Guidances

Guidelines for the Use of Guidelines for the Use of Antiretroviral Agents in Antiretroviral Agents in Pediatric HIV InfectionPediatric HIV Infection

A comparison of A comparison of WHOWHO and and HHS HHS recommendations for 2010recommendations for 2010.

Robert D. JohnsonRobert D. Johnson

SummarySummary

Summer 2010 WHO and HHS released updated guidelines.

• Both guidelines describe “When to Start” ART

With emphasis on Earlier initiation of therapy.

• Both describe “What to Start”

With attention to ART-naive and NVP-exposed children.

• Both introduced a Rating-System to indicate Quality of Evidence.

(HHS: A, B, C // I, II, III) -vs- (WHO: H, M, L, VL // S, C)

WHO: New guidance on HIV/TB Co-infection and IPT

HHS: Virological Dx at Birth for High-risk newborns, lots Rx/ADE's

ID of PERINATAL HIV Exposure (HHS)ID of PERINATAL HIV Exposure (HHS)Panel's Recommendations (AII):

• Voluntary HIV test in Early pregnancy, Opt-OUT focus.

• Third-trimester screens for high-risk behavior or high-prevalence area.

• Rapid HIV Ab test for Undocumented women seen at labor. -or-

• In Immediate post-partum period: Rapid HIV Ab test for Mom OR Newborn

Dx of HIV Infants (HHS)Dx of HIV Infants (HHS)Panel's Recommendations:

• Virologic assays MUST be used to Dx <18 months.

• (>18 months Ab assay alone adequate.)

• Virologic testing in infants with KNOWN Peri-natal exposure (x3) at:

• 2-3 weeks, 1-2 months -and- 4-6 months

• Confirmation = two (2) separate (+) virologic samples.

• Definitive Exclusion = two (2) separate (-) virologic samples.

• At > 1 month AND at > 4 months.(AII)

*Some feel exclusion includes (-) Ab assay at 12-18 months w/ prior (-) virologic test (BIII).

PCP prophylaxis at 4-6 weeks for exposed, until HIV status determined.

Dx of HIV Infants (WHO)Dx of HIV Infants (WHO)

Recommendations:

• All infants need HIV EXPOSURE status determined at first contact with health system. First via Mom, then infant but always < 6 weeks.

• • ExposedExposed infants tested at 4-6 weeks via virologyvirology

• If (-), then serology at 9 months.

• If (+), then Start ART, and repeat test to confirm.

• Identify patient(s) as a “mother-baby pair”.

• 12-18 month olds: dx by virology if possible.if possible.

• Otherwise Virology to confirm initial AB assays (a theme)

(>18 months Ab assay alone adequate.)

PCP, Candida spp., LIP, KS, Crypto. Spp. = Serology stat.

On AssaysOn Assays• • HIV SerologyHIV Serology

Should have Sens: 99% and Spec: 98% for use.

Children may serovert between 12 and 24 months.

• • DNADNA

Whole Blood or DBS / Sensitivity increases quickly with age (Sens: 96% and Spec: 99%) at 28 days.

• • RNARNA

Plasma or DBS / Can assess baseline Viral Load.

HHS: RNA better for Non-B Subtypes

• • Up24AgUp24Ag

DBS also very practical here.

HHSHHS:: Not recommended (Sens/Spec too low)

WHO:WHO: Can be used.

• J Acquir Immune Defic Syndr. 2010 Aug 31.

• Sens: 95% and Spec 99%

When to Start ART in infants, When to Start ART in infants, children (WHO)children (WHO)

Recommendations:

• • Infants:Infants: ART for all HIV(+) irrespective of CD4 count.

• • 12 – 24 mo:12 – 24 mo: ART for all HIV(+) irrespective of CD4

• • 24-59 mo: 24-59 mo: ART if CD4 <750 cells/m3 -or- %CD4 <25%

• • 5 y/o+:5 y/o+: ART if CD4 <350 (as in adults)

Strong recommendations with low evidence quality:

• ART in any HIV(+) child in WHO clinical stages 3 and 4.

