People receiving ART: 2003-2012 WHO Global update on HIV treatment 2013 WHO 3 by 5 campaign 9.7 million by 2012 630,000 children 9.7 million by 2012 630,000 children 0.3 million at 2002 WHO 2015 Target 15 million on Treatment 4.2 million AIDS death averted from ART
Children (0-14 yr) receiving ART by 2012 WHO Global update on HIV treatment 2013
New Pediatric HIV case: 1996-2012 WHO Global update on HIV treatment 2013 2015 Target Elimination of HIV PMTCT > 90% of pregnant women received ART 800,000 new pediatric HIV has been averted during 2005-2012 2015
PMTCT coverage by WHO region WHO Global update on HIV treatment 2013
Framework of HIV treatment and care WHO Global update on HIV treatment 2013 ENTRY POINT S PED ARV CLINICS UNDERSTAND DYNAMICS
Early infant diagnosis HIV functional cure: Mississippi Baby Update WHO treatment guideline 2013 Thai MOPH treatment guideline 2013 When to start ?
HIV diagnosis: 1 st step of linkage to care Entry Points: Infant born from HIV +ve mother Mother: 2 HIV tests at 1 st, 3 rd 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
Linkage into HIV care: Thailand Mean age (days) at first CD4517429379269176 Mean age (days) at ART535425398268156 NAP database: 30 Jun 2012
Functional cure: a Mississippi baby 30 hours HIV DNA+ AZT/3TC/NVP started on day 1 AZT/3TC/LPV/r from day 7 Persaud D, 2013 Oral late breaker, Abstract 48LB HIV RNA Loss to follow up and stop ART at age 18 months
When to start: WHO guideline 2013 AGE GROUP 2010 RECOMMENDATIONS <1 YEARSTreat ALL Strong recommendation, moderate-quality evidence 1-2 YEARSTreat ALL Conditional recommendation, very-low-quality evidence 2-5 YEARSInitiate ART with CD4 count ≤750 cells/mm3 or <25%, irrespective of WHO clinical stage ≥5 YEARSInitiate 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 YEARTreat ALL Strong recommendation, moderate-quality evidence 1-5 YEARSTreat ALL Conditional recommendation, very-low- quality evidence Priority: children < 2 years or WHO stage 3-4 or CD4 count ≤ 750 cells/mm3 or < 25% ≥5 YEARSCD4 ≤ 500 cells/mm3 Conditional recommendation, very-low- quality evidence CD4 ≤350 cells/mm³ as a priority (As in Adults) Strong recommendation, moderate-quality evidence
When to start: Thai guideline: 2013 US 2012PENTA 2009Thai 2013 < 1 yearAll 1-3 yearCDC cat B, C or CD4 < 25%, < 1000 cell/mm3 CDC cat B, C or CD4 < 25%, < 1000 cell/mm3 CDC cat B, C or CD4 < 25% or < 1000 cell/mm3 3-5 yearCDC cat B, C or CD4 < 25%, < 750 cell/mm3 CDC cat B, C or CD4 < 25%, < 500 cell/mm3 CDC cat B, C or CD4 < 25% or < 500 cell/mm3 5- 15 yearCDC cat B, C or CD4 < 500 cell/mm3 < 350 cell (AI) 350-500 cell (BII) CDC cat B, C or CD4 < 350 cell/mm3 CDC cat B, C or CD4 < 500 cell/mm3
Infant < 3 mo: Early treatment lower AIDS/Death CHER trial CIPRA South Africa; Violari A. NEJM 2008;359:2233-44. Death: 4% versus 16% (HR = 0.24, p <0.001) Cat C: 6.3% versus 25.6% ( HR = 0.25, p<0.001) Death: 4% versus 16% (HR = 0.24, p <0.001) Cat C: 6.3% versus 25.6% ( HR = 0.25, p<0.001)
Children: when to start ? PREDICT trial 1 (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 SA 2 (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) Early N =886 Defer N = 877 Criteria to Rx: CD4 cell350-550 cell< 250, < 350 cell No. of infected partner127< 0.0001 Morbidity/mortality4065 Death1013 Extrapulmonary TB370.001 Cohen M et al. N Eng J Med 2011; 365:493-505. HAART initiation when CD4 350-550 cell/mm3 versus CD4 < 350 cell 96% reduction in HIV transmission to uninfected partners
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 What to start- 1 st line HAART ?
