Pediatric HIV and co-infection 25-26 July, 2013 แนวทางการดูแลรักษาเด็กและวัยรุ่นติดเชื้อเอช ไอ วี พ. ศ. 2556 รศ พญ ธันยวีร์ ภูธนกิจ หน่วยโรคติดเชื้อ ภาควิชากุมารเวชศาสตร์ คณะแพทยศาสตร์ จุฬาลงกรณ์มหาวิทยาลัย HIVNAT, ศูนย์วิจัยโรคเอดส์ สภากาชาดไทย thanyawee.p@hivnat.org 02-256-4930 Pediatric HIV and co-infection 25-26 July, 2013

แนวทางการดูแลเด็กและวัยรุ่นติดเชื้อเอชไอวี 2013 สถานการณ์ การรักษาผู้ติดเชื้อเอชไอวีทั่วโลก การเริ่มยาต้านไวรัส (When to start?) ในทารก-เด็ก-วัยรุ่น สูตรยาต้านไวรัส (What to start?) ในทารก-เด็ก-วัยรุ่น การติดตามหลังเริ่มยาต้านไวรัส (Treatment monitoring)

People receiving ART: 2003-2012 WHO 2015 Target 15 million on Treatment WHO 3 by 5 campaign 9.7 million by 2012 630,000 children 4.2 million AIDS death averted from ART 0.3 million at 2002 By 2012, reach 65% of 2015 – 15 million people on treatment target 2015 PMTCT: elimination -- > 90% of pregnant women received ART. WHO Global update on HIV treatment 2013

Children (0-14 yr) receiving ART by 2012 WHO Global update on HIV treatment 2013

New Pediatric HIV case: 1996-2012 2015 Target Elimination of HIV PMTCT > 90% of pregnant women received ART 800,000 new pediatric HIV has been averted during 2005-2012 2015 WHO Global update on HIV treatment 2013

PMTCT coverage by WHO region SEA: Thailand, Malaysia reached target. WHO Global update on HIV treatment 2013

Framework of HIV treatment and care 1 2 3 PED ARV CLINICS ENTRY POINTS UNDERSTAND DYNAMICS WHO Global update on HIV treatment 2013

When to start ? Early infant diagnosis HIV functional cure: Mississippi Baby Update WHO treatment guideline 2013 Thai MOPH treatment guideline 2013

HIV diagnosis: 1st step of linkage to care Entry Points: Infant born from HIV +ve mother Mother: 2 HIV tests at 1st, 3rd trimester Statistics 2012: Prevalence of HIV in pregnant ANC = 0.6% no ANC = 3.1% Father: couple counseling Statistics 2012: only 20% of father was tested Other entry points: severe infection, TB clinic, malnutrition, immunization clinic

การวินิจฉัยการติดเชื้อเอชไอวีในทารก Laboratory for Early Infant Diagnosis HIV DNA PCR (ตรวจหาเชื้อไวรัสจากเม็ดเลือดขาว) +/- HIV RNA PCR (ตรวจหาปริมาณไวรัสในพลาสมา) copies/ml ควรเริ่มตรวจเมื่อไหร่ ความเสี่ยงสูง (มารดาได้รับยาต้าน < 4 สัปดาห์ หรือ HIV VL > 1000 c/ml) แนะนำเจาะเลือด 3 ครั้ง 1,2,4 เดือน (หากผลเลือดบวก จะได้ไม่ต้องหยุด ART) ความเสี่ยงต่ำ แนะนำเจาะเลือด 2 ครั้ง ครั้งแรกอายุ 1-2 เดือน และซ้ำเมื่ออายุ ตั้งแต่ 4 เดือน ควรเจาะเลือดซ้ำเมื่อไหร่ (ต้องการผลยืนยัน 2 ครั้ง) หากผลPCR เมื่ออายุ 1-2 เดือนเป็นบวก ควรรีบตรวจซ้ำทันที หากผล PCR เมื่ออายุ 1-2 เดือนเป็นลบ ควรตรวจซ้ำเมื่ออายุ 4 เดือน

