Antiretroviral Therapy in Children With Drug Resistance Virus

1
Antiretroviral Therapy in Children With Drug
Resistance Virus

• By
• Kulkanya Chokephaibulkit, MD
• Department of Pediatrics
• Faculty of Medicine Siriraj Hospital
• Mahidol University

2
Recommended Drug Regimen to Start
WHO (2008)
EU (2004)
USA (2008)

• First choice
• 2NRTIs LPV/r or NFV or
• 2NRTIsEFV or NVP

• Preferred
• 2NRTIs LPV/r or ATV/r
• 2NRTI EFV (or NVP
• in lt 3Y)
• Choices of 2NRTI
• AZT3TC/FTC
• ABC3TC/FTC
• ddIFTC
• TDF3TC/FTC (gt18yo)
• May use AZTABC,
• AZTddI

• Preferred Options
• AZT/ABC/d4T3TC
• NVP/EFV
• For infants exposed to SD-NVP consider
• AZT/d4T/ABC3TC LPV/r
• THAILAND (2007)
• AZT/d4T3TC
• NVP / EFV (in gt 3yo)

AIDSinfo.nih.gov Sharland M.
HIV Med 2004 www.who.int
3
 Children Do Not Response to HAART As Well As
Adults VL and CD4 At 12 Months After Initiation
of HAART
Judd A. CID 200745918-24.
4
In Usual Practice in UK
By 6 Years of Treatment

• 
  N4306
• Virological failure 38
• gt1 major mutation 27
• Mutation gt 2 drug classes 20
• gtgtPI with RTV had lower risk of resistance

The UK Collaborative Group on HIV Drug
Resistance, UK CHIC Study Group
5
Survival of children who started HAART in Takeo
and Siem Reap.
Effectiveness of HAART in HIV-Positive Children
Evaluation at 12 Months in a Routine Program
in Cambodia
Factors associated with VLgt400 after 12 M of
HAART is being orphans
Janssens B. Pediatrics 2008120e1134-1140.
6
Predictors of Long-Term Viral Failure Among
Ugandan Children and Adults Treated With
Antiretroviral Therapy
Kamya MR. JAIDS 200746187-93.
7
Clinical Criteria
for Treatment Failure

• US and Thai
• Progressive neuroldevelopmental deterioration
• Growth failure
• Severe / recurrent infection / illness
• WHO
• New stage 4 condition (very same to AIDS)
• May consider in new stage 3 condition

8
Immunologic Criteria for Treatment Failure

• US
• For severe immunologic stage, CD4 response lt5
  (or lt 50 cells) after 1 yr of Rx
• CD4 decline gt5 or to less than baseline
• Thai
• Change in immunologic classification
  
• In those with CD4 lt15, persistent decline gt5
• Rapid decline (30 in 6 mo)
• WHO
• CD4 decline to lt15 in 1-3 yo., lt10 in 3-5
  yo., lt100 cells in lt 5 yo.

9
Failure Rate of NVP-Based VS
EFV-Based regimens in Thai children (Siriraj
Hospital) Median F/U 3 yr
Experience
Naive
EFV
NVP
EFV
NVP
10/44
9/23
2/34
1/38
- No. of failure needed to
(22.7)
(39)
(5.8)
(2.6)
switch from NNRTI
18
24
24
24
- Median duration of Rx before switching (mo.)
All were switched to boosted PI or double boosted
PI
10
Virologic Criteria for Treatment Failure

• US
• Incomplete response to RX (VL decline lt 1 log
  after 3 mo of Rx (gt6 mo in experienced cases) or
  VL still gt 400 after 6 mo
• Viral rebound (Increase gt0.5log (3-fold) in gt2 yo
  or gt0.7 log (5-fold) in lt2 yo)
• Thai
• Same as US
• WHO
• No criteria. However, if CD4 and clinical
  criteria are conflicting, then use HIV-RNA
  gt100,00 copies/mL as consideration to change
  treatment

