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: François-Xavier Bagnoud Center, Rutgers School of Nursing

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the field of HIV care is changing rapidly, users are cautioned that the information in this presentation may become out of date quickly.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

Table of Contents March 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 Slide Number

Table of Contents March 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 91

Rating Scheme for Recommendations March Strength of RecommendationQuality of Evidence for Recommendation A: Strong recommendation for the statement B: Moderate recommendation for the statement C: Optional recommendation I: One or more randomized trials in children with clinical outcomes and/or validated laboratory endpoints I*: One or more randomized trials in adults with clinical outcomes and/or validated laboratory endpoints with accompanying data in children from one or more well- designed, nonrandomized trials or observational cohort studies with long-term clinical outcomes II: One or more well-designed, nonrandomized trials or observational cohort studies in children with long-term clinical outcomes II*: One or more well-designed nonrandomized trials or observational cohort studies in adults with long-term clinical outcomes with accompanying data in children from one or more smaller nonrandomized trials or cohort studies with clinical outcome data III: Expert opinion

Abbreviated Words March 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)

Drug Abbreviations March NRTI Abacavir (ABC) Didanosine (ddI) Emtricitabine (FTC) Lamivudine (3TC) Stavudine (d4T) Tenofovir DF (TDF) Zidovudine (AZT, ZDV) NNRTI Efavirenz (EFV) Etravirine (ETR) Nevirapine (NVP) Rilpivirine (RPV) Delavirdine (DLV) PI Atazanavir (ATV) Darunavir (DRV) Fosamprenavir (FPV) Indinavir (IDV) Lopinavir (LPV) Nelfinavir (NFV) Saquinavir (SQV) Tipranavir (TPV) Pharmacokinetic Enhancers Ritonavir (RTV, /r) Cobicistat (COBI) Fusion Inhibitor Enfuvirtide (ENF, T-20) CCR5 Antagonist Maraviroc (MVC) INSTI Raltegravir (RAL) Elvitegravir (EVG) Dolutegravir (DTG)

Special Considerations in Pediatric cART March  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 most perinatally infected children  Diagnosis requires HIV virologic test for infants <18 months of age

Special Considerations in Pediatric cART (2) March  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

Identification of Perinatal HIV Exposure

Screening during Pregnancy March  HIV testing in early pregnancy is recommended for all pregnant women in the United States (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)

Screening in Labor and Delivery March  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)

Screening during Postnatal Period March  If no previous HIV results are 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

Screening during Postnatal Period (2) March  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

HIV Diagnosis in Children

Diagnostic Testing in Children with Perinatal HIV Exposure March  Use virologic assays to diagnose HIV infection in infants younger than 18 months (AII)  HIV antibody (Ab) tests should not be used because maternal HIV Abs may persist  Two virologic tests from separate samples should be used to confirm HIV infection  Virologic diagnostic testing for infants with known perinatal HIV exposure is recommended at ages days, 1-2 months, AND 4-6 months (AII)  HIV DNA and HIV RNA nucleic acid tests (NATs) are recommended as the preferred virologic assays (AII)

Diagnostic Testing in Children with Perinatal HIV Exposure (2) March  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  Caution: the sensitivity and specificity of noncommercial HIV-1 DNA tests may differ from FDA-approved commercial tests

Diagnostic Testing in Children with Perinatal HIV Exposure (3) March  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 % by 2-3 months  HIV RNA can be used as a supplemental/confirmatory test for infants with positive HIV DNA  Less expensive and provides baseline HIV RNA

Diagnostic Testing in Children with Perinatal HIV Exposure (4) Recommended Testing with NAT Diagnosis of HIV infection Definitive Exclusion of HIV Infection Additional Testing Consider at birth for infants at high risk of infection (AIII) Recommended at ages below: days, 1-2 months, AND 4-6 months (AII) A positive virologic test result should be confirmed as soon as possible by a repeat virologic test on a 2nd specimen (AII) Two or more negative NATs at ≥1 month and ≥4 months (AII) Consider additional NAT 2-4 weeks after cessation of ARV prophylaxis if prior NAT testing was negative while the infant was receiving ARV prophylaxis (BIII) For non-breastfed infants ≥6 months of age with no clinical or virologic evidence of HIV infection, two negative antibody tests from separate specimens can also be used to definitely exclude HIV infection (AII) Some experts confirm the absence of HIV infection at age 12 to 18 months with an antibody test to document loss of maternal HIV Abs (BIII) March

Diagnostic Testing in Children with Perinatal HIV Exposure (5) March  Additional testing after cessation of ARV prophylaxis should be considered since ARVs may affect the sensitivity of virologic tests (BIII)  Most HIV-exposed but uninfected children will serorevert by age months  For children 18 to 24 months of age who test Ab positive (eg, possible late seroreverters with residual maternal Abs), a NAT should be used for definitive exclusion or confirmation of HIV infection (AII)

Diagnostic Testing in Children with Perinatal HIV Exposure >24 months of Age or in Children with Non-Perinatal HIV Exposure March  HIV diagnosis in children >24 months of age with perinatal HIV exposure or in children with non-perinatal HIV exposure relies primarily on Ab tests (AII)  See Guidelines page C-6 for FDA-approved tests  If acute HIV infection or end-stage AIDS is suspected in children, a virologic test may be necessary since Ab test results can be negative in these situations (AII)