What to start ? WHO 2013 Age group 2013 recommendations < 3 years PILPV/r is preferrred NVP as alternative 2 NRTIsABC+ 3TC or AZT +3TC 3-10 years NNRTIEFV is preferred NVP as alternative 2NRTIsIn preferential order: ABC + 3TC or AZT + 3TC or TDF + FTC (3TC) 10-19 years (weighing ≥35 kg) NNRTIEFV is preferred NVP as alternative 2NRTIsIn preferential order: 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 Prefer red AZT+3TC +LPV/r ABC+3TC +LPV/r AZT+ 3TC+ LPV/r ABC+ 3TC+ LPV/r AZT+ 3TC+ NVP ABC+ 3TC+NV P AZT+ 3TC + EFV ABC+ 3TC + EFV TDF + 3TC + EFV Altern ativ e AZT+3TC +NVP d4T +3TC +NVP d4T +3TC +LPV/r d4T +3TC+N VP AZT+3TC +NVP TDF +3TC + EFV AZT +3TC +EFV AZT +3TC +NVP
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) 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) Continue LPV/r-based Switch to NPV-based Kuhn L. Lancet Infect Dis 2012:12:521-30. 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
- 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 HAART in children: EFV, NVP, PI
Children: EFV versus NVP-based ART Lowenthal ED. JAMA 2013;309:1803-9. Botswana-Baylor retrospective cohort HIV-infected children 3-16 years (N= 804) Median age 8 years, CD4 = 13%, Plasma HIV RNA = 5.3 log 10 copies/ml NRTI backbone: AZT/3TC 92% F/U time 69 months VL failure at 5 year EFV = 12.8% NVP = 25.1% VL failure at 5 year EFV = 12.8% NVP = 25.1%
Children: PI and NNRTI-based similar VL outcome The PENPACT-1 Study Team. Lancet Infect Dis. 2011;11:273-83. NRTI RAM 1-2 > 3 6% 2% 22% 5%
Efavirenz:FDA approved for > 3 mo May 2013; EFV was approved for children 3-36 month Body weightDosage 3.5 to 5 kg100 mg 5 to 7.5 kg150 mg 7.5 to 15 kg200 mg 15 to 20 kg250 mg 20 to 25 kg300 mg 25 to 32.5 kg350 mg 32.5 to 40 kg400 mg > 40 kg600 mg Open capsule mixed with food Use within 30 min after mixing Avoid food 2 hours after http://www.fda.gov/ForConsumers/ByAudience/ForPatientAd vocates/HIVandAIDSActivities/ucm350744.htm
EFV: adult dose 400 mg vs 600 mg EFV 400 mg (N=321) EFV 600 mg ( N=309) Baseline characteristics Mean age (years)36 (10) Mean CD4 cell273(97)271(101) Median HIV RNA (log10)4.76 (0.84)4.73(0.90) At week 48 HIV RNA < 200 copies/ml94.1%92.2% EFV-related adverse events36.8%47.2% % Discontinuation due to EFV- AE1.9%5.8% Puls R, ENCORE1 Study Group: IAS 2013 WELBB01 EFV 400 mg has non-inferior virological efficacy compare to EFV 600 mg and has lower rate of discontinuation due to adverse events
- Start with non-thymidine analogue - Once daily regimen - Abacavir, Tenofovir HAART in children: NRTIs backbone
ART Regimen Sequences Current practice AZT(d4T) + 3TC + EFV(NVP) TDF+ 3TC + Boosted PI New approach TDF (ABC) + 3TC + EFV (NVP) NRTIs + LPV/r or ATV/r
Abacavir use in children PRO 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 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 CON 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 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.
Tenofovir disoproxil fumarate (TDF)in children Body weightTDF daily dose 17 - < 22 kg150 mg 22-<28 kg200 mg 28-<35 kg250 mg > 35 kg300 mg Jan 18, 2012: US FDA approved tenofovir for treatment of HIV-infected children > 2 years Without LPV/r With LPV/rTDF daily dosage 20 to 30 kg20-40 kg150 mg >30-40 kg>40-55 kg225 mg > 40 kg> 55 kg 300 mg Bouazza N, et al. JAIDS 2011; 58: 283-8. Population PK among 93 children from 5-18 years of age with 283 samples LPV/r decrease tenofovir clearance 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 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
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) Tenofovir/emtricitabine/elvitegravir/cobicistat (Quad 1/ Stribild) Age > 18 years Tenofovir 300 /emtricitabine 200 /rilpivirine 25(Complera) Age > 18 years Age > 12 years and BW > 40 kg 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 IC 90 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
Point of care testing CD4 Point of care testing plasma HIV RNA Treatment monitoring “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 Alere TM 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 200920102011 2012 2013 HumaCount Partec Min i Alere Pima CD4 Daktari Omega Diagnostics mBio Zyomyx Instruments Disposable *Estimated - timeline and sequence may change BD 2014 Murtagh slide collection
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 Gale et al.Clin Infect Dis 2013; 56:1340-3. How to break the habit ?
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) 2012 2013 2014 2015 2016 Alere Q NWGHF VL Lynx EID SAMBA EID SAMBA VL Liat WAVE 80 EOSCAPE Gene XPert Micronics Biohelix ALL Cavidi AMP Lumora Murtagh slide collection
Recommend further readings http://www.jiasociety.org/index.php/jias/pages /view/thematicadolescents http://www.who.int/hiv/pub/guid elines/arv2013/en/index.html