Linkage into HIV care: Thailand ให้เน้นประเด็นว่าเด็กส่วนใหญ่ที่วินิจฉัยว่าติดเชื้อโดย PCR กว่าจะได้ตรวจ CD4 หรือเริ่มรักษาช้ามาก มีเพียงครึ่งเดียวที่ได้ยาในปีแรก Mean age (days) at first CD4 517 429 379 269 176 Mean age (days) at ART 535 425 398 268 156 NAP database: 30 Jun 2012

Functional cure: a Mississippi baby HIV RNA Loss to follow up and stop ART at age 18 months 30 hours HIV DNA+ AZT/3TC/LPV/r from day 7 AZT/3TC/NVP started on day 1 Persaud D, 2013 Oral late breaker, Abstract 48LB

When to start: WHO guideline 2013 AGE GROUP 2010 RECOMMENDATIONS <1 YEARS Treat ALL Strong recommendation, moderate-quality evidence 1-2 YEARS Treat  ALL Conditional recommendation, very-low-quality evidence 2-5 YEARS Initiate ART with CD4 count ≤750 cells/mm3 or <25%, irrespective of WHO clinical stage ≥5 YEARS Initiate ART with CD4 count ≤350 cells/mm3 (As in adults), irrespective of WHO clinical stage AND WHO clinical stage 3 or 4 AGE GROUP 2013 RECOMMENDATIONS < 1 YEAR Treat  ALL Strong recommendation, moderate-quality evidence 1-5 YEARS Conditional recommendation, very-low-quality evidence Priority: children < 2 years or WHO stage 3-4 or CD4 count ≤ 750 cells/mm3 or < 25% ≥5 YEARS CD4 ≤ 500 cells/mm3 CD4 ≤350 cells/mm³ as a priority (As in Adults)

When to start: Thai guideline: 2013 US 2012 PENTA 2009 Thai 2013 < 1 year All 1-3 year CDC cat B, C or CD4 < 25%, < 1000 cell/mm3 CD4 < 25% or < 1000 cell/mm3 3-5 year CD4 < 25%, < 750 CD4 < 25%, < 500 CD4 < 25% or < 500 5- 15 year CD4 < 500 cell/mm3 < 350 cell (AI) 350-500 cell (BII) CD4 < 350 cell/mm3 New WHO 2013, move towards treat all childen under 5 years, strongly recommmended in < 1, conditional recommend 1-5

Infant < 3 mo: Early treatment lower AIDS/Death Death: 4% versus 16% (HR = 0.24, p <0.001) Cat C: 6.3% versus 25.6% ( HR = 0.25, p<0.001) Why? Can not predict who will be rapid progessor ? CHER trial CIPRA South Africa; Violari A. NEJM 2008;359:2233-44.

Children: when to start ? PREDICT trial1 (1-12 years, RCT n=300) AIDS-free survival did not differ between deferred (CD4 <15%) and early treatment (CD4 15-24%) 144 week survival = 98.7% vs 97.9% IeDea SA2 (2-5 years, cohort n = 5,732) 3-year mortality rate was not difference in Rx all and using CD4 threshold All vs CD4 < 25% vs CD4 < 15%  4.5% vs 4.5% vs 5.3% 1 Puthanakit T. Lancet Infect Dis 2012:933-941. 2 Schomaker M. IeDEA Southern Africa Collaboration 2012

Children: Effect of ART Growth outcomes South African cohort (N= 2,399) 2 year of HAART: only 81%, 64% achieved normal weight, height Risk factors of poor recovery: age > 3 year, baseline severe growth failure PREDICT study Early treatment has better growth parameter at 3 years of F/U Cognitive function outcomes No different in cognitive function at 3 years of F/U between early and deferred treatment in the PREDICT study Feinstien L et al. J Acquir Immune Defic Syndr 2012;61:235–242 Puthanakit T et al. Ped Infect Dis J 2013:32:501-8.

Adult: Treatment as Prevention (TasP) HAART initiation when CD4 350-550 cell/mm3 versus CD4 < 350 cell 96% reduction in HIV transmission to uninfected partners Early N =886 Defer N = 877 Criteria to Rx: CD4 cell 350-550 cell < 250 , < 350 cell No. of infected partner 1 27 < 0.0001 Morbidity/mortality 40 65 Death 10 13 Extrapulmonary TB 3 7 0.001 Cohen M et al. N Eng J Med 2011; 365:493-505.