Diagnostic Testing in Children with Perinatal HIV Exposure >24 months of Age or in Children with Non-Perinatal HIV Exposure (2) March  Sources of non-perinatal or late perinatal HIV exposure:  Breast-feeding  Sexual abuse  Parenteral exposure via contaminated blood products (eg, some international adoptions)  Receipt of premasticated food from an HIV-infected caregiver  Accidental needlesticks  Behavioral risks (in older children)

Diagnostic Testing in Children with Postnatal HIV Infection (1) March  Although rare, postnatal HIV infection can occur in HIV-exposed infants with prior negative HIV virologic tests when there are additional HIV transmission risks (eg, breastfeeding or receipt of premasticated food from HIV-infected caregiver)  Appropriate diagnostic testing will depend on the age of the child and type of exposure (perinatal vs. non-perinatal)

Diagnostic Testing in Children with Postnatal HIV Infection (2 ) March  Recommended HIV testing 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, 3 months, and 6 months after breast-feeding cessation if initial results are negative

Diagnosis of Nonsubtype B and Group O Infection March  HIV-1 Group M subtype B is the most prevalent viral subtype in the United States  HIV DNA PCR  Less sensitive in nonsubtype B  False-negatives reported  HIV RNA PCR assays  Newer real-time RNA assays more sensitive for nonsubtype B and Group O HIV detection

Diagnosis of Nonsubtype B and Group O Infection (2) March  If nonsubtype B 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

Diagnosis of HIV-2 Infections March  HIV-2 should be suspected in pregnant women who are from (or have partners from) endemic countries with:  HIV-1 Ab-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

Diagnosis of HIV-2 Infections (2) March  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 ( ) can provide a list of sites performing this testing

Diagnosis of HIV-2 Infections (3) March  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

Clinical and Laboratory Monitoring

Virologic and Immunologic Parameters in Pediatric HIV Infection March  CD4 counts and % values are much higher in healthy infants and young children than in healthy adults; they slowly decline to adult levels by age 5 years  Absolute CD4 count is recommended for monitoring immune status in children of all ages, with CD4% as an alternative (AII)  HPPMCS study: CD4% provided little or no added prognostic value compared with CD4 count regarding short-term disease progression in children  Current pediatric HIV classification and thresholds for treatment are based on absolute CD4 count

Virologic and Immunologic Parameters in Pediatric HIV Infection (2) March  HIV RNA (viral load or VL) is generally low at birth (<10,000 copies/mL)  In untreated children, HIV RNA increases to high values (eg, >100,000 copies/mL) by 2 months of age and then decreases slowly; high viral load persists for prolonged periods

Virologic and Immunologic Parameters in Pediatric HIV Infection (2) March  Viral suppression: plasma VL below the detection limit of the assay used (generally <20-75 copies/mL)  Confirm HIV RNA or CD4 count/% with a second test before making decisions about initiating or changing therapy based on HIV RNA or CD4 count/%  Changes in HIV RNA copies/mL of less than 5-fold (0.7 log 10 ) in infants <2 years of age or 3-fold (0.5 log 10 ) in children aged ≥2 years are usually not biologically or clinically significant

Virologic and Immunologic Parameters in Pediatric HIV Infection (3) March  Consider the age of child when interpreting the risk of disease progression based on CD4 count/% and plasma HIV RNA level  For any CD4 count/%, younger children (especially <12 months) have higher risk of disease progression  Although data indicate high VL is associated with disease progression, predictive value of HIV RNA for an individual child is moderate  The use of CD4 count or CD4% and HIV RNA together more accurately defines prognosis

CDC HIV Infection Stage Based on Age- Specific CD4 Count or Percentage Age on Date of CD4 Test CDC Stage < 1 year1 to < 6 years> 6 years Cells/µL% % % Stage 1> 1500> 33%> 1000> 30%> 500> 26% Stage % % % Stage 3< 750< 26%< 500< 23%< 200< 14% March  Stage is based primarily on the CD4 count; the CD4% is considered only if the count is missing.  If a Stage 3-defining opportunistic illness has been diagnosed (see Guidelines Table 6), then the stage is 3 regardless of CD4 test results.

Baseline Assessment: Entry into Care March  CD4 count and %  HIV RNA  Resistance test (genotype)  Clinical history and physical exam  CBC w/ differential  Chemistries  Lipid panel  Urinalysis  HLA-B*5701 (if treatment with ABC is being considered)  Hepatitis B virus (HBV) screening (if considering treatment with 3TC, TDF, or FTC) Refer to Guidelines Table 3 for updated clinical and lab monitoring schedule.

Monitoring of Pediatric HIV Infection March  Use primary, FDA-approved assays to monitor VL (Refer to Guidelines Table 4)  For children not on cART:  Monitor CD4 count/% and HIV RNA at initial diagnosis and at least every 3-4 months (AIII)  More frequent monitoring should be implemented for suspected clinical, immunologic, or virologic deterioration or to confirm an abnormal value (AIII)

Monitoring of Pediatric HIV Infection (2) March  After starting or changing cART regimen:  Evaluate for side effects and support adherence within 1- 2 weeks (AIII)  Lab testing at 2-4 weeks for toxicity and VL response (AIII)  Routinely assess children every 3-4 months for therapy adherence, effectiveness (CD4 count/%, VL), and toxicities (history, physical, selected labs) (AII)  CD4 count/% can be monitored less frequently (every months) in children with cART adherence, CD4 well above threshold for OI risk, sustained virologic suppression, and stable clinical status for >2-3 years (BII)

cART Initiation in Children

cART Initiation or Change: Factors to Consider March  HIV disease severity and risk of progression as determined by age, presence or history of HIV- related illnesses, degree of CD4 immunosuppression  Availability of appropriate and palatable drug formulations  Regimen potency, complexity, and potential adverse effects  Effect of initial regimen choice on later options

cART Initiation or Change: Factors to Consider (2) March  cART history  Presence of ARV-resistant virus  Presence of comorbidities  Potential interactions with other medications  Anticipated ability of the child and caregiver to adhere to the regimen

