8/2/2014 1 HIV: Antiretroviral Therapy Ploenchan Chetchotisakd, MD Professor of Medicine Division of Infectious Diseases and Tropical Medicine Department of Medicine Faculty of Medicine Khon Kaen University Based on Thai Guideline, Asymptomatic HIV จะเริ่มยาต้านไวรัสเมื่อใด? A. CD4 > 500 B. CD4 < 500 C. CD4 < 350 D. CD4 < 200 E. เมื ่อใดก็ได้เมื ่อผู ้ป่ วยพร้อม Lab ใดบ้างที่ ต้องตรวจในผู้ป่วย newly diagnosed HIV? A. CD4 B. Viral load C. HBs Ag D. HCV Ab E. VDRL F. CXR G. LFT H. Pap smear in women I. Lipid profiles จงจับคู ่ยา ARV ว่าอยู ่ในกลุ่มใด 1. AZT 2. TDF 3. 3TC, FTC 4. NVP 5. IDV 6. RTV 7. ddI 8. d4T 9. EFV 10. LPV A. NRTI B. NNRTI C. PI ยาคู ่ใดที่ ไม่ใช้ ร่วมกัน A. AZT+d4T B. AZT+3TC C. AZT+TDF D. ddI + d4T E. FTC+3TC F. TDF +ddI G. TDF+3TC จงจับคู ่ ARV และ side effect A. AZT B. d4T C. TDF D. NVP E. EFV F. LPV/r G. IDV/r 1. CNS side effect 2. Nephrolithiasis 3. Lipoatrophy 4. Diarrhea 5. Anemia 6. Fanconi syndrome 7. Hepatitis and rash
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HIV: Antiretroviral Asymptomatic HIV Therapy ART... · C. AZT+TDF C. D. ddI + d4T E. FTC+3TC F. TDF +ddI G. TDF+3TC งจบัคู่ARV และ side effect A. AZT B. d4T TDF
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8/2/2014
1
HIV: Antiretroviral Therapy
Ploenchan Chetchotisakd, MD
Professor of Medicine
Division of Infectious Diseases
and Tropical Medicine
Department of Medicine
Faculty of Medicine
Khon Kaen University
Based on Thai Guideline, Asymptomatic HIV จะเรมยาตานไวรสเมอใด?
A. CD4 > 500
B. CD4 < 500
C. CD4 < 350
D. CD4 < 200
E. เมอใดกไดเมอผปวยพรอม
Lab ใดบางทตองตรวจในผปวย newly diagnosed HIV?
A. CD4
B. Viral load
C. HBs Ag
D. HCV Ab
E. VDRL
F. CXR
G. LFT
H. Pap smear in women
I. Lipid profiles
จงจบคยา ARV วาอยในกลมใด
1. AZT
2. TDF
3. 3TC, FTC
4. NVP
5. IDV
6. RTV
7. ddI
8. d4T
9. EFV
10. LPV
A. NRTI
B. NNRTI
C. PI
ยาคใดทไมใชรวมกน
A. AZT+d4T
B. AZT+3TC
C. AZT+TDF
D. ddI + d4T
E. FTC+3TC
F. TDF +ddI
G. TDF+3TC
จงจบค ARV และ side effect
A. AZT
B. d4T
C. TDF
D. NVP
E. EFV
F. LPV/r
G. IDV/r
1. CNS side effect
2. Nephrolithiasis
3. Lipoatrophy
4. Diarrhea
5. Anemia
6. Fanconi syndrome
7. Hepatitis and rash
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2
จงจบค fixed combination ARV
A. d4T+3TC+NVP
B. AZT+3TC+NVP
C. AZT+3TC
D. d4T+3TC
E. TDF+FTC
F. LPV+RTV
G. TDF+FTC+EFV
1. Zilarvir
2. GPO VIR-S
3. Lopinavir
4. Lastavir
5. Atripla, Teevir
6. Truvada, Ricovir EM
7. GPO VIR-Z
GENERAL KNOWLEDGE OF HIV
9
Deaths per 100 Person-Years
0
5
10
15
20
25
30
35
40
1995 1996 1997 1998 1999 2000 2001
De
ath
s p
er
10
0 p
ers
on
-ye
ars
0
25
50
75
100 Pe
rce
nta
ge
of p
atie
nt-d
ays
on
AR
T
DEATHS
USE OF ART
Mortality vs. ART utilization
Palella F et al. 8thCROI 2001; abstract 268b.