What to start- 1st line HAART ? Infant < 3 year : LPV/r is better than NVP : Switch strategies Children 3-10 year : EFV > NVP Adolescent > 10 year: TDF-based once daily regimen

Approved antiretroviral drugs in children NRTI NNRTI Protease Inhibitor Integrase Entry inhibitor Zidovudine Nevirapine Lopinavir/r ( > 2 week) Raltegravir (> 2 years) Enfuvirtide (> 6 years) Stavudine Efavirenz (> 3 mo) Atazanavir/r Elvitegravir Maraviroc > 16 years Lamivudine Emtricitabine Etravirine Darunavir/r (> 3 years) Dolutegravir Didanosine > 2 weeks Rilpivirine > 12 years Fosamprenavir (> 6 months) Abacavir > 3 months Tipranavir/r Tenofovir > 2 years Entry inhibitor = Fusion inhibitors / Chemokine receptor antagonist Adult dose: raltegravir 400 BID, Dolutegravir 50 mg OD DHHS pediatric HIV treatment guideline Nov 1, 2012

What to start ? WHO 2013 Age group 2013 recommendations < 3 years PI LPV/r is preferrred NVP as alternative 2 NRTIs ABC+ 3TC or AZT +3TC 3-10 years NNRTI EFV is preferred NVP as alternative 2NRTIs In preferential order: ABC + 3TC or AZT + 3TC or TDF + FTC (3TC) 10-19 years (weighing ≥35 kg) TDF + FTC or 3TC ABC + 3TC AZT + 3TC

What to start: Thai guideline 2013 (draft) < 1 year 1-3 years 3-12 years > 12 years Preferred AZT+3TC+LPV/r ABC+3TC+LPV/r AZT+ 3TC+ LPV/r ABC+ 3TC+ LPV/r AZT+ 3TC+ NVP ABC+ 3TC+NVP AZT+ 3TC + EFV ABC+ 3TC + EFV TDF + 3TC + EFV Alternative AZT+3TC +NVP d4T +3TC +NVP d4T +3TC +LPV/r d4T +3TC+NVP TDF +3TC + EFV AZT +3TC +EFV AZT +3TC +NVP Exposed to NVP: 24 week-failure rate 9.9% versus 29% Never exposed to NVP: failure rate NVP> LPV/r = 21.5%

Efficacy of LPV/r-based HAART in infants 6 mo-3 yr(P1060) Cohort I: Exposed to SD-NVP (N =164) Palumbo P et al. N Eng J Med 2010;363:1511-20.

Efficacy of LPV/r-based HAART in infants 6 mo-3 yr(P1060) Cohort II: Not exposed to SD-NVP (N =288) CD4 = 15%, 5.7 log10 copies/ml Explaination; High VL and ramp-up strategies The finding is difference from PENPACT-1 older children mean age 6 years and also OCTANE- post partum women Violari A et al. N Eng J Med 2012;366:2380-9.

Treatment switch to NVP-based after initial VL suppression with LPV/r-based ART (NEVEREST) Cumulative probability of VL rebound > 1000 c/ml At week 72 = 10% vs 24% Can switch from LPV/r to NVP after VL < 50 copies/ml. Must perform at 24-48week after switch to detect one with VL rebound Continue LPV/r-based Switch to NPV-based Kuhn L. Lancet Infect Dis 2012:12:521-30.

HAART in children: EFV, NVP, PI Efficacy of EFV versus NVP, EFV versus boosted PI Dosage of EFV in children 3 month to 3 years Dosage in adult 400 mg versus 600 mg (ENCORE study) Metaanalysis on risk of congenital malformation when use in women with child bearing age

Children: EFV versus NVP-based ART Botswana-Baylor retrospective cohort HIV-infected children 3-16 years (N= 804) Median age 8 years, CD4 = 13%, Plasma HIV RNA = 5.3 log10 copies/ml NRTI backbone: AZT/3TC 92% F/U time 69 months VL failure at 5 year EFV = 12.8% NVP = 25.1% Lowenthal ED. JAMA 2013;309:1803-9.