Goals of cART March  Prevent and 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 partners in adolescents who are sexually active  Reduce risk of perinatal transmission in adolescent females who become pregnant

Initiation of cART in ARV-Naive Children March  Treatment recommendations have been revised to incorporate the updated CDC Surveillance Case Definition for HIV infection  The Panel has stratified the urgency for initiation of treatment based on the risk of disease progression in children <12 months of age or the presence of CDC Stage 3- defining opportunistic illness or Stage 3 CD4 counts (see Guidelines Tables 6 & 7)

Initiation of cART in ARV-Naive Children (2) March 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

Initiation of cART in ARV-Naive Children (3) March cART should be initiated urgently in any of the following situations:  All HIV infected children age <12 months (AI for infants <12 weeks, AII for infants 12 weeks to 12 months)  A CDC Stage 3-defining opportunistic illness (AI) (See Guidelines Table 7)  CDC Stage 3 CD4 count (AI)  Ages 1 to <6 years, CD4 count <500 cells/µL  Age ≥6 years, CD4 count <200 cells/µL

Initiation of cART in ARV-Naive Children (4) March cART should be initiated in HIV-infected children age ≥1 year with any of the following:  Moderate HIV-related symptoms (AII) (See Guidelines Table 7)  Plasma HIV RNA >100,000 copies/mL (AII)  CDC Stage 2:  Ages 1 to <6 years, CD4 count cells/µL (AII)  Age ≥6 years, with CD4 count < cells/µL (AI* if CD4 count <350 cells/µL, AII* if CD4 count cells/µL)

Initiation of cART in ARV-Naive Children (5) March  cART should be considered for HIV-infected children aged ≥1 year who are asymptomatic or have mild symptoms (see Guidelines Table 7) and have CDC Stage 1 CD4 count:  Ages 1 to <6 years, CD4 count ≥1,000 cells/µL (BIII)  Age ≥6 years, CD4 count ≥500 cells/µL (BIII)

Initiation of cART in ARV-Naive Children (6) March  CD4 counts should be confirmed by a second test to meet treatment criteria before initiation of cART  To avoid overestimation of temporary blips in viral load, HIV RNA >100,000 copies/mL should be confirmed before initiating cART  Temporary blips can occur during intercurrent illnesses

Initiation of cART in ARV-Naive Children (7) March  Urgent treatment is recommended in children with the highest risk of disease progression, morbidity, mortality  Treatment should be initiated within 1-2 weeks, including an expedited discussion on adherence and increased, intensive follow- up for support

Initiation of cART in Children March AgeCriteriaRecommendation <12 Months Regardless of clinical symptoms, immune status or viral load Urgent treatment (AI for <12 weeks of age; AII for ≥12 weeks) 1 to <6 Years CDC Stage 3-defining opportunistic illnesses b Urgent treatment (AI*) CDC Stage 3 immunodeficiency: d CD4 count <500 cells/mm 3 Urgent treatment (AI*) Moderate HIV-related symptoms b Treat (AII) HIV RNA >100,000 copies/mL c Treat (AII) CD4 count d cells/mm 3 Treat (AII) Asymptomatic or mild symptoms b and CD4 count d ≥1,000 cells/mm 3 Consider treatment (BIII) a Children in whom cART is deferred need close follow-up. Factors to consider in deciding when to initiate therapy in children in whom treatment was deferred include: CD4 cell count or percentage values approaching the age-related threshold for treatment; Development of clinical symptoms; and The ability of caregiver and child to adhere to the prescribed regimen. b Table 7 c To avoid overinterpretation of temporary blips in viral load (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. d Laboratory data should be confirmed with a second test to meet the treatment criteria before initiation of cART.

Initiation of cART in Children (2) March AgeCriteriaRecommendation ≥6 Years CDC Stage 3-defining opportunistic illnesses b Urgent treatment (AI*) CDC Stage 3 immunodeficiency: d CD4 count <200 cells/mm 3 Urgent treatment (AI*) Moderate HIV-related symptoms b Treat (AII) HIV RNA >100,000 copies/mL c Treat (AII) CD4 count d cells/mm 3 Treat (AI* for CD4 count <350 cells/mm 3 and AII* for CD4 count cells/mm 3 ) Asymptomatic or mild symptoms b and CD4 count d ≥500 cells/mm 3 Consider treatment (BIII) a Children in whom cART is deferred need close follow-up. Factors to consider in deciding when to initiate therapy in children in whom treatment was deferred include: CD4 cell count or percentage values approaching the age-related threshold for treatment; Development of clinical symptoms; and The ability of caregiver and child to adhere to the prescribed regimen. b Table 7 c To avoid overinterpretation of temporary blips in viral load (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. d Laboratory data should be confirmed with a second test to meet the treatment criteria before initiation of cART.

