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Clinicopathologic Conference Advanced Update in HIV Medicine and Clinical Research October 1, 2009 Tammy M. Meyers, BA, MBBCh (WITS), FCPaed (SA), Mmed, DTM&H University of the Witwatersrand Thumbi Ndung'u, DVM, PhD. Nelson R. Mandela School of Medicine “A 7-year-old boy with elevated HIV ribonucleic acid levels despite antiretroviral medications” Presentation of Case Brian C. Zanoni, M.D. Differential Diagnosis Dr. Tammy M. Meyers Differential Diagnosis Dr. Tammy M. Meyers Management of patient Missed Opportunities for intervention; • Mom was not tested in pregnancy despite receiving prenatal care – Assume vertical transmission of HIV (since mom HIVinfected and dad died mysteriously) • No education or support for feeding choice, breast fed for 3 months and then replacement fed – Unlikely to have exclusively breast fed. Only 7% of infants < 6 months of age are exclusively breastfed(Department of Health/Medical Research Council/Measure DHS,1998): – Early weaning → ↓HIV-free survival (Kuhn et al NEJM 2008) • Child presented to health care services with HIVrelated conditions but not tested for HIV testing (supp OM and TB) Updated WHO, PENTA, DHHS guidelines Globally unanimous (hopefully soon officially in SA): ALL HIV-infected infants <1 year start ART SA Clinician’s Society Age Clinical Stage CD4 Criteria < 1year All infants Any CD4 1 – 5 years WHO stage III, IV CD4 20%*# >5 years WHO stage III, IV CD4 <350 cells # *Consider ART with an absolute CD4 count <750 cell/μl in this age #If WHO stage I or II Admission at 5 years 10months • Pneumonia (likely severe) – Received cover for suspected community acquired, atypical and PJP pneumonia • TB treatment commenced empirically (common practice in SA) – Micobacteriological yield is low in children (Zar et al, The Lancet 2005, Marais et al CID 2006) • Dose of TB medication according to standard recommendations likely to have been FDC – Concern that INH treatment under dosed in the current FDC formulation • Started on ART simultaneously – Guidelines recommend start TB treatment first and ART within 2 weeks in ill children (SA DoH 2005) – Ideal timing of starting ART in relation to TB treatment? – In adults simultaneous TB/HIV treatment associated with improved survival (Velasco Met al, J Acquir Immune Defic Syndr. 2009;50:148-152) • Treatment adherence training? Adherence • Treatment adherence usually → viral suppression • Inadequate viral suppression as a result of inadequate drug levels from whatever reason can result in the development of resistance mutations • Poor adherence most common reason for virological failure and development of resistance Adherence Challenges Patient factors Medication factors Provider/Site factors Children are dependent on care giver (age, illness, poverty, relationship, etc.) Formulations (EFV) Cost of treatment (outpatient fees, transport, work absenteeism, child care) Child may have developmental delay Palatability (Kaletra, ritonavir) Type of facility/resources Storage (d4T) Family dynamics Dosing (Kaletra, EFV) HW communication skills Disclosure Administration (ddI) Adolescence High “pill” burden Family care ART regimen • Regimen started was not consistent with SA national guidelines (SA DoH 2005) • Ritonavir not recommended as part of first line treatment; – EFV was recommended for children >3 years to be used concomitantly with TB treatment – Ritonavir was only recommended to be used with TB treatment in children < 3 years (no dose for LPV/r and no dose for EFV in this age group) Regimens for Children (SA DOH Guidelines) <3years 1st line stavudine (d4T) lamivudine (3TC) Kaletra® ≥3 years (>10kg) stavudine (d4T) lamivudine(3TC) efavirenz (Stocrin) Recommendations for TB cotreatment • Children not yet on ART with diagnosed TB – Start TB treatment first and within 1-2 weeks start ART – > 3 years use EFV at dose recommended for TB uninfected (Ren et al J Acquir Immune Defic Syndr 2007) – <3 years super-boosting LPV/r (extra ritonavir to make LPV:R 1:1) (Ren et al J Acquir Immune Defic Syndr 2008) • Children starting TB treatment after ART started, dose ART as above Ritonavir • Poorly palatable liquid formulation and adherence difficult • Ritonavir AUC reduced 35% by rifampicin (Hsu et al, Clin Parmacokinetics 1998) – Ritonavir not recommended with TB treatment (UCSF) • Dose of ritonavir 350-400mg/m2 – Initial dose appropriate – not increased according to weight Neverest Time to Viral Suppression <400 copies stratified for TB co-treatment 1.00 never TB TB at ART initiation TB after ART initiation 0.75 Censored never TB Censored TB at ART initiation Censored TB after ART initiation 0.50 0.25 0.00 0 50 100 150 200 250 300 350 Reitz C, Coovadia A et al CROI 2009 days Subsequent Course • Abscess development probably IRIS – Likely TB IRIS as responded to continued TB treatment – BCG IRIS possible as had BCG immunisation, BCG IRIS occurred as the most common IRIS event in the Neverest study (Smith et al AIDS 2009) • Treatment for TB continued through IRIS event stopped after 6 months – Duration of TB treatment in HIV? • Had immunological response to the HAART regimen and although ↓ VL never fully virally suppressed • Definition of