Children: PI and NNRTI-based similar VL outcome NRTI RAM 1-2 > 3 6% 2% 22% 5% The PENPACT-1 Study Team. Lancet Infect Dis. 2011;11:273-83.

Efavirenz:FDA approved for > 3 mo May 2013; EFV was approved for children 3-36 month Body weight Dosage 3.5 to 5 kg 100 mg 5 to 7.5 kg 150 mg 7.5 to 15 kg 200 mg 15 to 20 kg 250 mg 20 to 25 kg 300 mg 25 to 32.5 kg 350 mg 32.5 to 40 kg 400 mg > 40 kg 600 mg Open capsule mixed with food Use within 30 min after mixing Avoid food 2 hours after http://www.fda.gov/ForConsumers/ByAudience/ForPatientAdvocates/HIVandAIDSActivities/ucm350744.htm

EFV: adult dose 400 mg vs 600 mg Baseline characteristics EFV 400 mg (N=321) EFV 600 mg ( N=309) Baseline characteristics Mean age (years) 36 (10) Mean CD4 cell 273(97) 271(101) Median HIV RNA (log10) 4.76 (0.84) 4.73(0.90) At week 48 HIV RNA < 200 copies/ml 94.1% 92.2% EFV-related adverse events 36.8% 47.2% % Discontinuation due to EFV- AE 1.9% 5.8% Note difference in efficacy = 1.8% (95% CI: -2.1 to 5.8) EFV 400 mg has non-inferior virological efficacy compare to EFV 600 mg and has lower rate of discontinuation due to adverse events Puls R, ENCORE1 Study Group: IAS 2013 WELBB01

HAART in children: NRTIs backbone Start with non-thymidine analogue Once daily regimen Abacavir, Tenofovir

ART Regimen Sequences Current practice New approach AZT(d4T) + 3TC + EFV(NVP) TDF+ 3TC + Boosted PI TDF (ABC) + 3TC + EFV (NVP) NRTIs + LPV/r or ATV/r + LPV/r for under 3 years of age TDF is endorse for > 12 years

Abacavir use in children PRO CON Use as a once daily Combination tablet: ABC/3TC (Kivexa) Low risk of metabolic complication Resistance mutation: K65R, M184V, L74V, Y115F Dosage (8 mg/kg/day) 14 to 21 kg 300 mg/day >21 to < 30 kg 450 mg/day > 30 kg 600 mg/day Cost, availablity Risk of ABC hypersensitivity, recommend for HLA-B*5701 screening prior to start Rx % HLA-B*5701 among Thais = 4.0% (95% CI: 1.6-8.0%) Few data in large scale program in children compare to AZT, d4T Puthanakit T. Ped Infect Dis J 2013;32:252-3.

Abacabir in children; ARROW trial VL < 400 copies/ml week 24 week 144 A: ABC/3TC/NNRTI 77% 84% B: ABC/AZT/3TC/NNRTI  ABC/3TC/NNRTI 88% C: ABC/AZT/3TC/NNRTI  ABC/AZT/3TC (p= 0.009) 65% (p =0.009) 3 month to 17 year; Uganda/ Zimbabwe NVP: EFV ratio around 60%: 40% ARROW Trial Lancet 2013; 381: 1391-1403

Poorer VL outcome: ABC vs d4T Johannesburg observational cohort VL < 400 c/ml ABC d4T 2010 change national guideline to replace d4T with ABC 81% versus 50% of children who received LPV/r versus EFV-based had VL > 5 log N 88 351 106 480 81 398 117 659 Technau KG, et al.Ped Infect Dis J 2013; 32:851-5.