Initiation of cART in ARV-Naive Children March  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  In nonurgent situations, parents/caregivers or providers may elect to defer therapy based on clinical and/or psychosocial factors on a case-by- case basis

Indicators of Need to Start cART in ARV- Naive Children March  Children in whom cART is deferred need close follow-up; factors to consider in deciding when to initiate cART in children in whom cART was deferred include: Increasing VL (such as VL approaching 100,000 copies/mL) CD4 count or % approaching age-related threshold for cART Development of clinical symptoms Ability of caregiver and child to adhere to regimen

Pediatric cART Regimens

Criteria Used for Recommendations about Specific ARV Drugs and Drug Regimens March  Data demonstrating durable viral suppression, immunologic and clinical improvement  Pediatric experience  Incidence and types of ARV toxicity  Availability/palatability of pediatric formulations  Dosing frequency, food and fluid requirements  Potential for drug interactions

Recommendations for Initial Therapy in ARV-Naive Children March  Preferred  Clinical trial data in children, more often data in adults, shows optimal and durable efficacy with acceptable toxicity and ease of use  Safety and efficacy are suggested using surrogate markers in pediatric studies  Alternative  Clinical trial data show efficacy, but there are disadvantages compared with preferred regimen (eg, more limited data in children, efficacy or durability less well defined, toxicity concerns)  Use in Special Circumstances  Regimens to be used only when preferred or alternative drugs or drug regimens cannot be used

Initial cART for ARV-Naive Children March Preferred Regimens Children aged ≥14 days to <3 years a Two NRTIs plus LPV/r Children aged ≥3 years to <6 yearsTwo NRTIs plus EFV b Two NRTIs plus LPV/r Children aged ≥6 years Two NRTIs plus EFV b Two NRTIs plus LPV/r a LPV/r should not be administered to neonates before a postmenstrual age (first day of the mother’s last menstrual period to birth plus the time elapsed after birth) of 42 weeks and postnatal age ≥14 days. b EFV is licensed for use in children aged ≥3 months who weigh ≥3.5 kg but is not recommended by the Panel as initial therapy in children aged ≥3 months to 3 years. Unless adequate contraception can be ensured, EFV-based therapy is not recommended for adolescent females who are sexually active and may become pregnant.

Initial cART for ARV-Naive Children March Alternative Regimens Children aged >14 daysTwo NRTIs plus NVP c Children aged ≥3 months to <6 years and weighing ≥10 kgTwo NRTIs plus ATV plus low-dose RTV Children aged ≥2 yearsTwo NRTIs plus RAL d Children aged ≥3 years to <12 yearsTwo NRTIs plus twice-daily DRV plus low-dose RTV Children aged ≥12 yearsTwo NRTIs plus once-daily DRV plus low-dose RTV e Two NRTIs plus DTG Regimens for Use in Special Circumstances Children aged ≥4 weeks and <2 years and weighing ≥3 kgTwo NRTIs plus RAL d Children aged ≥6 monthsTwo NRTIs plus FPVf plus low-dose RTV Children aged ≥2 yearsTwo NRTIs plus NFV Children ≥12 yearsTwo NRTIs plus DTG Treatment-naive adolescents aged ≥13 years and weighing >39 kgTwo NRTIs plus ATV unboosted c NVP should not be used in postpubertal girls with CD4 cell count >250/mm3, unless the benefit clearly outweighs the risk. NVP is FDA-approved for treatment of infants aged ≥15 days. d RAL pills or chewable tablets can be used in children aged ≥2 years as an alternate INSTI. Use of granules or chewable tablets in infants and children aged 4 weeks to 2 years can be considered in special circumstances. e DRV once daily should not be used if any one of the following resistance-associated substitutions are present (V11I, V32I, L33F, I47V, I50V, I54L, I54M,T74P, L76V, I84V, and L89V). f FPV with low-dose RTV should only be administered to infants born at ≥38 weeks’ gestation who have attained a postnatal age of 28 days and to infants born before 38 weeks’ gestation who have reached a postmenstrual age of 42 weeks.

Initial cART for ARV-Naive Children March Preferred 2-NRTI Backbone Options for Use in Combination with Additional Drugs Children, birth to 3 monthsZDV plus (3TC or FTC) Children aged ≥3 months and ≤12 yearsABC plus (3TC or FTC) ZDV plus (3TC or FTC) Adolescents aged ≥13 years at Tanner Stage ≤3ABC plus (3TC or FTC) Adolescents at Tanner Stage 4 or 5ABC plus (3TC or FTC) TDF plus (3TC or FTC) Alternative 2-NRTI Backbone Options for Use in Combination with Additional Drugs Children aged ≥2 weeksddI plus (3TC or FTC ZDV plus ddI Children ≥3 monthsZDV plus ABC Children and adolescents at Tanner Stage 3TDF plus (3TC or FTC) Adolescents ≥13 yearsZDV plus (3TC or FTC) 2-NRTI Regimens for Use in Special Circumstances in Combination with Additional Drugs d4T plus (3TC or FTC) TDF plus (3TC or FTC) (prepubertal children aged ≥2 years and adolescents, Tanner Stage 1 or 2)

Factors to Consider When Selecting an Initial Regimen March  Selection of regimen should be individualized; consider (AIII) :  Characteristics of the regimen  Including barriers to adherence (eg, palatability)  Potential limitations in subsequent treatment options should resistance develop  Patient characteristics  Results of resistance testing  Note that an “alternative” regimen may be preferred for some patients

