Roles of protease inhibitors
for HIV infected children
By
Kulkanya Chokephaibulkit, MD
Faculty of Medicine Siriraj Hospital
Mahidol University
WHO Recommendation
When to Start ART in
Children: 2013
WHO Recommendation for 1st Line ART: 2013
WHO Recommendation for 2nd Line ARV 2013
US Recommended First Line Regimens
• NRTI + NNRTI or PI:
• Choice of NNRTI or PI
– ≥6 years: atazanavir/ritonavir (AI*)
– ≥3 years: efavirenz (AI*)
– ≥42 weeks postmenstrual and ≥14 days postnatal:
lopinavir/ritonavir (AI)
• Choices of NRTI
– ≥3 months: abacavir + (lamivudine or emtricitabine) (AI)
– Adolescents, Tanner Stage 4 or 5: tenofovir + (lamivudine
or emtricitabine) (AI*)
– Any age: zidovudine + (lamivudine or emtricitabine) (AI*)
First-line ART with a PI vs NNRTI an open-label,
randomised (PENTACT-1): Time to switch
71% were still on 1st line
57% were virologic suppress on 1st line
The PENPACT-1 (PENTA 9/PACTG 390) Study Team. The Lancet. Feb 1, 2011:1-11.
LPV/r Better Than NVP in Infants 2-36 Month-Old Who Had
No Exposure to NVP: 6 African countries and India (N=288)
May be NVP require step-up dosing, or LPV/r is more forgiving.
Violari A. NEJM 2012;366:2380-9
เกณฑ์ การเริ่มยาต้ านไวรั สในเด็กติดเชือ้ เอชไอวี
2013 (Draft)
อาการแสดง
ทางคลินิก
หรื อ
อายุ < 1 ปี
อายุ 1-5 ปี
> 5 ปี
เริ่มการ
รั กษา
CDC cat B, C
หรื อ WHO stage 3, 4
CDC catB, C
หรื อ WHO stage 3,
4
ระดับ CD4 ที่ควรพิจารณาเริ่มยาต้ านไวรั ส
% CD4 หรื อ
ระดับ CD4
เริ่มการ
รั กษา
%CD4 <25 OR
CD4 <500cells/mm3
1-3 yr CD4 < 1000 cell
3-5 yr CD4 < 500 cell
ยาต้ านไวรัสในเด็กติดเชือ้ เอชไอวี ARV naïve
Thai guideline 2013 (draft)
Preferred
< 1 year
1-3 years
3-12 years
> 12 years
AZT (ABC)
/3TC/LPV/r
AZT (ABC)/ 3TC
+ LPV/r or NVP
AZT (ABC)/ 3TC
+ EFV
TDF/3TC
+ EFV
AZT /3TC
/NVP
Alternative
AZT (d4T)
/3TC/NVP
d4T/3TC
+ LPV/r or NVP
If anemia d4T first 6 mo.
TDF/ 3TC + EFV
(NVP)
AZT/ 3TC
+ EFV or NVP
If anemia d4T first 6 mo.