Viral Failure in Children Aim of antiretroviral therapy is to suppress viral load (in SA <50 copies/ml) • No definition of viral failure in previous guidelines and WHO defines treatment failure clinically (WHO guidelines for ) • No data in children to guide VL switch – Data from PENPACT 1 (switch at 1 000 vs switch at 30 000) anticipated shortly • Increasing discomfort about allowing children to fail virologically, immunological and clinical deterioration occur at a later stage – Delay in switching from a failing NNRTI regimen may be associated with ↑ disease progression and all-cause mortality (Pietersen et al CROI 2008) • Updated SA paediatric guidelines will include virological guidance Management at Paeds HIV Clinic • Comprehensive assessment • Received adherence training for the first time – reported to be adherent previously, stable family with mother having health background and grandmother as treatment supporter • Was the child disclosed to? • Was mother’s health assessed? • Blood results – Mild Anaemia – WCC, plts normal • Any other blood tests?, Lipids? • VL not suppressed (4300) • Was resistance testing done? – switched 1 drug in failing regimen, resistance testing may have been helpful at that point Salient features • Delayed access to diagnosis and ART→ child severely immunocompromised at ART start • No apparent adherence counselling to mom before ART start • No age-appropriate disclosure to child • Use of ritonavir first line as the 3rd drug (poorly palatable in liquid formulation likely to impact adherence) • Significant drug interaction with rifampicin (UCSF drug interaction website does not recommend use of ritonavir with rifampicin) • Dose of ritonavir was not increased with growth of the child • At initial visit to Paeds HIV clinic, ritonavir substituted with LPV/r (single drug switch in the face of a VL of 4300copies/ml Diagnosis • Treatment failure – Poor adherence (palatability, mom not counseled initially child not disclosed to) – Treatment interaction with rifampicin and ritonavir – Failure to increase dose with growth – Likely to have resistant virus • • • • • PI resistance mutations NRTI resistance M184V TAMS No PMTCT exposure and no previous NNRTI’s used so unlikely to have NNRTI resistance Final Diagnosis Drug resistant HIV Discussion of Management Dr. Tammy M. Meyers IeDEA South Africa; delayed response to treatment failure 0.20 Kaplan-Meier probability of virologic failure and switch n=310 0.10 virologic failure (>10000 copies/ml x2) all switches to second line n=146 0.05 Probability 0.15 62/148 (42%) of children remaining in care for at least a year after failure are switched. n=95 0.00 switch meeting failure definition 0 6 12 18 24 30 36 Time in months since ART start Number at risk (Virologic failure) 5484 (1) 4163 (126) 3174 (95) 2355 (43) 1706 (22) 1113 (12) 589 Median time between failure and switch: 4.6 months (IQR: 1.5 – 8.5) Davies M et al for the IeDEA collaboration IAS 2009 Response to failing regimens of switching regimens • In the UK delays in switching regimens occur – 34% of 694 patients failing regimen remained on the same regimen at least 6 months before switching (CHIC, AIDS 2008) Principles of switching regimens after treatment failure • Full assessment of reasons for failure • No RCT’s to guide decisions around 2nd line Rx • Regimen switch should be guided by drug history and genotyping (where available) – In particular depends on whether there is failure of NNRTI- or PI- based regimen • Switch to 3 or at least 2 active agents if possible • NRTI’s traditionally included in 2nd line but other agents can be used Second line therapy for NNRTI resistance • There is no place for maintaining patients failing NNRTI regimen on the same regimen – The longer maintained the more resistance mutations likely to occur • The regimen should be changed to a boosted PI with 2 active NRTI’s (where available, newer agents may be an option) Second line therapy with PI resistance • Patients on boosted PI regimen not suppressing may have no PI and minimal NRTI mutations→ resume original regimen – (3/23 children failing boosted PI regimen at Harriet Shezi children’s clinic had low level PI resistance, the rest had no PI RAM Riddick et al IAS 2009) • In NNRTI naïve patients with no NNRTI and few NRTI resistance mutations simple switch to 2 NRTI’s +NNRTI may be appropriate • Patients with multiple PI mutations may achieve viral control when another boosted PI is used – Recently newer PI’s Darunavir and Tipranavir demonstrate improved control in this situation Darunavir • Non-peptide protease inhibitor • Binds rapidly to protease at a unique site and disassociates slowly → 2X higher binding strength vs other PI’s • Potent even against PI resistant strains • Together with tipranavir, darunavir is one of the only new agents licensed for use in treatment experienced children > 6years (licensed Dec 2008 FDA, awaiting EMEA registration, not MCC approved in SA) Darunavir • TITAN study (Rx experienced adults): – DRV/r compared to LPV/r in treatment experienced, DRV/r superior to LPV/r in the presence of ≥1 PI mutation at baseline (although not powered to detect a difference in sub-group anlysis) • POWER -1 and -2 study(Rx experienced