NNRTI-Based Regimens March Advantages  Long half-lives  Lower risk of dyslipidemia and fat maldistribution than seen with PIs  PI-sparing  Lower pill burden Disadvantages  Single mutation can confer high-level resistance; cross-resistance between EFV and NVP  Risk of serious or life- threatening rash (eg, SJS) and hepatitis (rare)  Potential for multiple drug interactions

PI-Based Regimens March Advantages  NNRTI-sparing  Efficacy well documented  Resistance requires multiple mutations  Targets HIV at 2 steps of viral replication when combined with dual- NRTI backbone  Some powder and liquid formulations available Disadvantages  Metabolic complications (eg, dyslipidemia, insulin resistance, fat maldistribution)  Potential for multiple drug interactions (particularly with low-dose ritonavir boosting needed for most PIs)  Higher pill burden  Poor palatability of liquid formulations

INSTI-Based Regimens Advantages  Susceptibility of HIV to a new class of ARVs  Some (RAL) available in chewable tablet or powder formulation Disadvantages  Limited data on pediatric dosing and safety  Potential drug-drug interactions  Potential for rare systemic allergic reaction or hepatitis (RAL) March

Guidelines Appendix A: Pediatric ARV Drug Information March  Provides concise drug tables with detailed dosing, selected adverse effects, special instructions, and metabolism  Also provides information about drug interactions, major toxicities, resistance, and pediatric use, including PK  Identifies situations wherein recommended pediatric use of an ARV differs from FDA approval; eg, although FDA approved EFV for ages ≥3 months, Guidelines Panel does not recommend its use for children <3 years

Initial Therapy for ARV-Naive Children March  For infants aged <42 weeks postmenstrual or <14 days postnatal, current data are insufficient to provide recommended dosing for a complete, effective cART regimen  Neonatal care providers should consult with pediatric HIV specialist before initiating cART on a preterm neonate or a full-term neonate <2 weeks of age or contact the National Perinatal HIV Hotline  Review Pediatric Opportunistic Infections Guidelines for preferred cART regimens to use with HBV, HCV, or TB coinfection

Initial Therapy for cART-Naive Children: Not Recommended March Not Recommended due to concerns about inferior virologic response, safety, or pharmacologic antagonism. Drugs/regimens not recommended due to insufficient data are denoted by *. Unboosted ATV for age <13 years and/or <39 kg (reduced exposure) DRV/r once daily for age ≥3 to 12 years* Unboosted DRV (not studied) Dual- (full-dose) PI regimens* EFV for children aged <3 years (appropriate dosage not determined) ENF* containing regimens (also injection) ETR–based regimens Unboosted FPV (reduced exposure, medication burden) IDV (renal toxicities) LPV/r once daily (reduced exposure) MVC-based regimens* NFV for age <2 years (dosage not determined) NRTI-only regimens (inferior virologic efficacy) EVG-based regimens DTG age <12 yrs or weight <40 kg *

Initial Therapy for cART-Naive Children: Not Recommended (2) March Not Recommended due to concerns about inferior virologic response, safety, or pharmacologic antagonism. Drugs/regimens not recommended due to insufficient data are denoted by *. RPV-based regimens* Full-dose RTV or RTV as sole PI (GI intolerance, metabolic toxicity) TDF for children aged <2 years (potential bone toxicity, dose not determined) TPV (increased RTV for boosting, intracranial hemorrhage) SQV (limited dosing and outcome data) ABC + ddI as dual NRTI* ABC + TDF as dual NRTI* d4T + ddI as dual NRTI (significant toxicities) TDF + ddI as dual NRTI (increased concentrations, high rate VF) 3-class regimens* 3 NRTIs + NNRTI*

ARV Regimens or Components Never Recommended for Children March Regimens or Regimen Components That Should NEVER Be Offered due to high rates of resistance, virologic failure, serious toxicity, and other reasons. See Guidelines Table 11 for specific rationale. Monotherapy (1 ARV drug) 2 NRTIs alone Certain dual-NRTI combinations as part of a regimen: 3TC + FTC ZDV + d4T Certain NRTI-only regimens: TDF + ddI + (3TC or FTC) TDF + ABC + (3TC or FTC) Unboosted DRV, SQV, or TPV ATV + IDV Dual-NNRTI combinations EFV in first trimester of pregnancy or for sexually active girls of childbearing potential when reliable contraception cannot be ensured Initiating NVP in adolescent girls with CD4 count >250 cells/µL or adolescent boys with CD4 count >400 cells/µL

Considerations for Adolescents

March  cART regimens MUST be tailored to meet the needs of the adolescent (AIII)  Dosing for adolescents may be complex and is dependent on multiple factors including body mass and composition, and pubertal development (AII)  Effective and appropriate precautions need to be taken to reduce the risk of unintended pregnancy and to prevent HIV transmission to sex partners (AI)  Awareness of potential interactions between ARVs and hormonal contraceptives that could lower contraceptive effectiveness (AII*)

Considerations for Adolescents (2) March  Regimens that do not include EFV should be strongly considered in adolescent females trying to conceive and in those who are not using effective and consistent contraception, assuming alternative regimens are acceptable (BIII)  Potential for teratogenicity with 1st-trimester EFV exposure  Perform pregnancy testing and conduct counseling about potential fetal risk and the desirability of avoiding pregnancy while receiving EFV (AIII)  Women with HIV can use all available contraceptive methods (including the IUD)