11
Some Facts

• Some patients who were on HAART may maintain
  clinical and immunological benefit up to 3 years
  despite detectable virus
• gtgt Patients who have persistent improvement of
  CD4 despite persistent viremia, should be
  considered to continue ART. However, if
  appropriate regimen is available, it is preferred
  to change before more resistance developed

12
Treatment Failure Defined by Immunologic Markers
Alone May Result in Unnecessary Regimen Change in
Resource-Limited Settings

• In 54 adherent, clinically stable patients with
  immunologic failure (category 3)
• HIV-1 RNA gt400 copies in 30 (56) cases
• Median HIV-1 RNA 93,686 copies/mL (range
  2611-694,993)
• HIV-1 RNA lt400 copies in 24 (44) cases

Basenero A, Castelnuovo B, Birabwa E, et al. 4th
IAS, July 22-25, 2007 Sydney, Australia.
Abstract WEAB102.
13
Number of Children Taking ART Under NHSO Was
7,908 (September 2008)
No.
Age in Yr
www.nhso.go.th
14
Result of HIV-RNA Tests (N 5,925
specimens)(September 2008)
www.nhso.go.th
15
Resistance is probably the cause of failure if
the patient takes medicine

• Fact
• Imperfect adherence hasten the time to failure

16
Resistance Development While on 2NRTINNRTI
Regimens

• Very early failure
• 3TC-R M184V

Early failure 3TC-R M184V NNRTI-R e.g.K103N,
Y181C/I, Y188L, G190A/S Other NRTI-R minimal or
none
Late failure 3TC-R M184V NNRTI-R e.g.K103N,
Y181C/I, Y188L, G190A/S TAMs M41L, D67N, K70R,
L210W, T215Y, K219Q/E
17
Drug Resistance Mutations in Adults Who Failed
FDC of d4T/3TC/NVP
Sungkanuparph S. CID 200744447-52.
18
Predictors of Long-Term Viral Failure Among
Ugandan Children and Adults Treated With
Antiretroviral Therapy
Kamya MR. JAIDS 200746187-93..
19
Class-Sparing Regimens for Initial Treatment of
HIV-1 Infection
EFV 2NRTI has lower chance of virologic failure
than LPV/r 2NRTI. EFVLPV/r was equal to
EFV2NRTI, but more likely associated with drug
resistance.
2NRTI
P lt0.003 _at_wk 96
2NRTI
Riddler SA. NEJM 200835820952106.
20
Emergence of Drug Resistance After Receipt of
First-Line HAARTA Systematic Review of Clinical
Trials at 48 wks by ITT
Virologic Failure _at_ 48 wk NNRTI 4.9
(3.9-6.1) bPI 5.3 (4.4-6.4)
Gupta R. CID 200847712-22.
21
Prevalence of NRTI Resistance Among 95
HIV-infected Children Who Had Received Dual NRTI
For gt 6 MonthsNAMs, 60 had lt4 NAMs, and 40 had
NAMs.
Lolekha R. CID 200540309-12.
22
Interpretation of Genotypic Resistance
TAM I M41L, L210W, T215Y TAM II D67N, K70R,
K219Q, K219E

• NRTIs
• Any TAM resist to AZT
• TAM I pathway More resistance TAM II still can
  use ddI, TDF
• M41L T215F/Y resist d4T
• 2-3 TAMS may be able to use ddI, TDF, ABC
• gt3 TAMs resist all NRTI
• M41L, L210W, T215Y pathway is more resistant than
  D67N, K70R, K219Q/E
• 69 insertion T215Y 2 of M41L, A62V, K70R, L210W
  resist to all NRTI
• Q151M complex Q151MF77L(A62V, V75I, F116Y)
  resist to all NRTI except TDF
• L74V, K65R resist to ABC and ddI
• K65R resist to TDF, but still susceptible to AZT