Proposed Second Line ARV Regimen
for Thai Children (2013)
Failing first line
Preferred Second line
AZT+3TC +NNRTI
TDF + 3TC + LPV/r*
TDF or ABC +3TC +NNRTI
AZT + 3TC + LPV/r*
AZT+3TC+LPV/r
TDF (ABC) + 3TC + EFV (if no NNRTI-R)
TDF (ABC) +3TC + DRV/r (if NNRTI-R)
ABC+3TC+LPV/r
TDF + AZT+ EFV (if no NNRTI-R)
TDF+ AZT + DRV/r (if NNRTI-R)
• *If cannot tolerate LPV/r or developey dyslipidemia, replace with ATV/r
• Avoid using ddI due to problems of absorption, formulation, interaction, AE
สูตรยาต้ านไวรัสที่ใช้ ในเด็ก
ภายใต้ หลักประกันสุขภาพถ้ วนหน้ า 2013 (จานวน 5565 คน)
EFV based
NVP based
PI based
0.01
29%
PI+NRTI
others
21%
EFV+NRTI
NVP+NRTI
49%
First Antiretroviral Regimens in Asian Children: TreatAsia
2010 (11 sites from Cambodia, Indonesia, India, Malaysia, and Thailand), N=1655
Hansudewechakul R. JAIDS 2010:55:503-9
Others 4%
PI-based 6%
EFV-based 29%
At start of HAART (Median)
Age = 7 year-old
CD4% = 8%
CD4 count (>6 yo) = 100.5
NVP-based 61%
Switch Rate
NNRTI to PI = 4.1/100 person-year
PI to NNRTI = 3.8/100 person-year
Outcomes of Second Line PI Regimen in
Asian Children (TApHOD data)
153 children who were receiving PI for >24 weeks
Median age 10 yo. 83% used LPV/r
At 48 weeks
At 96 weeks
Immune recovery
61%
70%
UD HIV-RNA
60%
65%
Hyper TG (>130 mg%)
73%
66%
Bunupuradah T. Antivir Ther 2013
High virologic response rate after second-line boosted protease inhibitor-based
antiretroviral therapy regimens in children from a resource limited setting
Puthanakit T. AIDS Research and Therapy 2012.
http://www.aidsrestherapy.com/content/9/1/20/abstract
Lopinavir/r in Children
Pros
Cons
• Well known efficacy
• Excellent short term
safety
• Cheapest
• Pediatric formulation
available
• Co-formulate with RTV
• The first PI
recommended in most
guidelines
• Long term metabolic
complications
• High pill count
• OD not approved for
children
Atazanavir/r in Children
Pro
Con
• OD
• Less dyslipidemia
• Recommended as
preferred PI in
children >6 yo
• Not for <6 year-old
• Hyperbilirubinemia
• Need RTV boosting
(no co-formulation)
• More expensive
Efficacy of Atazanavir in Children 6-18 Year-Old
at 24 Weeks of Rx
15-25 kg: 150/80 mg; 25-32 kg: 200/100 mg,
32-39 kg: 250/100 mg; >39 kg: 300/100 mg
180
•
Safety:
Cough 21%
171 Jaundice 13%
Fever 19% Increase bilirubin 49%
160
140
116
120
100
80
60
40
Rx naïve
(24/41)
Rx experienced
59
(14/58)
24
20
0
% with VL < 50
CD4 gain
http://www.aidsmap.com/en/news/80F577BE-9DFE-4796-B4A7-BC9E0CB33149.asp
Characteristics of Lipodystrophy from Protease Inhibitors
• Fat gain on abdomen, breast, and dorsocervical
hump
• Fat loss from peripheral extremities
• Fat gain in visceral organs
Dyslipidemia found 40%-80% in children, associated with receiving
PI and lipodystrophy1-3
Prevalence of Dyslipidemia in a European cohort of HIV-infected children and
adolescents (N=426), 60% receiving PI4
Fasting Hypertriglyceridemia
66%
45%
21%
Hyper-cholesterolemia
49%
28%
1%
Glucose intolerance
5%
4%
1.Lapphra K. J Med Assoc Thai. 2005. 2. Taylor P. Pediatrics 2004. 3. Amaya RA. Pediatr Infect Dis J. 2002, 4. Alam NM. J Acquir
Immune Defic Syndr. 2012 March 1; 59(3): 314–324