• ART in any child <18 mo with presumptive clinical Dx

““When to Initiate Therapy in When to Initiate Therapy in Antiretroviral-Naive Children” (HHS)Antiretroviral-Naive Children” (HHS)Panel's Recommendations:

• • Infants:Infants: ART for all HIV(+) irrespective of CD4 count.

• ART for children >1 yr with AIDS/symptoms

• ART for children >1 yr with single episode of:

• Serious Bacterial infxn

• LIP

• ART for children >1 yr who have met age-related CD4 threshold criteria:

• 1-5 y/o: CD4 < 25%< 25%

• 5+ y/o: CD4 <350 cells/mm3

• ART may be deferred or considered (CIII):

• >1 y/o and Asymptomatic w/ > 25% CD4

• 1-5 y/o w/ >350 cells/mm3

• > 5 y/o: w/ plasma HIV RNA < 100k copies

First-line ART for Infants (WHO)First-line ART for Infants (WHO)What to start:

ARV-naive infants (or Unk(?) exposure): NVP + 2 NRTI's

Exposed-infants: LVP/r + 2 NRTI's

This regimen is same for children 12-24 months.

First-line ART for Children (WHO)First-line ART for Children (WHO)What to start:

2-3 y/o: NVP + 2 NRTI's

3+ y/o: NVP -or- EFV + 2 NRTI's

Special Considerations:Special Considerations:

• w/ anemia/neutropenia: No AZT.

• >12 y/o with Hep B: TDF + FTC -or- 3TC + NNRTI

• w/ TB:

• <3 y/o = NVP + 2 NRTI's (or a triple regimen)

• >3 y/o = EFV + 2 NRTI's

First-line ART for Children (HHS)First-line ART for Children (HHS)General ConsiderationsGeneral ConsiderationsPanel's Recommendations:

• D/C chemoprophylaxis if infant tests (+), start Combo tx.

• ARV Drug Resistance Testing recommended prior to initiating tx in naïve children.

• Combo tx should be at least three (3) drugs:

An NNRTI -or- PI-or- PI plus 2 NRTI's

• HLA-B*5701 genetic testing prior to abacavir

• No tenofovir (TDF) in Tanner Stages 1-3

• No triple-class regimens as initial tx.

• No Maraviroc (Pfizer), No Raltegravir (Merck), No Enfuvirtide (Roche) as initial tx.

First-line ART for Children (HHS)First-line ART for Children (HHS)Preferred Regimens:

Children <3 y/o: LVP/r + 2 NRTI's -or- NVP + 2 NRTI's (if no peripartum exposure)

Children > 3 y/o: LVP/r + 2 NRTI's -or- EFV + 2 NRTI's

Alternative Regimens:

Children 3-6 y/o: NVP + 2 NRTI's

Children > 6 y/o: 2 NRTI's + LOW-DOSE LVP/r + :

• Atazanavir -or- darunavir -or- fosamprenavir

ARV Regimens that should NEVER be offeredARV Regimens that should NEVER be offered • Monotherapy • Two NRTI's alone • Two NNRTI's • Certain Two-NRTIS combinations:

Lamivudine + Emtricitabine (Same resistance, no added benefit)

Zidovudine + Stavudine (Antagonism)

• Saquinavir, darunavir or tipranavir without ritonavir “boosting”.

• Three NRTI-regimen of: Tenofovir + (Didanosine or abacavir) + (lamivudine or

emtricabine) Early non-response in adults, not to be tried in kids.