23
Drug Options for Salvage Regimens

• NRTI
• AZT if no bad TAMs
• ddI, TDF, ABC if lt 4 TAMs, and no K65R
• (TDF should not be used for lt18 yo, and ABC is
  expensive)
• 3TC may still use with M184V to reduce fitness
• NNRTI once resist, no option left
• PI
• LPV/r is excellent esp. for PI naïve
• ATV/r is expensive, use with dyslipidemia
• SQV is expensive, and only pill available
• IDV/r is less potent and renal toxic

24
Interpretation of Genotypic Resistance

• NNRT Any single mutation cause high level
  resistance
• PI need more than 3-4 mutations to confer
  resistance
• 2 UPAM (universal PI-asso mutation) at 82, 84,
  and 90 position will resist to RTV, IDV, SQV, APV

25
Options for a Second-Line Regimen For Adults Who
Failed FDC of d4T/3TC/NVP
Sungkanuparph S. CID 200744447-52.
26
What Regimen to Change To (US)
Guideline for the Use of Antiretroviral Agents in
Pediatric HIV Infection Oct26, 2006
27
RECOMMENDED SECOND-LINE REGIMENS IN INFANTS AND
CHILDREN IN THE EVENT OF TREATMENT FAILURE OF
FIRST-LINE REGIMENS
WHO Guideline 2006
28
Nelfinavir
Contamination with a carcinogen, ethyl methane
sulfonate (EMS) during the production. Do Not
Use
29
Problems of Drugs for Salvage Regimens for
Children in Thailand

• ddI available in giant generic tablet to dissolve
  in water, unfriendly taste. ddI-EC is not
  available by NHSO, and not for young children.
• ABC is expensive and not available by NHSO
• TDF is available but can use only in adolescents
  and adults
• LPV/r available only in adult generic tablet
  (200/50), children need to cut the pill
• IDV is available, but the TDM is not feasible in
  routine
• SQV is expensive and not available by NHSO
• ATV is limited available, and only in adult
  tablet formulation

30
Lopinavir/ritonavir (Cap133/33, Tab 200/50, Tab
100/25)

• Heat stable tablet is easier
• Recommended dose using 200/50 mg tab
• 15-25 kg 1 tab
• 25-35 kg 1.5 tab
• gt 35 kg 2 tab

Abbott 133/33 mg
Matrix 200/50 mg
Study in 33 children (14 used 1.5 tab) at
Siriraj, QSNICH, HIVNAT Mean Ctrough (SD) 8.2
(5.7) using Abbott 8.2 (5.4) mg/L using
Matrix
31
Recommendation of Salvage Regimen in Thai Children
TAM mutation 41L, 215Y, 210W, 67N, 70R,
219Q/E
32
Salvage Regimen for The Patients Who Fail dual
NRTIs Regimens

• If lt 3 TAMs or good TAMs
• New 2NRTI boosted PI
• If gt 3 TAMs (esp bad TAMs 41L, 210W, 215Y)
• NNRTI boosted PI 1-2NRTI
• Careful if to salvage with NRTIs NNRTI
• Always check genotype if to continue NRTI

33
Advantages vs Drawbacks of Each PI
34
Efficacy of 2NRTIlopinavir/ritonavir

In 21 PI-naïve
Children Who Failed 2NRTINNRTI
100
92
86
71
Delaugerre, et al. J Acquir Immune Defic Syndr
200437 1269-1275.
35
Factors Influencing Virologic Response (VLlt400
copies/mL) In Children Receiving LPV/r Salvage
Regimens ( Response in 56/67 66)
a Beginning of HAART protocol with LPV and other
new drugs.
Resino S. JAC200454921-31.
36
FDA Approved ATV In Children March 2008