Frequency of abnormal lipid profile in Thai
adolescents
Siriraj, Bangkok, 2013
HIV-infected
N = 100
Healthy
Total = 50
P value
CHOL > 200 mg/dl
25 (25%)
12 (24%)
0.867
LDL > 130 mg/dl
16 (16%)
8 (16%)
0.733
HDL < 35 mg/dl
8 (8%)
0 (0)
0.017
TG > 150 mg/dl
37 (37%)
1 (2%)
<0.001
49%
receiving PI
V. Poomlek. 7th IAS 2013, KL, MOPE047
Metabolic Syndrome in children and adolescents:
The clusters of metabolic risk factors
(International Diabetes Federation)
FBS > 100
mg/dl
BP>130/85m
mHg
Waist circumference >
P90
HDL<40 mg/dl
(<50 mg/dl in
female >16 yo
Presence of metabolic
syndrome increases the
risk of DM and CVD
TG>150 mg/dl
The cIMT in association with on PI > 6 months in
HIV-infected Thai adolescents
cIMT (mm)
Receiving PI
> 6 months
(n=53)
Receiving PI
< 6 months or P value
never(n=47)
Proximal CCA
0.393 (0.284-0.478)
0.369 (0.289-0.448)
0.019
Distal CCA
0.40 (0.273-0.475)
0.381 (0.311-0.441)
0.022
ICA
0.353 (0.283-0.514)
0.345 (0.26-0.431)
0.179
Overall cIMT
0.379 (0.284-0.451)
0.372 (0.287-0.423)
0.02
The values were presented in median (range)
Risk of Myocardial Infarction in Patients Exposed to Specific
Individual Antiretroviral Drugs : The Data Collection on Adverse
Events of Anti-HIV Drugs (D:A:D)
Worm SW. JID 2010;201:318-30.
Contribution of risks factors for CAD
in HIV-Positive Persons
1.04
1.25
1.47
Estimated effect (95%CI) on the
odds ratio of a first CAD event
for:
- genetic risk score quartile
(black dots),
- HIV-related variables (gray
triangles)
- traditional CAD risk factors
(gray squares).
Rotger M. CID 2013 Jul;57(1):112-21.
Estimated chronic kidney disease and
antiretroviral drug use in HIV-positive patients
CKD defined as confirmed (persisting for 3 months) decrease in eGFR to 60 ml/min per 1.73m2 or less
if eGFR at baseline above 60 ml/min per 1.73m2 or confirmed 25% decrease in eGFR if baseline eGFR
60 ml/min per 1.73m2 or less).
Mocroft A. AIDS 2010;24:1667-78.
After failing second line or AE
from second line regimens,
what’s next?
• Integrase inihibitor: RAL
• PI: DRV/r
• NNRTI: ETV
New regimen should compose
of 2-3 fully active drugs
An Adolescents who resist to everything
Date
26/11/1996
Age
5Y1M
23/3/1999
7Y3M
9/10/2001
9Y9M
18/3/2003
10/8/2004
17/7/2007
11Y3M
12Y8M
15Y7M
20/8/2007
15Y8M
22/1/2008
28/4/2009
Regimen
Start
AZT+ddI
Start
AZT+3TC+EFV
Start
AZT+3TC+IDV/r
“
“
“
Start
TDF+3TC+LPV/r
16Y1M
“
17Y4M
“
CD4 CD4%
312 6.43
VL
-
Remark
514
2.07
-
27
0.69
-
357
654
468
9.44
16.55
14.87
72,000
<400
4,830 V-Resistant
NRTI=M41L, D67N, K70R, M184V,
K219Q
NNRTI=A98G, G190A
LPV and TDF became available
544
-
12.49
-
997
8,240
V-Resistant
RT=M41L, D67N, T69N, K70R, A98G,
M184V*, G190A, H208Y*, T215S*
PR=L10F, G16E, K20I, M36I, M46I,
K55R, H69K, L89M, L90M, I93L
The genotype of AC076
Date
Age
28/4/2009 17Y4M
28/7/2009 17Y7M
27/4/2010 18Y3M
6/7/2010 18Y7M
18/1/2011 19Y1M
Regimen
“
CD4
%
Remark
544 12.49 8,240 V-Resistant
RT=M41L, D67N, T69N,
K70R, A98G, M184V*,
G190A, H208Y*, T215S*
PR=L10F, G16E, K20I,
M36I, M46I, K55R,
H69K, L89M, L90M, I93L
“
376 14.53
Start
AZT/3TC+TDF +DRV/r
“
“
VL
-
435 11.01 9,910
418 14.96 <40
ได้ ยา DRV จาก Dance
Program
Case Failure With Extensive Resistance
Date.