Tenofovir disoproxil fumarate (TDF)in children Jan 18, 2012: US FDA approved tenofovir for treatment of HIV-infected children > 2 years LPV/r decrease tenofovir clearance Population PK among 93 children from 5-18 years of age with 283 samples Body weight TDF daily dose 17 - < 22 kg 150 mg 22-<28 kg 200 mg 28-<35 kg 250 mg > 35 kg 300 mg Without LPV/r With LPV/r TDF daily dosage 20 to 30 kg 20-40 kg 150 mg >30-40 kg >40-55 kg 225 mg > 40 kg > 55 kg 300 mg 2012 DHHS guideline recommend TDF for children with Tanner stage 4-5 and consider in stage 3 and use as alternative in stage 1-2 2013: WHO guideline recommend TDF for age > 10 years and BW > 35 kg Bouazza N, et al. JAIDS 2011; 58: 283-8.

Tenofovir use in children: Monitoring for toxicity Renal toxicity Risk for acute renal failure or eGFR < 60 /ml/min:0.2-1.7% Proximal tubular dysfunction – hypophosphatemia: 2-4% Longer exposure – increase risk More risk of toxicity when combine with boosted PI > NNRTI Bone mineral density Decline in BMD from baseline, usually occur during first 6-12 months of treatment, stable thereafter Adult: risk of osetoporotic fracture 1.12 compare to non-tenofovir regimen Children: clinical significance of low BMD is unknown GS-7340 (TAF)specific uptakes in the lymphoid cells; 25 mg compare to 300 mg TDF

Single tablet regimens for children Tenofovir 300/emtricitabine 200 /efavirenz 600(Atripla) Age > 12 years and BW > 40 kg Tenofovir 300 /emtricitabine 200 /rilpivirine 25(Complera) Age > 18 years Tenofovir/emtricitabine/elvitegravir/cobicistat (Quad 1/ Stribild) Age > 18 years Cobicistat = a pharmacoenhancer, inhibitor P450 3A enzymes, = boosts intestinal absorption of atazanavir, darunavir, GS7340

Drug development: monthly injectable ART GSK 744 HIV integrase inhibitor/ dolutegravir analogue Injectable nanosuspension; IM SC Achieve plasma concentration > 4 times IC90 in healthy adults TMC-278 LA Long-acting nanosuspension of rilpivirine (NNRTI) IM loading 1200 mg then maintenance 600 mg q 4 week Plasma level comparable to oral rilpivirine 25 mg/day Spreen W. IAS 2013 WEAB0103

Treatment monitoring Point of care testing CD4 Point of care testing plasma HIV RNA “International drug purchasing facility” established in 2006 To improve access to treatment and diagnositics for HIV TB Malaria in low-income countries.

Laboratory monitoring: CD4 CD4 test Point of care testing will help for linkage to HIV treatment AlereTM Prima CD4 25 ul of whole blood CD4 cell count report in 20 min http://alerehiv.com/hiv-monitoring/alere-pima-cd4/

CD4 Product Pipeline Instruments BD Zyomyx mBio Daktari 2009 2010 2011 Alere Pima CD4 HumaCount mBio Omega Diagnostics Partec Mini Daktari 2009 2010 2011 2012 2013 2014 Instruments Disposable Murtagh slide collection *Estimated - timeline and sequence may change 43

CD4 monitoring Less important after immune recovery to threshold level and have HIV virological suppression Adult patient who had CD4 > 300 cell/mm3 and HIV RNA < 200 copies/ml are unlikely to have CD4 drop < 200 cell/mm3, Only 3% in 4 years of follow-up How to break the habit ? Gale et al.Clin Infect Dis 2013; 56:1340-3.

Laboratory monitoring: Viral load Plasma HIV Viral load Recommended for treatment monitoring Base on NHSO data; only 60% of children have annual VL testing WHO threshold for switching regimen: VL > 1000 copies/ml Point of care testing for HIV Viral load Liat Platform 200 Ul plasma or 50 ul fingerstick blood Turn around time 30-55 min

Pipeline: HIV Viral Load and Early Infant diagnosis (EID) Liat Micronics Alere Q WAVE 80 EOSCAPE ALL Cavidi AMP Lynx EID Biohelix SAMBA VL SAMBA EID Gene XPert NWGHF VL Lumora 2012 2013 2014 2015 2016 Murtagh slide collection 46

Recommend further readings http://www.jiasociety.org/index.php/jias/pages /view/thematicadolescents http://www.who.int/hiv/pub/guidelines/arv2013/en/index.html

Thank you for your attention