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Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection. HHS Panel on Antiretroviral Therapy and Medical Management of HIV-Infected Children – A Working Group of the Office of AIDS Research Advisory Council

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Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection

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  1. Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection HHS Panel on Antiretroviral Therapy and Medical Management of HIV-Infected Children – A Working Group of the Office of AIDS Research Advisory Council Slides prepared by:AETC NRC, François-Xavier Bagnoud Center, Rutgers School of Nursing

  2. About This Presentation These slides were developed using the Pediatric Antiretroviral Guidelines, updated in February 2014. The intended audience is clinicians involved in the care of patients with HIV infection. For the complete text of the guidelines, please visit: www.aidsinfo.nih.gov. Because the field of HIV care is changing rapidly, users are cautioned that the information in this presentation may become out of date quickly.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 www.aidsetc.org www.aidsetc.org

  3. Table of Contents • Topic • Rating Scheme for Recommendations • Abbreviations • Identification of Perinatal HIV Exposure • HIV Diagnosis in Children • Clinical and Laboratory Monitoring • cART Initiation in Children • Pediatric cART Regimens • Initial cART Regimens for ARV-Naive Children Slide Number 5 6 10 15 33 40 52 60 www.aidsetc.org

  4. Table of Contents • Topic • Considerations for Adolescents • cART Adherence Issues • Management of cART Toxicity or Intolerance • Modifying cART in Children to Promote Sustained Viral Suppression • Treatment Failure • Discontinuation or Interruption of cART • Therapeutic Drug Monitoring • ARV Drug Resistance Testing Slide Number 70 74 85 89 105 107 110 92 www.aidsetc.org

  5. Rating Scheme for Recommendations www.aidsetc.org

  6. Abbreviated Words Antibody (Ab) Antigen (Ag) Antiretroviral (ARV) Centers for Disease Control and Prevention (CDC) Combination Antiretroviral Therapy (cART) Directly Observed Therapy (DOT) Enzyme Immunoassay (EIA) Immune Reconstitution Inflammatory Syndrome (IRIS) Integrase Strand Transfer Inhibitor (INSTI) Modified Directly Observed Therapy (m-DOT) Nucleoside/Nucleotide Analogue Reverse Transciptase Inhibitor (NRTI) Non-Nucleoside Analogue Reverse Transciptase Inhibitor (NNRTI) Opportunistic Infection (OI) Pharmacokinetic (PK) Polymerase Chain Reaction (PCR) Protease Inhibitor (PI) Viral Load (VL) www.aidsetc.org

  7. Drug Abbreviations www.aidsetc.org

  8. Special Considerations in Pediatric cART • Similar pathogenesis as well as virologic and immunologic principles for cART apply to children, adolescents, and adults with HIV infection • Unique considerations in infants, children, and adolescents exist • For most children, infection transmitted via perinatal exposure • In utero,intrapartum, and/or postpartum neonatal exposure to ARV drugs in mostperinatally infected children • Diagnosis requires HIV virologic test for infants <18 months of age www.aidsetc.org

  9. Special Considerations in Pediatric cART(2) • Age-specific differences in interpreting CD4 counts • Higher viral loads in perinatally infected infants (compared with adults and adolescents) • Changes in PK parameters with age • Differences in the clinical manifestations and treatment of HIV infection • Special considerations associated with adherence to ARV treatment in infants, children, and adolescents www.aidsetc.org

  10. Identification of Perinatal HIV Exposure

  11. Screening during Pregnancy • HIV testing in early pregnancy is recommended for all pregnant women in the U.S.(AII) • Repeat HIV testing in the 3rd trimester: • Should be considered for all HIV-uninfected pregnant women • Is recommended for pregnant women who are at high risk or reside in a high-prevalence area (AIII) www.aidsetc.org

  12. Screening in Labor and Delivery • Rapid or expedited testing should be performed during labor for women without documented HIV status; immediately initiate intrapartum ARV prophylaxis if screening is positive pending confirmation results.(AII) • If acute HIV infection is suspected in a woman whose HIV Ab is negative, a virologic test (eg, plasma HIV RNA assay or combined Ag/Ab immunoassay) should be performed (AII) www.aidsetc.org

  13. Screening during Postnatal Period • If no previous HIV results available, offer immediate rapid/expedited postpartum maternal test or newborn HIV test (AII) • If positive, initiate neonatal ARV prophylaxis (preferably no later than 12 hours after birth) and advise mother not to breast-feed pending results of confirmatory testing. • If confirmation is negative and acute HIV infection is ruled out, infant ARV prophylaxis can be stopped. www.aidsetc.org