Clinical and Laboratory Monitoring Clinical and Laboratory Monitoring (WHO)(WHO)Recommendations:

CD4CD4

At time of Dx, then every 6 moAt time of Dx, then every 6 mo

Prior to initiating ART, then every 6 moPrior to initiating ART, then every 6 mo

Where staging events or clinical changes occurWhere staging events or clinical changes occur

Viral LoadViral Load

Desirable but not essentialDesirable but not essential

To confirm failure, prior to switching regimensTo confirm failure, prior to switching regimens

Routine LabsRoutine LabsWBC's and Hb. Any labs for tox. (i.e.; full chem but not at baseline)WBC's and Hb. Any labs for tox. (i.e.; full chem but not at baseline)

Baseline Clinical AssessmentBaseline Clinical AssessmentMalaria, Malaria, TB Dz or exposureTB Dz or exposure, OI's, Hepatitis, nutrition, pregnancy, OI's, Hepatitis, nutrition, pregnancy

Clinical and Laboratory Monitoring (HHS)Clinical and Laboratory Monitoring (HHS)Panel's Recommendations:

CD4CD4

At time of Dx, then every At time of Dx, then every 3-4 mo 3-4 mo (more frequently in infants)(more frequently in infants)

Where staging events or clinical changes occurWhere staging events or clinical changes occur

When initiating or changing therapyWhen initiating or changing therapy

Viral LoadViral Load

At time of Dx, then every 3-4 moAt time of Dx, then every 3-4 mo

An “ultrasensitive viral load assay” should be used to confirm An “ultrasensitive viral load assay” should be used to confirm maximal suppression of viremia.maximal suppression of viremia.

Routine Clinical Monitoring Routine Clinical Monitoring Recommendations (HHS)Recommendations (HHS)On-phone or in-person interview 1-2 weeks after initiation.

Some suggest “adherence screen at 1-2 weeks” via RNA.

Evaluate at 4-8 weeks for AE via full chemistries.

Q 3-4Q 3-4 Months for Tox Screen,Tox Screen, should become routine.

Lipid panel q6-12 months for all.

Routine Clinical Monitoring Routine Clinical Monitoring Recommendations (WHO)Recommendations (WHO)Infants: Follow-up at weeks 2, 4, 8 then monthly.

Children: Follow-up at weeks 2, 4, 8, 12 then q2-3q2-3 months.

At visits:

Review interim medical Hx including TB Exposure.

Consider as response to therapy:• Improved growth• Overcoming development delays• Decreased OI's

Treatment Failure (HHS)Treatment Failure (HHS)Panel's Recommendations:

Assess barriers to adherence.

Consider individual PK differences.

Perform ART-resistance testing.• (Including tropism assays potentially).

Collaborate with a pediatric HIV specialist.

Exclude also when considering failure:• Non-B subtypes?• Protein-calorie malnutrition• Untreated TuberculosisTuberculosis• Malignancy

Treatment Failure (WHO)Treatment Failure (WHO)

WHO Stage 3 or 4, after 24 weeks of adherent ART is treatment failure.

“National programmes need to provide standard second-standard second-line regimensline regimens that are expected to be potent and well tolerated,”

Early switching = Increased cost

Late switching = Resistance development

*LPV/r is the preferred boosted PI for 2nd-line ART after *LPV/r is the preferred boosted PI for 2nd-line ART after NNRTI failure (Strong, high)NNRTI failure (Strong, high)

WHO also reminds us that:

Clinical “deterioration” may be due to IRIS, ex TB* was subclinical.

BCG-associated IRIS is very common.

Also, Tx of OI's, INCLUDING TB can unmask IRIS.

Time is required to reverse catabolic state.

.

WHO Proposal for Clinical Case Definition WHO Proposal for Clinical Case Definition of Paradoxical TB-associated IRISof Paradoxical TB-associated IRIS

One (1) MajorOne (1) Major plus Two (2) minor Two (2) minor criteria w/i 3 mo of ART.

Meintjes, G., et al., Tuberculosis-associated immune reconstitution inflammatorysyndrome: Case definitions for use in resource-limited settings. Lancet Infect Dis, 2008. 8: p. 516-23.

ARV Drug Toxicity (WHO)ARV Drug Toxicity (WHO)Principles:

AE differ somewhat between adults/kids.

WHO requests increased:

• Pharmacovigilance

• Post-marketing surveillance

EFV-related rash, TDF-related osteopenia, higher in peds.

Tox: Mild, Mod. Severe, Life-threatening

• Mod, Severe require substitution, not d/c.not d/c.