• ATV capsule can be used from gt6 yo.
• It should be used with RTV
• It should not be used in lt3 mo.
• Safety Cough 21 Jaundice 13
• Fever 19 Diarrhea 8
• Headache 7 Running nose 6
• Increase bilirubin 49
• Efficacy at 24 wk, VL lt50
• Rx-naïve 59
• Rx-exp 24
• Increase CD4 171 cell/mm3

http//www.aidsmap.com/en/news/80F577BE-9DFE-4796-
B4A7-BC9E0CB33149.asp
37
Indinavir Plasma Levels at Different Dosage IDV
can be used safely at 220-300 mg/M2 plus RTV 100
mg
Level associate with toxicity
Minimum target trough
Bergshoeff AS. AAC 200448 1904-7.
Plipat N, et al. PIDJ 20072686-8
Cressey TR, et al. JAC 2005551041-4.,
38
National Access Program to ART (NHSO) (September
2008)
A AZT/d4T3TCNVP/EFV B AZT/d4T3TCIDV/r
intolerance to A C ddI/TDF3TCIDV/r or NNRTI D
2NRTI LPV/r D others
www.nhso.go.th
39
At least half of the infants exposed to perinatal
single-dose NVP developed NVP resistance.
Infants may need SECOND-LINE regimen from the
start!
Check genotype for NVP-R to all infants exposed
to SD-NVP
40
Frequency of Development of NVP Resistance in
Infants
Rate ()
100
NVP-R reduced by eliminate maternal NVP and use
of neonatal NVPAZT
87
90
80
74
70
57
60
50
Mom - Baby
40
A1 NVP - NVP
27
30
A2 NVP - NVP/AZT
20
B1 NO - NVP
B2 NO - NVP/AZT
10
0
NVP- R
Eshleman SH. JID 2006193479-81.
41
Response to NVP-based HAART After Exposure to
Peripartum SD-NVP (MASHI)
100
92
90
88
VL lt400 at 6 mo Rx
58
23
Plt0.001 P 0.39
Mean age of Rx initiation 8 mo.
N 60 N 158 Time from SD-NVP/Pla
Lockman S. NEJM 200735611135-47.
42
We Should Test for Drug Resistance in All Infants
Exposed to SD-NVP

• More incidence of NVP-R in adults recently
• High rate of NVP-R in infected infants (50)
  after single dose perinatal exposure

• What if Genotyping is not available
• May try NVP regimen with close VL monitoring
• Infants who have a very rapid disease
  progression should not try NVP regimen, but
  should get LPV/r

43
A Cases Scenario

• A 3 week old infant, healthy, came for F/U
• The mother received AZT from 34 week and SD-NVP
  at labour
• The infant received AZT3TCSD-NVP
• The PCR at birth was positive

• Need to start HAART ASAP, and check if there
  is NVP-R
• Dont forget to give AZT3TC plus NVP (SD or 2
  wks) in high risk cases (late Rx, poor compliance)

44
Antiretroviral Drugs for Neonates Exposed to HIV

• Drugs Dose
  Duration
• Syr. AZT 2 mg/kg Q 6 hr 1-6 wks
• or 4 mg/kg Q 12 hr
  1-6 wks
• SD-NVP 2 mg/kg _at_ 48-72 hr-old once
  (or twice)
• NVP 2 mg/kg Q 24 hr x 7 d
  total 2 wk
• then 4 mg/kg Q24 hr x 7 d
• Syr 3TC 2 mg/kg Q 12 hr 1-4 wk

Thai-MOPH SD-NVP 2 mg/kg _at_ birth or 48-72 hr.
Syr. AZT 2 mg/kg Q 6 hr x1 wk if maternal AZT
gt4 wks OR x 6 wks if maternal AZT lt4 wks
45
LPV/r in Infants Younger than 6 Month

• Slightly higher clearance than older children
• At 24 weeks, 53 had VL lt 400 cp/mL
• Poor adherence is the problem of virologic
  failure
• Suggested dose in lt 6 mo 300/75 mg/M2 (vs
  230/57.5 mg/m_at_ in gt 6 mo)
• PACTG 1030 After 24 wks of LPV/r-HAART initiate
  before 6 mo, 70 had VLlt50 cp/mL