  14. Screening during Postnatal Period (2) • Document results of maternal HIV testing in the newborn medical record and communicate result to the newborn’s primary care provider (AIII) • Consider infant HIV Ab testing to determine exposure status for infants in foster care and adoptees if maternal status is unknown (AIII) • Breast-feeding women with possible acute HIV infection should stop breast-feeding immediately until HIV infection is ruled out www.aidsetc.org

  15. HIV Diagnosis in Children

  16. Diagnostic Testing in Children • Use virologic assays to diagnose HIV infection in infants younger than 18 months (AII) • HIV Ab testing cannot establish HIV infection in this age group because maternal HIV Abs may persist • Preferred virologic assays include: HIV DNA PCR and HIV RNA PCR assays (AII) • For HIV-exposed infants, perform virologic testing at ages(AII): • 14-21 days • 1-2 months, and • 4-6 months www.aidsetc.org

  17. Diagnostic Testing in Children (2) • Virologic diagnostic testing at birth should be considered for infants at high risk of HIV (BIII) • A positive virologic test result should be confirmed as soon as possible by a repeat virologic test on a 2nd specimen (AII) • For HIV-exposed infants who received ARV prophylaxis, consider virologic diagnostic testing 2-4 weeks after cessation of ARV prophylaxis, if HIV virologic test results were negative while on prophylaxis (BIII) • ARVs may affect the sensitivity of virologic tests www.aidsetc.org

  18. Diagnostic Testing in Children (3) • Definitive exclusion of HIV infection in non-breastfed HIV-exposed infants is based on (AII): • ≥2 negative virologic test results including one at age ≥1 month AND one at age ≥4 months • OR • 2 negative HIV Ab results on separate specimens at ≥6 months • For children aged ≥18 months, screening HIV Ab assays plus confirmatory Ab or virologic test may be used to diagnose HIV infection in those with perinatal or nonperinatal exposure risks (AII) www.aidsetc.org

  19. Diagnostic Testing in Children (4) • In infants with prior negative virologic test results, some experts perform an Ab test at 12-18 months to confirm the absence of HIV infection (BIII) • Although the majority of HIV-uninfected infants serorevert by age 15-18 months, some serorevert between 18-24 months www.aidsetc.org

  20. Choice of Diagnostic Test • HIV DNA PCR • Specificity: 99.8% at birth and 100% at 1, 3, and 6 months • Sensitivity: at birth 55% but >90% by 2-4 weeks, and 100% at 3 and 6 months www.aidsetc.org

  21. Choice of Diagnostic Test (2) • HIV RNA assays • Specificity for results ≥5,000 copies/mL: • 100% at birth, 1, 3, and 6 months of age • RNA levels <5,000 copies/mL may not be reproducible and tests should be repeated before they are interpreted as documenting HIV infection • Sensitivity: 25-58% during first weeks of life, 89% at 1 month, and 90-100% by 2-3 months www.aidsetc.org

  22. Choice of Diagnostic Test (3) • HIV culture: not used for routine HIV diagnostic testing • Sensitivity similar to HIV DNA PCR • Complex, expensive, results in 2-4 weeks • Generally not available outside research laboratories • HIV p24 antigen assay is not recommended for infant diagnostic testing in the United States www.aidsetc.org

  23. Confirmation of HIV Infection • Infants <18 months: • Confirmation of HIV infection requires 2 positive virologic tests obtained from separate blood samples (AII) • Children ≥18 months of age and children with nonperinatal exposure: • HIV Ab assays alone can be used for diagnosis (AII) • Additional virologic testing may be necessary if acute HIV infection or end-stage AIDS is suspected because antibody test results can be negative in these situations www.aidsetc.org

  24. Diagnostic Testing in Perinatally Exposed Children: Late Seroreverters • On rare occasions, nonbreast-fed perinatally exposed infants may have residual HIV Abs for up to 24 months (“late seroreverters”) • May have positive EIA results but indeterminate confirmatory tests • Repeat Ab testing at a later time to document seroreversion www.aidsetc.org

  25. Diagnostic Testing in Perinatally Exposed Children: Postnatal HIV Infection • Postnatal HIV infections have been reported in HIV-exposed infants who had prior negative HIV virologic test results; infection has occurred through postnatal exposure after completion of initial testing (eg, receipt of infected breast milk or premasticated food) • If a confirmatory HIV Ab result is positive at 18 months, repeat virologic testing to distinguish true HIV infection from residual maternal antibodies www.aidsetc.org