Age
Regimen
22/9/98
1Y5M
Start
CD4 CD4%
VL
956
15
-
890
30
-
Remark
AZT+3TC
30/10/01
4Y7M
Start
ddI+d4T+EFV
18/11/03
6Y8M
“
1,240
27
-
14/2/06
8Y11M
Start
814
26
-
627
22
Only NNRTI available.
(Should not be done.)
Lipodystrophy.
AZT+3TC+EFV
14/8/07
10Y5M
“
10,400 V-Resistant
NRTI = D67N, K70KR,
M184V,T215F, K219Q,
G333E
NNRTI = Y188L
26/2/08
10Y11M
Start
898
22
-
Check IDV level ok
3TC+IDV+LPV/r
19/8/08
11Y5M
“
884
27
<40
11/8/09
12Y5M
Start
595
32
<40
AZT/3TC+DRV/r
Hyperlipidemia.
Darunavir/r
The third line PI of choice
Pros
• Most potent PI
• Works in patients
resisted to other PIs
• Less dyslipidemia
• Well tolerate
• Approve from 3
year-old
Cons
• Expensive
• Need RTV boosting,
no co-formulation
• OD only in >12 yearold
Risk of triple-class virological failure in children with HIV:
a retrospective cohort study
Incidence per 100
person-years (95%
CI) of triple-class
virological failure in
children with HIV by
duration of
antiretroviral
therapy
*At end of year 9.
The Pursuing Later Treatment Options II (PLATO II) project team for the Collaboration of Observational HIV
Epidemiological Research Europe (COHERE)*. The Lancet 2011;377:1580-7.
DELPHI: Darunavir EvaLuation in Pediatric HIV-1Infected treatment-experienced patients
• Patients
– ARV treatment-experienced, HIV-1-infected pediatric patients (aged
6–17 years, on HAART ≥12 weeks, HIV-1 RNA ≥1000 copies/mL)
• Objective
– Evaluate safety, tolerability and efficacy of Darunavir/r plus an OBR
over 48 weeks in an open-label, Phase II study (TMC114-C212)
• 6–17 years old
• On HAART
≥12 weeks
• HIV-1 RNA ≥1000
copies/mL
• (N=80)
20–<30kg: Darunavir/r 375/50mg bid (n=20)
30–<40kg: Darunavir/r 450/60mg bid (n=24)
≥40kg: Darunavir/r 600/100mg bid (n=36)
ARV = antiretroviral; HAART = highly-active antiretroviral therapy;
OBR = optimized background regimen (≥2 ARVs)
Bologna R, Spinosa-Guzman S, et al. 15th CROI 2008. Abstract 78LB
Summary of antiretrovirals
used at screening (N=80)
NRTIs
NNRTIs
PIs
3TC
ABC
AZT
d4T
ddI
TDF
FTC
EFV
NVP
LPV
SQV
APV
TPV
ATV
NFV
IDV
ENF
0
10
20
30
40
50
60
70
Patients who had used drug at screening (%)
PIs = protease inhibitors
Meyers T, et al. 5th IAS 2009. Abstract 2133
NRTIs used in the OBR
NRTI used, n (%)
Group A (N=22)
Group B (N=22)
Lamivudine
12 (55)
10 (45)
Abacavir
8 (36)
5 (23)
Zidovudine
6 (27)
7 (32)
Emtricitabine
4 (18)
3 (14)
Tenofovir
12 (55)
8 (36)
Stavudine
7 (32)
5 (23)
Didanosine
5 (23)
10 (45)
Spinosa-Guzman S, et al. 4th IAS 2007. Abstract TUPEB125
DELPHI: baseline characteristics
Darunavir/r (N=80)
Demographics
57 (71)
Male, n (%)
Age at screening, years (± SD)
6–<12 years, n (%)
12–17 years, n (%)
Perinatal infection, n (%)