Chadwick EG. AIDS 2008 1122(2)249-55
Persaud D. JID 20071951402-10
46
LPV/r-Based Versus NVP-Based HAART For Infants

• LPV/r
• Advantages
• Highly effective
• Better immunologic response
• Liquid formulation available
• No pre-existing resistance
• High resistance barrier
• Disadvantages
• Expensive
• Not good taste
• Should be refrigerated
• Less experience in lt 6 mo. (not approved)

• NVP
• Advantages
• Cheap, affordable in all settings
• Better taste
• Liquid formulation available
• May be less effective
• FDC available
• Disadvantages
• May have pre-existing resistance esp. from
  perinatal NVP use
• Low resistance barrier
• Potential A/E in 15-20 (hepatitis, rash)

47
Management of Some Adverse Events From ARV

• Switch ARV
• Anemia -gt change AZT
• Lipodystrophy -gt change d4T
• Rash, hepatitis-gt change NVP (sometimes EFV)
• Dyslipidemia start intervention when
• Cholesterol gt 200 mg
• LDL gt 130 mg
• Triglyceride gt 200 mg
• Start with diet control, exercise
• If not improve, consider switch to ATV (now
  approve from 5 yo.)

48
Prevalence of Dyslipidemia from the Data
Collection on Adverse Events of Anti-HIV Drugs
(DAD)
Fontas E. JID 20041891056-74.
49
Rash from Nevirapine

• Found in 15-20 mostly within
• 2-4 wks (up to 12 wks)
• may associated with hepatitis
• Cant be prevented by steroid
• Rx stop NVP, antihistamine (steroid)

50
Lipodystrophy Associated with Stavudine Mostly
found in older children getting into puberty 1/3
improved after stopping d4T and with growth spurt
51
Risk of Extensive Virological Failure to The
Three Antiretroviral Drug Classes An
Observational cohort study
Cumulative risk of extensive triple-class
virological failure
Cumulative risk of virological failure of for
individual drug classes according to years from
start of that class
Phillips AN. The Lancet 20073701923-8.
PI/rritonavir-boosted protease inhibitor.
52
Lower Risk of AIDS If Stay On Failing
RegimensFrench cohort 2000-2005 in patients
with CD4
lt200 for gt 6 months
- New AIDS event associated with CD4 lt50, VL
gt30,000 - Interrupt Rx had highest risk of AIDS
Kousignian I. CID 200746296-304
53
What need to investigate next in
children?

• Double boosted vs single boosted PI in PI-naïve
  patients
• From initiation of salvage
• After successful viral suppression
• What to use after first-line PI resistance
• New PI Darunavir
• New class Integrase inhibitor, receptor
  antagonist

54
Second-line regimen in childrenRetrospective
cohort 8 centers from Thailand 241 children
failed NNRTI-based regimen
Puthanakit and Ananworanich, et al.-in preparation
55
Changes in Risk of Death After HIV
Seroconversion Compared With Mortality in the
General Population
Excess Mortality (/1000 person year)
40.8
31.4
11.9
9.5
8.5
6.1
Bhaskaran K. JAMA 200830051-9.
56
Adjusted Life Expectancy On CART In High-Income
CountriesAn analysis of 14 cohort studies by
year of F/U and baseline CD4
The average number of years remaining to be lived
at age 20 years was about 2/3 of that in the
general population in these countries.
The Lancet 2008372293-9.
57
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58
Next Challenging Issues For The Grown-Up
HIV-Infected Children

• Disclosure children need to know their diagnosis
  and get positive attitude before becoming
  adolescent
• Lifelong adherence
• Being a teenager
• Sex issues
• Peers acceptance
• High risk behaviors
• Future education and career
• Making own family

59
Care Givers Family
Care Provider Team

• Treatment
• Supportive
• Specific
• Palliative

60
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