Considerations for Adolescents (3) March  Prepare adolescents for the transition to adult care settings (AIII), taking into account features of an adult care setting that the adolescent/young adult identifies as most important in going for care; social determinants to consider include:  Developmental status/peer pressure/disclosure issues  Behavioral/mental health/substance use issues  Housing issues  Family or other support(s)  Employment issues  Recent discharge from foster care or incarceration

cART Adherence Issues

Adherence March  Prior to initiating or changing cART, address strategies to maximize adherence (AIII)  Stress adherence to therapy at each visit; continue to explore strategies to maintain or improve adherence (AIII)  In addition to viral load monitoring, use at least one other method of measuring cART adherence (AII)  A once-daily cART regimen should be used, if feasible (AI*)

Adherence March  Providers should maintain a nonjudgmental attitude, establish trust with patients/caregivers, and identify mutually accepted goals to improve and support adherence (AII*)

Adherence Issues Specific to Children March  Availability of drugs in palatable, liquid, powder or mixable formulations; pill swallowing difficulties  Dependence on caregivers for administration  Families’reluctance to disclose HIV diagnosis may limit medication administration  Reliance on older child to self-administer without appropriate caregiver monitoring

Adherence Issues Specific to Children (2) March  Timing issues (eg, during school hours)  Barriers faced by adult caregivers (eg, forgetting doses, changes in routine, being too busy, and child refusal)  Social issues within the family, such as illicit substance use, caregiver illness, unstable housing, and involvement with the criminal justice system

Adherence Issues Specific to Adolescents March  Pill burden  Lack of belief in the effectiveness of ARVs  Low self-esteem  Depression  Alcohol and substance use  Advanced HIV disease, illness  Regimen fatigue  Denial and fear of HIV infection  Misinformation  Distrust of the medical establishment  Disclosure issues  Lack of familial and social support  Unstructured and chaotic lifestyle

Supporting Adherence with Adolescents March  Assess readiness to adhere and understanding of adherence  Involve family, peers, partners when possible  Use reminder systems (eg, SMS text message reminders)  Use pillboxes and medication organizers

Assessing and Monitoring Adherence March  Difficult to assess accurately  Adherence can change over time; regular follow-up is essential (particularly when starting or restarting cART)  Use at least one method in addition to VL:  Quantitative self-report (most recent past 3-day or 7-day report of adherence or nonadherence)  Targeted questions  Pharmacy refill checks, pill counts  Electronic monitoring devices: Medication Event Monitoring Systems (MEMS); SMS text messaging  Home visits; DOT or m-DOT

Assessing and Monitoring Adherence : Initial Adherence Intervention Strategies March  Establish trust; identify mutually acceptable goals for care  Obtain explicit agreement on a treatment plan (including need for cART and need for adherence)  Identify and treat mental health issues  Identify a support team (family, friends, health care team)  Educate patient and family (adherence, partial adherence, resistance)  Specify the adherence target: ≥95% of prescribed doses  Establish readiness (practice sessions or other means)  In selected circumstances, consider brief hospitalization (to initiate cART, evaluate tolerability, and provide education)

Strategies to Improve Adherence: Medication Strategies to Support Adherence March  Choose the simplest regimen possible, reducing dosing frequency and number of pills  Consider patient/family’s daily and weekly routines  Consider palatability (pharmacist may be able to add flavor/syrup)  Choose drugs with fewest side effects; provide anticipatory guidance on management  Simplify food requirements for dosing  Avoid adverse drug-drug interactions  Assess pill-swallowing; offer training

Strategies to Improve Adherence: Follow-Up Strategies to Support Adherence March  Monitor adherence at each visit and in between by phone, SMS text, or letter  Support, encourage, and understand difficulties  Use education aids (eg, pictures, calendars, stickers)  Encourage use of supports such as pillboxes, alarms  Provide support groups, counseling, mental health or drug treatment access  Establish pharmacist-based support (eg, education, refill reminders, home delivery of medications)  In selected circumstances, consider: brief hospitalization, gastrostomy tube placement, DOT

Management of cART Toxicity or Intolerance

March  Adverse effects or side effects of ARVs are generally mild to moderate  Recognize that even mild adverse effects may negatively impact adherence  It is very important to assess, anticipate, and manage common adverse effects  For mild-to-moderate transient intolerance, treat symptomatically  Refer to the Guidelines toxicity tables for information about specific adverse effects, including prevention and management

Management of cART Toxicity or Intolerance (2) March  If severe or life-threatening toxicity: stop ALL ARVs immediately (AIII)  When modifying cART due to toxicity or intolerance of a specific ARV in a child with virologic suppression, it is permissible to change just one drug in the regimen to another active agent with a different toxicity/side-effect profile (AI*)  Once toxicity has been resolved, resume cART with substitute ARV(s) for the offending agent(s) (AII*)  Document toxicity and the responsible ARV(s); advise caregiver and patient of the adverse effect (AIII)

Management of cART Toxicity or Intolerance (3) March  Dosage reduction is NOT recommended for ARV toxicity management except for the few ARVs for which therapeutic range plasma concentrations detected by therapeutic drug monitoring correlates with toxicity (AII*)  If necessary, change to another ARV (within the same drug class) to which the patient’s virus is sensitive  If necessary, change to another drug class (different from the previous toxic/intolerant ARV class) to which the patient’s virus is sensitive

Modifying cART in Children to Promote Sustained Viral Suppression

Recommendations March  For children with sustained virologic suppression on a particular cART regimen (eg, 6-12 months), changing to a new cART regimen with improved pill burden or tolerance should be considered to promote adherence and improve safety (BII)  Review of past ART failures and drug-resistance testing is essential to avoid selection of a suboptimal new cART regimen  To promote ease of cART administration and adherence, possible changes include substitution of:  Pill formulation for liquid  Once-daily regimen for twice-daily regimen  1 pill for 2 or more pills