24 (30)
56 (70)
62 (78)
Disease characteristics
CDC classification C, n (%)
Mean (± SD) log10 HIV-1 RNA
Median CD4 cell count, cells/mm3 (range)
Median CD4% (range)
Mean duration of known HIV infection, years (± SD)
40 (50)
4.64  0.80
330 (6–1505)
17 (0.7–47)
10.7 (3.2)
SD = standard deviation
Bologna R, Spinosa-Guzman S, et al. 15th CROI 2008. Abstract 78LB
DELPHI: baseline characteristics (cont’d)
Darunavir/r (N=80)
Previous ARV treatment
Median number of ARVs (range)
PIs: ≥1, n (%)
NNRTIs: ≥1, n (%)
NRTIs: ≥2, n (%)
Enfuvirtide (ENF), n (%)
9 (3–19)
77 (96)
63 (79)
80 (100)
8 (10)
Median number IAS USA mutations1
Primary PI mutations (range)
PI RAMs (range)
NNRTI RAMs (range)
NRTI RAMs (range)
3 (0–6)
11 (0–19)
1 (0–4)
4 (0–8)
1. Johnson VA, et al. Top HIV Med 2006;14:125–130
PI = protease inhibitor; RAMs = resistance-associated mutations
Bologna R, Spinosa-Guzman S, et al. 15th CROI 2008. Abstract 78LB
DELPHI: Virologic response to Week 48
(ITT-TLOVR)
≥1 log10 HIV-1 RNA reduction
HIV-1 RNA <400 copies/mL
HIV-1 RNA <50 copies/mL
Response rate (%)
100
80
65%
59%
48%
60
40
20
0
0 2 4
N = 80
8
12
16
20 24
32
Time (weeks)
40
48
80
ITT = intent-to-treat; TLOVR = time-to-loss of virologic response
Blanche S, et al. AIDS 2009;23:2005–13
DELPHI: Mean change in CD4 cell count to
Week 48 (ITT-NC=F)
Mean change in CD4 count
(cells/mm3 ±SE)
200
150
+147
100
50
0
0 2 4
8
12
16
N = 80
20 24
32
Time (weeks)
40
48
80
NC=F = non-completer considered failure
Blanche S, et al. AIDS 2009;23:2005–13
DELPHI: Effect of number of baseline
DRV resistance-associated mutations on virologic
response – Week 48 analysis
Responders
At least 1 log10
decrease
VL <50
copies/mL
DRV resistanceassociated mutations at
baseline
N
n
%
n
%
0
39
29
74
23
59
1
17
12
71
8
47
2
15
9
60
7
47
≥3
9
2
22
0
0
Blanche S, et al. AIDS 2009;23:2005–13
DELPHI: AEs regardless of causality –
Week 48 analysis‡
N=80
Mean exposure (weeks)
60
Incidence
n
%
1 adverse event (AE)
74
93
1 grade 3 or 4 AE
21
26
1 serious AE
11
14
1 AE leading to permanent discontinuation
1
1*
Death
0
0
‡Since
first intake of drug; *Grade 3 anxiety considered unrelated to DRV/r
Blanche S, et al. AIDS 2009;23:2005–13
DELPHI: Grade 2–4 treatment-related clinical AEs
(incidence ≥1%)* – Week 48 analysis
N=80
Mean exposure (weeks)
60
Incidence
n
%
Diarrhea
1
1
Rash
1
1
*Laboratory abnormalities reported as AEs not shown in the table
Blanche S, et al. AIDS 2009;23:2005–13
DELPHI: Grade 2–4 laboratory abnormalities
(incidence ≥1%) – Week 48 analysis
Mean exposure (weeks)
Incidence
N=80
60
ANC decreased
n
10
%
13
Pancreatic amylase
9
11
ALT increased
5
6
AST increased
4
5
Lipase
3
4