adults): – DRV/r compared to comparator boosted PI in pretreated adults with PI resistance, DRV/r superior (VL<50 copies/ml 45% vs 10% in comparator) • Delphi – 80 treatment experienced children 48% VL<50 copies/ml, those with >3 darunavir RAMS more likely to fail. No serious AE’s Neely, Covacs . Managing treatment-experienced pediatric and adolescent HIV patients: role of darunavir. Therapeutics and Clinical Risk Management 2009:5 595–615 Tipranavir • Licensed for use in children >2 years • Rx failure with darunavir preserves activity of tipranavir and vice versa • Darunavir has lower pill burden • Darunavir less serious adverse events In the setting of multiple PI and NRTI resistance mutations darunavir or tipranavir can be used, ideally in combination with a newer agent eg new NNRTI (etravirine/ raltegravir/ CCR5 antagonist if has CCR5-tropic virus) New Generation NNRTI’s – Etravirine (licensed for use in adults) • In phase II trials in treatment experienced children (PAINT study) • Active against HIV strains resistant to Efavirenz , Nevirapine and Delavirdine – TMC-278 (Rilpivirine) • entering paediatric phase II trials (naïve adolescents) Integrase inhibitors • Raltegravir licensed in adults. Paediatric formulations in phase II trial treatment experienced (poloxymer and chewable formulations) (IMPAACT P1066) • • • • • 87 children enrolled Raltegravir was well tolerated Few drug related Grade 3 AE Preliminary data suggest positive CD4 and viral load responses PKs are challenging » Fed versus non fed state » Different for poloxamer vs. chewable preparations – RAL not a CYP substrate, inducer or inhibitor • Elvitegravir: not yet in kids CCR5 inhibitors • Require CCR5 tropic virus – Maraviroc licensed in adults – Vicriviroc, the newest CCR5 antagonist • • • • Being developed by Schering-Plough Currently in Phase III Treatment experienced children P1071 first enrolment last week – The medication is boosted significantly by ritonavir, and has been shown to be active against strains that are resistant to other medications, including Enfuvirtide Which NRTI’s? • Failing regimens containing 3TC select for M184V (one of 1st mutations to occur) – M184V reduces viral replication ability and viral fitness (also enhances susceptibility to AZT, D4T,TDF) – Retention of 3TC/FTC reasonable with another NRTI • In the absence of K65R/K70E, TDF ideal agent to continue or introduce as the 2nd NRTI (not recommended for young children because of bone metabolic and renal toxicities) • ddI may be used in combination with 3TC or FTC when thymidine analogues (d4T and AZT) or abacavir cannot be used What to prescribe for this child? • Ideally if able to afford it and after counseling patient and family, would apply for section 21 through MCC to use darunavir • Since there are no NNRTI mutations, EFV still active agent, (readily available through CCMT programme) • Choice of NRTI? – Multiple NRTI mutations – TDF intermediate resistance but not recommended for use in children – ddI intermediate resistance licensed for children and would use in regimen (readily available through CCMT programme) – Retain 3TC Darunavir/r + EFV + ddI + 3TC Resource Limited World • Darunavir unavailable and unaffordable in many settings, options include; – Switching to EFV/ddI/3TC (unlikley to be durable and likely to develop NNRTI resistance as well) – Holding regimen until newer drugs become available through CCMT? (no data in children) • 3TC monotherapy, promising results in small adult study (Catagna et al AIDS 2008) • Trizivir +TDF prevented immunogical decline and delay in viral evolution in 28 heavily experienced adults (Libre et al HIV Medicine 2008) Lessons Learnt • Viral resistance in children can be prevented; – Optimal first line regimen (boosted PI or EFV as3rd drug) – Rx and adherence training of family, ongoing adherence counselling – Initiating early enough in attempt to avoid OI’s eg TB and the need for polypharmacy – Increasing doses as children grow – Understanding drug interactions and optimising regimens accordingly – Ensure health of family maintained (switching of caregivers when ill or dying impacts regimen adherence) – Disclosure to children • Monitor treatment response and act on results – – – – – Regular VL, CD4 monitoring available in SA Repeat abnormal results preferably within a month Resistance testing helpful to guide regimen choice Assess reasons for failure, intervene to improve adherence as available Consider switching therapy early before multiple resistance mutations occur Lessons learnt • 2nd line drug regimen switch – – – – Previous drug exposure needs to be considered Resistance mutations may help guide choice Use 3 or 2 active agents in new regimen Approach resistance to PI vs NNRTI 1st line regimens differently • NNRTI – 2nd line available in SA • PI – depends on number of PI and NRTI mutations present • Need more treatment options for children – – – – – Simplified regimens Expedite trials of newer agents in children Registration by MCC of agents approved by FDA/EMEA lengthy Review current regimens as newer agents become available Need to lobby pharmaceutical industry to provide more appropriate regimens at affordable rates Followup Brian C. Zanoni, M.D.