  26. Diagnostic Testing in Perinatally Exposed Children: Postnatal HIV Infection (2) • Recommendations for infants who are breast-fed by an HIV-infected woman: • Immediate virologic testing • Discontinue breast-feeding • Follow-up virologic testing at 4-6 weeks and at 3 and 6 months after breast-feeding cessation if initial results are negative www.aidsetc.org

  27. Diagnostic Testing in Perinatally Exposed Children: Postnatal HIV Infection (3) • Other potential sources of HIV exposure: • Sexual abuse • Parenteral exposure via contaminated blood products (eg, some international adoptions) • Receipt of premasticatedfood from an HIV-infected caregiver • Accidental needle sticks • Behavioral risks (in older children) www.aidsetc.org

  28. Diagnosis of NonsubtypeB and Group O Infection • HIV-1 Group M subtype B is the most prevalent viral subtype in the United States • HIV DNA PCR • Less sensitive in nonsubtypeB • False negatives reported • HIV RNA PCR assays • Newer real-time RNA assays more sensitivefor nonsubtype B and Group O HIV detection www.aidsetc.org

  29. Diagnosis of NonsubtypeB and Group O Infection (2) • If nonsubtypeB exposure is suspected in infants (eg, parent from Africa or Asia) with negative HIV DNA PCR, repeat test with one of the newer real-time RNA assays • Consult with an expert and monitor closely • Conduct Ab testing at 18 months of age www.aidsetc.org

  30. Diagnosis of HIV-2 Infections • HIV-2 should be suspected in pregnant women who are from (or have partners from) endemic countries with: • HIV-1 antibody-positive results on EIA screen • Repeatedly indeterminate results on HIV-1 Western blot, and • HIV-1 RNA at or below the limit of detection • Use Ab test that detects HIV-2 • Most tests detect both HIV-1 and HIV-2 but do not distinguish the two types; can use Multispot or (if HIV-2 suspected) HIV-2-specific test (Western blot or immunoblot) www.aidsetc.org

  31. Diagnosis of HIV-2 Infections (2) • Infants born to HIV-2-infected mothers should be tested with HIV-2-specific virologic assays (HIV-2 DNA PCR) at time points similar to those used for HIV-1 testing • HIV-2 virologic assays are not commercially available, but the National Perinatal HIV Hotline (1-888-448-8765) can provide a list of sites performing this testing www.aidsetc.org

  32. Diagnosis of HIV-2 Infections (3) • Suspected cases should be reported to the state or local health department in order to arrange confirmatory testing via the CDC • Consult with a pediatric HIV infection expert when caring for an infant with suspected or known HIV-2 exposure www.aidsetc.org

  33. Clinical and Laboratory Monitoring

  34. Virologic and Immunologic Parameters in Pediatric HIV Infection • Consider the age of child when interpreting the risk of disease progression based on CD4% or CD4 count and plasma HIV RNA level (AII) • In children <5 years: • CD4 counts are much higher than in adults; CD4 counts and CD4% slowly decline to adult levels by age 5 • CD4% is generally preferred for monitoring immune status, although absolute CD4 count may be used (AII) • For any CD4% or count, younger children (especially <12 months) have higher risk of disease progression www.aidsetc.org

  35. Virologic and Immunologic Parameters in Pediatric HIV Infection (2) • HIV RNA generally low at birth, increases to high values by 2 months, then decreases slowly over several years (in untreated children) • High HIV RNA is associated with disease progression in adolescents and adults, but the predictive value of HIV RNA alone for an individual perinatally infected child is moderate • The use of CD4% or count and HIV RNA together more accurately defines prognosis www.aidsetc.org

  36. HIV RNA (Viral Load) Considerations • Viral suppression: plasma VL below the detection limit of the assay used (generally <20-75 copies/mL) • A 5-fold (0.7 log10) change in HIV RNA copies/mL in infants <2 years of age or 3-fold (0.5 log10) change in children aged ≥2 years is biologically and clinically significant • Confirm HIV RNA changes with a second test before making clinical decisions based on HIV RNA • Consult a pediatric HIV specialist when interpreting HIV RNA test results www.aidsetc.org

  37. Baseline Assessment: Entry into Care • CD4 count and percentage • HIV RNA • Resistance testing (genotype) • Clinical history and PE • CBC w/ differential • Chemistries • Lipid panel • Urinalysis • HLA-B*5701 (if treatment with ABC is being considered) Refer to Guidelines Table 3 for updated clinical and lab monitoring schedule. www.aidsetc.org

  38. Monitoring of Pediatric HIV Infection • For children not on cART: • Monitor CD4%/count and HIV RNA at initial diagnosis and at least every 3-4 months (AIII) • Consider more frequent monitoring to confirm suspected deterioration or an abnormal value (AIII) www.aidsetc.org