ANC = absolute neutrophil count; ALT = alanine aminotransferase;
AST= aspartate aminotransferase
Blanche S, et al. AIDS 2009;23:2005–13
DELPHI: Mean lipid levels at baseline and Week 48
Baseline
Week 48
2.8
250
Left axis mg/dL; right axis mmol/L
6.5
250
p<0.01
Mean concentration
Normal values
p<0.05
p<0.001
p<0.05
200
2.3
200
5.2
150
1.7
150
3.9
100
1.1
100
2.6
50
0.6
50
1.3
0
0.0
0
0.0
Triglycerides
Total
cholesterol
LDL calculated
HDL
SI unit scales are different due to different conversion factors (0.0113 for triglycerides and 0.0259 for cholesterol)
Blanche S, et al. AIDS 2009;23:2005–13
Lipid Changes at Week 48 with Baseline in
PI Studies
Small Changes of Lipid Profile Following
DRV/r and ATV/r
METABOLIK: Week 48
Jules Levin. 10th International Congress on Drug Therapy in HIV Infection, Glasgow, November 7-11, 2010
เกณฑ์ การอนุมัตกิ ารใช้ ยา DRV ของ สปสช
(มีเฉพาะขนาดเม็ด 300 มก)
1. ไม่ เป็ น terminal ill
2. ข้ อใดข้ อหนึ่ง
– 2.1 Failing while on PI regimen > 6 months with triple class
mutation, >2 major PI mutation ([D30N, V32I, M46I, M46L,
I47A, I47V, G48V, I50L I50V, I54L, I54M, T74P, L76V,
V82A, V82F, V82L, V82S, V82T, I84V, N88S, L90M], but
still susceptible to DRV and available effective backbone
– Intolerance to PI
3. Likely to have good compliance
Darunavir Pediatric dose (6- <18 Year-old)
Recommended dose for treatmentexperienced pediatric patients
(6 to < 18 years of age)
Body weight (kg)
Dose DRV/r (mg)
≥ 20 kg–< 30 kg
375 / 50 mg b.i.d.
≥ 30 kg–< 40 kg
450 /60 mg b.i.d.
≥ 40 kg
600 /100 mg b.i.d.
ขนาดยาที่แนะนาในเด็กไทย ปรับตามยาเม็ดที่มี
ขนาด 300 มก เท่ านัน้
นา้ หนัก* (กิโลกรัม)
ขนาดยาที่แนะนาในเด็กไทย (สปสช) กินพร้ อมอาหาร
12–<15
DRV 300 มก. bid (ร่ วมกับ RTV 50** หรือ 100 มก.)
15–<30
DRV 450 มก. เช้ า, 300 mg เย็น (ร่ วมกับ RTV 50** หรือ100 มก.)
30–<40
DRV 450 มก. bid (ร่ วมกับ RTV 100 มก.)
≥40#
DRV 600 มก. bid (ร่ วมกับ RTV 100 มก.)
DRV Pharmacokinetic in Thai Children Using RTV 100
mg boosting for all
Median plasma concentration (mg/l)
10
● 20-30kg, ■ 30-40kg, ▲ >40kg
BID dosing
DRV/r
Standard
DRV/r
Thai
20 to < 30kg
375/50
375/100
30 to < 40kg
450/60
450/100
≥ 40 kg
600/100
600/100
8
6
4
2
0
0
2
4
6
8
10
12
Time (h)
Available in 75mg, 150mg, 300mg, 400mg, 600mg tablets
Chokephaibulkit K, Ananworanich J, et al Antiviral Therapy 2012
Food effect of DRV
Sekar V. Clin Pharmacol 2007;47:479-84
Resistance Pattern in 44 Thai Children Who Fail
Second Line Regimens
Ananworanich J. OUTCOMES OF THIRD-LINE ANTIRETROVIRAL THERAPY CONTAINING DARUNAVIR, ETRAVIRINE OR RALTEGRAVIR IN THAI
CHILDREN WITH HIV INFECTION 4th International Workshop on HIV Pediatrics 20-24 July 2012,
XIX International AIDS Conference 22-27 July 2012.
