Transcript Clinicopathologic Conference

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.