Possible Regimen Simplification Changes for Virologically Suppressed Children March * d4T may be replaced with a safer drug even before sustained viral suppression because of long-term safety concerns ARV Drug(s)Current Age Body SizePotential ARV Regimen Change ZDV, ddI, or d4T*≥1 yearN/AABC (once-daily dosing) ABC twice daily≥1 yearAnyABC once-daily dosing LPV/r twice daily≥1 year≥3 kgRAL (better palatability) or ATV/r (once- daily dosing) LPV/r twice daily≥3 yearsN/AEFV (once-daily dosing), DRV/r; better palatability and lipid profile LPV/r twice daily≥12 years≥40 kgDRV/r (once-daily dosing) ZDV or ddI≥13 yearsTanner Stage IV-V TDF or ABC (once-daily dosing) Any multi-pill or twice-daily regimen ≥13 yearsTanner Stage IV-V Coformulated TDF/FTC/EFV, TDF/FTC/RPV, TDF/FTC/EVG/COBI, or ABC/3TC/DTG (all 1 pill once daily)

Treatment Failure

March  Assess and address causes of virologic treatment failure, including poor adherence, drug resistance, poor drug absorption, inadequate dosing, and drug- drug interactions (AII)  Following treatment failure, the goal is to achieve and maintain virologic suppression (AI*)  ARV regimens should be chosen based on treatment history and the results of both current and past drug- resistance testing (AI*)

Treatment Failure (2) March  Perform ARV drug-resistance testing when virologic failure occurs, while the patient is still taking the failing regimen and before changing to a new regimen (AI*)  The new regimen should include at least 2, but preferably 3, fully active ARV drugs with assessment of anticipated ARV activity based on resistance test results and past treatment history (AII*)  Evaluation and management of treatment failure should be conducted in collaboration with a pediatric HIV specialist (AI*)  When complete virologic suppression is unobtainable, the goals are to preserve/restore immunologic function, prevent disease progression, and prevent more drug resistance (AII)

Virologic Failure March  Incomplete initial virologic response to cART or viral rebound after achieving virologic suppression  HIV RNA >200 copies/mL after 6 months of cART, or  Repeated HIV RNA above the level of detection after 12 months of cART, using most sensitive assay  Virologic suppression is defined as having plasma HIV RNA below the limit of quantification by the most sensitive assay (ie, <20-75 copies/mL)  Use of assays unable to quantify levels below 200 or 400 copies/mL is not recommended

Virologic Failure (2) March  Infants with high viral loads at initiation of therapy occasionally take >6 months to reach undetectable levels  Isolated “blips” (above the level of quantification but <500 copies/mL) followed by a return to viral suppression are common and generally do not indicate failure  Repeated plasma HIV RNA detection above the level of detectable quantification (especially if >500 copies/mL) after achieving viral suppression usually indicates virologic failure

Immunologic Failure March  Defined as an incomplete immunologic response to cART or immunologic decline while on cART such that there is a failure to achieve or maintain a CD4% or count that is above the age-specific range for severe immunodeficiency  Consider normal age-related changes in CD4 cell count  CD4 count values decline with age whereas CD4% varies less with age  Absolute CD4 counts approach those of adults by age 5  Absolute CD4 count may be used at ≥5 years of age

Clinical Failure March  The occurrence of a new OI or other clinical evidence of HIV disease progression during cART  The most concerning type of treatment failure and requires immediate evaluation  Clinical events in the first several months after cART initiation often do not represent clinical failure; may reflect persistent immune dysfunction or IRIS  Must be viewed alongside virologic and immunologic response to cART; if virologic and immunologic measures are stable, events may not have resulted from treatment failure

Differences in Virologic, Immunologic, and Clinical Responses to Treatment March  Failure of viral suppression generally leads to immunologic and/or clinical failure  However, some children can present with failure in one domain with a good response in the other two  It is important to consider and evaluate alternative causes for discordance between virologic, immunologic, and clinical responses before concluding that treatment failure has occurred  Host genetic or virologic characteristics, lab error, adverse drug effects, medical conditions (eg, malnutrition, malignancy, pulmonary tuberculosis), IRIS, malnutrition, loss of CD4 reserve, etc

Assessment and Management of Treatment Failure: Adherence to Therapy March AssessmentIntervention Interview child and caretaker  24-hour or 7-day recall  Ask about the who gives, when takes, what takes, where kept/given, and how feels of med administration  Explore barriers and challenges Review pharmacy records Observe medication administration Conduct psychosocial assessment (caregiver, substance use, mental health, health beliefs, disclosure, and peer pressure issues) Identify or reengage adherence support persons/supervision Establish fixed times and routines Review generic/trade names Explore possibilities for DOT Simplify regimen, if possible Substitute new ARV if single ARV not tolerated Consider gastric tube, DOT Use tools (eg, pillboxes, reminders) Address behavior, mental illness, competing needs Initiate disclosure discussions Consider child protective services/alternative care settings See Guidelines Table 14 about the assessment and management of treatment failure.