• Life-threatening requires temporary d/c. (Hepatotox w/ NVP)

WHOWHOPg 49

Management of Toxicity or Intolerance Management of Toxicity or Intolerance (HHS)(HHS)Panel's Recommendations:

D/C all components in life-threatening reactions.

Document and relate to caregiver the TOXICITY profile, not just the offending drug, for future care.

Dose-reduction not recommended.

• Therapeutic drug monitoring is not routine.

• Might be used if excess dose was suspected.

(HHS) ARV AE and Management Recommendations(HHS) ARV AE and Management Recommendations

Considerations for Infant and Children Considerations for Infant and Children With Tuberculosis and HIV (WHO)With Tuberculosis and HIV (WHO) EVERY visit requires evaluation for TB exposure.

“ALL HIV-infected infants and children exposedexposed to TB through household contactshousehold contacts, but with nono evidence of active disease should begin IPTIPT”. (Strong, VL q of e)

• INH 10mg/kg day (300 mg/day max)

Children w/ HIV should get 6 mo IPT

as part of a “package” of HIV care. (Infants should not (unless household contact).) All Infants and children should get

co-trimoxazoleo-trimoxazole tx, especially HIV/TB coinfected.

Diagnosis of TBDiagnosis of TB

Interferon-ɣ release assays.

- May be more sensitive than TST.

- Unaffected by prior BCG vaccination.

Co-infected children may have Neg (-) TST.

Diagnosis is presumptive often in young people.

If TB is dx'd while child is on ART, must review the regimen to optimize tx of BOTH.

ARV Regimens in TBARV Regimens in TB

Rifampin reduces levels of NVP (CYP3A).

< 3 y/o< 3 y/o:

→ 2 NRTI's + NVP (unless< 2 y/o w/ prior exposure)

-or- 3 NRTI's: (d4T/AZT) + 3TC + ABC

>3 y/o:>3 y/o:

→ 2 NRTI's + EFV

(-or- 3 NRTI's: (d4T/AZT) + 3TC + ABC)

Nelfinavir should not be given w/ rifampicin.

ReviewReview

1. Rapid antibody screen for undocumented mom-baby pair.

2. Virologic assay to confirm, and to test in age < 18 months.

3. PCP prophylaxis until HIV status determined in exposed baby.

4. WHO for -vs- HHS against Up24 Antigen assay.

5. ART for all HIV(+) irrespective of CD4 (WHO) for some -vs- more stringent threshold criteria in HHS guidance. (12-24 mo./old)

6. Some regimens:

• NVP + 2 NRTI's

• LVP/r + 2 NRTI's

• EFV + 2 NRTI's

• TDF + FTC -or- 3TC + NNRTI

• 2 NRTI's + LOW-DOSE LVP/r + :ATV -or- DRV -

or- FPV

ReviewReview

7. CD4: CD4: q 3 mo (HHS) -vs- q 6 mo (WHO)

8. VL: VL: at Dx and q 3 mo (HHS) -vs- to confirm tx failure (WHO)

9. Clinical Monitoring: Clinical Monitoring: q 3-4 mo (HHS) -vs- q 2-3 mo (WHO)

10. Watch for toxicity within classes of Rx.

11. Look for, and treat TB activelyactively, adjust ART appropriately.

12. Prophylaxis with INH for the exposed.

SourcesAntiretroviral Therapy for HIV Infection in Infants and Antiretroviral Therapy for HIV Infection in Infants and

Children: Towards Universal Access. Children: Towards Universal Access. Recommendations for a public health approach. Recommendations for a public health approach. 2010 2010 Revision. WHO HIV/AIDS ProgrammeRevision. WHO HIV/AIDS Programme

Guidelines for the Use of Antiretroviral Agents in Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection. August 16, 2010. HHS Panel Pediatric HIV Infection. August 16, 2010. HHS Panel on Antiretroviral Therapy and Medical Management in on Antiretroviral Therapy and Medical Management in HIV-Infected ChildrenHIV-Infected Children