OUTCOMES OF THIRD-LINE ANTIRETROVIRAL THERAPY CONTAINING
DARUNAVIR, ETRAVIRINE OR RALTEGRAVIR IN 44 THAI CHILDREN WITH HIV
Ananworanich J. OUTCOMES OF THIRD-LINE ANTIRETROVIRAL THERAPY CONTAINING DARUNAVIR, ETRAVIRINE OR RALTEGRAVIR IN THAI
CHILDREN WITH HIV INFECTION 4th International Workshop on HIV Pediatrics 20-24 July 2012,
XIX International AIDS Conference 22-27 July 2012.
OUTCOMES OF THIRD-LINE ANTIRETROVIRAL THERAPY CONTAINING
DARUNAVIR, ETRAVIRINE OR RALTEGRAVIR IN 44 THAI CHILDREN WITH HIV
Ananworanich J. OUTCOMES OF THIRD-LINE ANTIRETROVIRAL THERAPY CONTAINING DARUNAVIR, ETRAVIRINE OR RALTEGRAVIR IN THAI
CHILDREN WITH HIV INFECTION 4th International Workshop on HIV Pediatrics 20-24 July 2012,
XIX International AIDS Conference 22-27 July 2012.
Treatment
Simplification
LPV/r วันละครั ง้ เทียบกับ วันละสองครั ง้ (+ optimized NRTIs) ในอาสาสมัครที่เคย
ได้ รับการรั กษามาก่ อน แต่ ไม่ เคยได้ รับยา LPV/r (VL>1000)
องค์ การอาหารและยา ประเทศสหรัฐอเมริกาได้ รับรองการใช้ ยา LPV/r วันละครัง้
สาหรับผู้ใหญ่ ท่ เี คยได้ รับการรั กษามาก่ อนที่มี =< 2 key mutations (พฤษภาคม 2010)
N=300 each arm
แสดงให้ เห็นว่ า ยา Lopinavir/Ritonavir วันละครัง้ ไม่ ด้อยไปกว่ า
วันละสองครัง้ ในผู้ใหญ่ ท่ เี คยได้ รับยาต้ านไวรัสมาก่ อน
R. Zajdenverg. M06-802 study.
5th IAS. Cape Town 19-22 July 09
Switching LPV/r from BID to OD in Children on 2nd Line Rx with
VL<50 copies/mL: N=11
All had VL < 50 copies/ml at 12, 24, and 48 weeks of OD dosing
• AUC for OD and BID were not different
• Cmin in OD was lower than in BID. 7 children had Cmin < 1 mcg/mL.
• Taking EFV (N=6) with LPV/r OD associated with lower Cmin , but no effect on AUC
Chokephaibulkit K, et al. JAC 2012, Aug 23. doi:10.1093/jac/dks332
DIONE: 24 Week Efficacy, Safety, Tolerability and Pharmacokinetics of Once
Daily DRV/r in Treatment-Naïve Adolescents, 12 to <18 years
Flynn P et al. 2011 6th IAS Conference, Rome, Italy Abs WePDB0101
HIV RNA <50 c/mL
200
Response (± SE):
HIV-1 RNA <50 copies/mL
(ITT-TLOVR; %)
92%
80
175
100
40
DRV/r (N=12)
20


CD4 cell count increase
150
60

Mean (± SE) change in CD4 cell
count (cells/mm3) (NC=F)
100
0
BAS 2 4
8
Time (weeks)
16
24
11/12 (92%) patients achieved HIV-1 RNA <50
copies/mL (ITT-Time Loss of Viral Response)
12/12 (100%) by FDA snapshot algorithm
One patient with one DRV RAM (V11I) at
baseline was a responder at Week 24




DRV/r (N=12)
50
0
BAS 2 4
8
Time (weeks)
16
24
Mean CD4 cell count increased by
175 cells/mm3
2 patients reported AEs at least possibly
related to treatment (all grade 1 or 2)
No patient discontinued DRV/r due to an AE
No deaths
ARIEL: PK substudy
• Optional for patients with confirmed HIV-1 RNA <50 copies/mL at Week 32
• DRV/rtv 40/7 mg/kg qd dose determined with population PK model using data