Assessment and Management of Virologic Failure: PK and Dosing Issues March AssessmentIntervention Recalculate dosages using weight or BSA Identify all concomitant medications, including prescription, OTC, recreational substances; assess for drug-drug interactions Consider checking drug levels for specific ARVs Adjust drug dosages Discontinue or substitute competing medications Reinforce applicable food restrictions

Assessment and Management of Virologic Failure: ARV Drug Resistance March AssessmentIntervention Perform resistance testing, as appropriate If no resistance detected, focus on improving adherence If resistance to current regimen detected, optimize adherence and evaluate potential for a new regimen

Options for Regimens in Patients with Treatment Failure and Viral Resistance March Prior RegimenRecommended Change (in order of relative preference) a 2 NRTIs + NNRTI2 NRTIs + PI 2 NRTIs + INSTI 2 NRTIs + PI2 NRTIs + NNRTI 2 NRTIs + different RTV-boosted PI 2 NRTIs + INSTI NRTI(s) + INSTI + (NNRTI or different RTV- boosted PI) a ARV regimens should be chosen based on treatment history and drug-resistance testing. Note that, with NNRTI- and INSTI-based regimens, resistance can develop rapidly if the NRTIs do not have full activity. See Guidelines. Consult with an expert in pediatric HIV infection; may consider:

Treatment Failure and Viral Resistance Options March Prior RegimenRecommended Change (in order of relative preference) a 3 NRTIs2 NRTIs + (NNRTI or PI) 2 NRTIs + INSTI INSTI + 2 other active drugs (chosen from NNRTI, PI, NRTI groups) Failed regimen(s) that included: NRTI(s), NNRTI(s), and PI(s) 2 NRTIs + INSTI (+ RTV-boosted PI if needed) NRTI(s) + RTV-boosted PI + INSTI (consider adding T20 and/or MCV b if needed) NRTI(s) + RTV-boosted DRV, LPV, or SQV + ETR (consider adding INSTI, T-20 and/or MCV b if needed) >1 NRTI + 2 RTV-boosted PIs (LPV/r + SQV, LPV/r + ATV) (consider adding INSTI or T-20 if needed) a ARV regimens should be chosen based on treatment history and drug-resistance testing. Note that, with NNRTI- and INSTI-based regimens, resistance can develop rapidly if the NRTIs do not have full activity. See Guidelines. b No current FDA-approved pediatric indication for maraviroc.

Discontinuation or Interruption of cART

cART Interruptions March  Structured interruptions of cART are NOT recommended except within the context of a clinical trial (AIII)  Short-term interruptions may occur as a result of: acute illness, drug-related toxicity, lack of medication, planned surgery, sedation or procedures that limit oral intake, and request of patient/caregiver; in these cases, cART should be restarted as soon as possible

Therapeutic Drug Monitoring

Role of Therapeutic ARV Drug Monitoring March  Evaluation of plasma concentrations of ARV drugs are not required of most HIV-infected children, but may be considered for children on cART under the following circumstances (BII) :  Use of ARV drugs with limited PK data and therapeutic experience in children  Unexpected suboptimal treatment response  Significant drug-drug or food-drug interactions  Suspected suboptimal drug absorption  Suspected dose-dependent toxicity

Role of Therapeutic ARV Drug Monitoring (2) March  Check for G516T polymorphism of cytochrome P450 (CYP450) 2B6, in combination with testing of plasma EFV levels, is recommended in children <3 years receiving EFV (AII), may be considered in older children and adolescents  This polymorphism is associated with EFV concentrations  Pretreatment evaluation of CYP450 genotype in children <3 years of age prior to initiating EFV for dosing purposes (see Guidelines)

ARV Drug Resistance Testing

Resistance Testing Recommendations March  ARV drug-resistance testing is recommended at the time of HIV diagnosis, before initiation of cART, in all ARV-naive patients (AII)  Genotypic resistance testing is preferred for initial resistance testing (AIII)  ARV drug-resistance testing is recommended before changing therapy because of treatment failure (AI*)  Testing should be done while patient is still on failing regimen or within 4 weeks of discontinuation (AII*)

Resistance Testing Recommendations (2) March  Use phenotype (usually in addition to genotype) for known or suspected complex drug resistance (BIII)  Absence of detectable resistance to a drug does not ensure its efficacy (mutations may not be detected once drug is stopped); ARV history and previous resistance test results must be considered when choosing new ARV drugs after virologic failure (AII)  Use viral coreceptor (tropism) assays when considering use of a CCR5 antagonist (AI*)  Consider tropism assays for patients with virologic failure on therapy containing a CCR5 antagonist (AI*)  Consultation with pediatric HIV specialist is recommended for interpreting resistance test results (AI*)

Resistance Testing Recommendations (3) March Resistance TestInitial TreatmentVirologic Failure Standard Genotype (protease, reverse transciptase) YES Integrase phenotype/genotype If concern for acquisition of resistant virus If failure on integrase inhibitor Coreceptor tropism assay If considering CCR5 antagonist in initial regimen If considering CCR5 antagonist for subsequent regimen Phenotype (protease, reverse transciptase) If genotypic evidence of multidrug-resistant virus May assist in determining most active cART regimen when multidrug resistance exists (use in conjunction with genotype results and cART history)

Conclusion March  Clinical care and treatment is complex and evolves rapidly – check current Guidelines  Because of the complexity of care issues, health care providers should consult with a pediatric HIV specialist when caring for a child with HIV  Published text posted on

About This Slide Set March  This presentation was prepared by John Nelson, PhD, CPNP; Deborah Storm, MSN, PhD; and Susa Coffey, MD, for the AETC NRC in March 2015  See for the most current version of this presentationwww.aidsetc.org