV infection  Misinformation  Distrust of the medical establishment  Fear of ARV  Lack of belief in the effectiveness of ARV  Low self-esteem  Unstructured and chaotic lifestyle  Lack of familial and social support

62. 11/04 Adherence Issues in Adolescents  Adolescents’ readiness  Reminder systems, beepers, timers  Stylish pill boxes

63. 11/04 Conclusion n Clinical care and treatment changes n U.S. Pediatric Guidelines Working Group meets monthly and reviews clinical trials result n Published text posted on www.aidsinfo.nih.gov n Current slide set with speaker notes posted on www.aidsetc.org