from the Week 2 analysis
• Ten patients participated: 5 female; 7 weighed ≥15kg, 3 weighed 14 to <15kg
DRV AUC0–24h geometric mean, μg•h/mL (SD)
DRV C0h geometric mean, ng/mL (SD)
ARIEL qd
sub-study
(n=10)
Adult (ARTEMIS)1
(N=335)
Adults, %
115 (40.6)
89.7 (27.0)
128
3029 (1715)
2027 (1168)
149
• No treatment-related or grade ≥2 AEs were reported
• All patients retained HIV-1 RNA <50 copies/mL during the two-week substudy
AUC0–24h=AUC between 0 to 24 hours
1. Janssen data on file
ARIEL: PK substudy
Virologically suppressed (<50 copies/mL) patients at ≥ Week 24 switched to
DRV/r 40/7mg/kg qd
14,000
DIONE Week 2 (n=12)
ARTEMIS* Week 4 (n=9)1
ARTEMIS* Week 24 (n=13)1
ARIEL substudy Weeks 32–40 (n=10)
12,000
DRV plasma concentration (ng/mL)
•
10,000
8000
6000
4000
2000
0
0
*Adults
4
8
12
16
20
24
Time (hours)
1. Janssen data on file
Pharmacokinetics and 48-weeks efficacy of once daily
darunavir/ritonavir in virologic suppressed HIV-infected Thai
children: a pilot study
Weight band
BID
OD
20 to <30 kg.
DRV 375 + RTV 100
DRV 450 + RTV 100
30 to <40 kg.
DRV 450 + RTV 100
DRV 600 + RTV 100
≥ 40 kg.
DRV 600 + RTV 100
DRV 900 + RTV 100
6/8 children maintained
virologic suppressed to 48
weeks of OD dosing
Chokephaibulkit K, 7th IAS 2013, Kuala Lumpur. Abs# MOPE047
Conclusions: Recommended DRV/rtv
pediatric dosing
3 to <6 years
ARVexperienced
10 to 15kg:
20/3mg/kg bid
15 to 20kg:
375/50mg bid
6 to <12 years
≥20 to <30kg: 375/50mg bid
≥30 to <40kg: 450/60mg bid
≥40kg: 600/100mg bid
10 to 15kg: 35/7mg/kg qd
ARVnaïve
15 to 30kg: 600/100mg qd
30 to 40kg: 675/100mg qd
US and EU
US only
12 to <18 years
40kg: 800/100mg
qd
DRV: drug interaction data available
No dose adjustment of DRV or co-administered drug
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Tenofovir (TDF)
Clarithromycin (CLAR)
Atazanavir (ATV)
Ketoconazole (KTZ) (max dose 200mg)
Efavirenz (EFV)
Paroxetine (PAR)
Sertraline (SER)
Didanosine (ddI)
Modify dose or schedule
of co-administered drug
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Atorvastatin (ATORV)
Sildenafil (SIL)
Pravastatin (PRA)
Ethinyl estradiol (EE)
Norethindrone (NE)
Digoxin
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Nevirapine (NVP)
Etravirine (ETR) TMC125
Ranitidine (RAN)
Omeprazole (OME)
Indinavir (IDV)
Enfuvirtide (ENF)
Methadone (MTD)
Not recommended
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Saquinavir (SQV)
Lopinavir (LPV)
Back D. et al Antivir Ther. 2008; 13:1-13
Raltegravir/Etravirine/r-Darunavir Combination in
Adolescents with Multidrug-Resistant Virus
Percent
(N=12)
100
100
90
92
80
70
83
75
60
VL <400
VL <50
50
40
42
30
20
42
25
10
0
Month
8
1
3
6
9
Of treatment
Thuret I. AIDS 2009;23:2364-6.
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