  39. Monitoring of Pediatric HIV Infection (2) • After starting or changing cARTregimen: • Evaluate for side effects and adherence in 1-2 weeks • Lab testing at 2-4 weeks for toxicity and HIV RNA response (AIII) • Lab monitoring (CD4%/count, VL, toxicity labs), physical exam, evaluation of adherence and side effects at least every 3-4 months (AII) • Less-frequent monitoring of CD4%/count (every 6-12 months) may be possible in children with cART adherence, stable clinical status, sustained virologic suppression, and CD4 count well above OI risk threshold for >2-3 years (BII) www.aidsetc.org

  40. cART Initiation in Children

  41. cART Initiation or Change: Factors to Consider • HIV disease severity and risk of progression • Availability of appropriate and palatable drug formulations • Regimen potency, complexity, and potential adverse effects • Effect of initial regimen choice on later options www.aidsetc.org

  42. cART Initiation or Change: Factors to Consider (2) • cART history and the presence of ARV-resistant virus • Presence of comorbidities • Potential interactions with other medications • Ability of the child and caregiver to adhere to the regimen www.aidsetc.org

  43. Goals of cART • Reduce HIV-related mortality and morbidity • Restore and preserve immune function • Achieve maximal and durable viral suppression • Prevent emergence of viral drug resistance • Minimize drug-related toxicity • Maintain normal physical growth and development • Improve quality of life • Reduce risk of sexual transmission to discordant partners in adolescents who are sexually active • Reduce risk of perinatal transmission in adolescent females who become pregnant www.aidsetc.org

  44. Initiation of cART in ARV-Naive Children • Infants <12 months of age: • Youngest children are at high risk of rapid disease progression • Clinical and laboratory markers are poor indicators of risk of rapid progression in infants • Observational data suggest early cART reduces risk of HIV progression and death www.aidsetc.org

  45. Initiation of cART in ARV-Naive Children (2) • cART should be initiated in: • All children with AIDS or significant symptoms (Clinical Category C and most Category B) regardless of CD4%/count or HIV RNA level (AI*) • All HIV-infected infants <12 months regardless of clinical status, CD4%, or HIV RNA VL(AI for infants <12 weeks; AII for infants ≥12 weeks-12 months) www.aidsetc.org

  46. Initiation of cART in ARV-Naive Children (3) • cART should be initiated in HIV-infected children ≥1 year • Who are asymptomatic or have mild symptoms with the following CD4 values: • Ages 1 to <3 years, with CD4 count <1,000 cells/µL or CD4% <25 (AII) • Ages 3 to <5 years, with CD4 count <750 cells/µLor CD4% <25 (AII) • Age ≥5 years, with CD4 count <350 cells/µL (AI*) or 350-500 cells/µL(BII*) • With confirmed plasma HIV RNA levels >100,000 copies/mL (AII) www.aidsetc.org

  47. Initiation of cART in ARV-Naive Children (4) • cART should be considered for HIV-infected children aged ≥1 year who are asymptomatic or have mild symptoms with the following CD4 values: • Ages 1 to <3 years, with CD4 count ≥1,000 cells/µL or CD4% ≥25 (BIII) • Ages 3 to <5 years, with CD4 count ≥750 cells/µL or CD4% ≥25 (BIII) • Age ≥5 years, with CD4 count >500 cells/µL (BIII) www.aidsetc.org

  48. Initiation of cART in ARV-Naive Children (6) b CDC Clinical Categories C and B (except single episode of serious bacterial infection) c CDC Clinical Category A or N or single episode of serious bacterial infection www.aidsetc.org

  49. Initiation of cART in ARV-Naive Children (7) b CDC clinical categories C and B (except single episode of serious bacterial infection) c CDC clinical category A or N or single episode of serious bacterial infection d To avoid overinterpretation of temporary blips in VL (which can occur during intercurrent illnesses, for example), plasma HIV RNA level >100,000 copies/mL should be confirmed by a second level before initiating cART. www.aidsetc.org

  50. Initiation of cART in ARV-Naive Children • Therapy adherence issues should be assessed and discussed with the HIV-infected child’s caregivers before initiation of cART(AIII) • Medication adherence is the core requirement for successful virologic control, but enforcing consistent adherence in childhood is often challenging • The panel generally recommends treatment; however, in children > 1 year who are asymptomatic or have mild symptoms, parents/caregivers or providers may elect to defer therapy based on clinical and/or psychosocial factors www.aidsetc.org

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