AIDS Mortality Rates: 1996-2001
EuroSIDA EuroSIDA November 2000
Durability of clinical effect of HAART: Incidence of AIDS and death 1994-2000
0
5
10
15
20
25
30
35
9/94-
3/95
3/95-
9/95
9/95-
3/96
3/96-
9/96
9/96-
3/97
3/97-
9/97
9/97-
3/98
3/98-
9/98
9/98-
3/99
3/99-
9/99
>9/99
Calendar period
Incid
en
ce (
per
100 P
YF
U)
0
20
40
60
80
100Deaths
AIDS
% on HAART
0
5
10
15
20
25
30
35
40
82 84 86 88 90 92 94 96 98*
De
ath
s p
er
10
0,0
00
Po
pu
lati
on
Unintentional
injuryCancer
Heart disease
Suicide
HIV infection
Homicide
Chronic liver
diseaseStroke
Diabetes*Preliminary 1998 data
Trends in Annual Rates of Death from Leading Causes of Death Among Persons 25-44 Years Old, USA, 1982-1998
National Center for Health Statistics National Vital Statistics System
ATHENA National Cohort[2] Johns Hopkins HIV Clinical Cohort[1]
Yrs on HAART
Me
dia
n C
D4
+ C
ell
Co
un
t
(ce
lls/m
m3)
1000
BL CD4+ Cell Count
0 48 96 144 192 240 288 336
Wks From Starting HAART
200
400
600
800
0
1000
> 500 351-500
201-350 51-200 < 50
BL CD4+ Cell Count 200
400
600
800
0 0
1 2 3 4 5
> 350
< 200 201-350
6
When to Start: 2012 DHHS Guidelines CD4+ Cell Count Recommendation
CD4+ cell count < 350 cells/mm³ Start ART (AI)
CD4+ cell count 350-500 cells/mm³ Start ART (AII)
CD4+ cell count > 500 cells/mm³ Start ART (BIII)
Clinical Conditions Initiation of Therapy Regardless of CD4+ Cell Count
History of AIDS-defining illness (AI)
Pregnancy (AI)
HIVAN (AII)
HBV coinfection (AII)
US Department of Health and Human Services. Available at: http://aidsinfo.nih.gov/Guidelines.
Commitment to adhere ARV
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European Guideline 2013 Condition Current CD4 count
350-500 >500
Asymptomatic HIV C C
To reduce transmission of HIV C C
Symptomatic HIV disease R R
Primary HIV infection C C
Pregnancy R R
HIV associated condition HIVAN Neurocognitive impairment Hodgkin’s lymphoma HPV associated cancers Non-AIDS defining cancers Autoimmune diseases High risk for CVD or history of CVD
R R R R C C C
R R R R C C C
Chronic viral hepatitis HBV requiring treatment HCV for which anti-HCV treatment is being considered or given HCV which anti-HCV treatment not feasible
ddI/TDF High rate of early virologic failure Rapid selection of resistance mutations Potential for immunologic nonresponse/CD4 decline
ddI + d4T High incidence of toxicities
d4T + AZT Antogonistism in vitro and in vivo
FTC + 3TC Similar resistance profiles Minimal additive antiviral activity
Fixed Combination drugs
• d4T+3TC+NVP= GPO VIR-S
• AZT+3TC+NVP= GPO VIR-Z
• AZT+3TC= Zilarvir
• d4T+3TC= Lastavir
• TDF+FTC= Truvada, Ricovir EM
• LPV+RTV= Lopinavir
• TDF+FTC+EFV=Teevir
Atripla
Boosted PI
• SQV 3x3
• RTV 6x2 (refrigerate)
• IDV 2x3 (q 8 hr with empty stomach)
• LPV/r
• ATV
• DRV
• SQV/r 1000/100 BID
• IDV/r 400/100 BID
• LPV/r 400/100 BID
• ATV/r 200-300/100 OD
• DRV/r 800/100 OD
Moyle G, et al. Drugs. 1996;51:701-712.
Boosting PI Levels With RTV
Time
Pla
sma
Co
nce
ntr
atio
n
PI
boosted PI
PI level required to overcome WT virus
PI level required to overcome “resistant” virus
PI toxicity threshold
HAART or cART NNRTI based regimens
3TC or FTC
d4T or AZT
ddI or ABC or TDF
EFV
NVP
RPV
PI based regimen
LPV/r
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Thailand 2014: Guidelines for Initial ARV Regimens
Dual NRTI NNRTI
Re
com
me
nd
ed
TDF/XTC* EFV
Alt
ern
ativ
e
AZT/3TC* ABC/3TC*
RPV NVP
+
Key 3rd Drug
LPV/r
ATV/r
If patients
cannot
tolerate
NNRTIs
XTC= FTC or 3TC
* Preferred STR (single-tablet regimen) or fixed dose combination pill
Rationale: One Regimen For All
• Simplicity: regimen is very effective, well tolerated and available as a single, once-daily FDC and therefore easy to prescribe and easy to take for patients – facilitates adherence
• Harmonizes regimens across range of populations (Adults, Pregnant Women (1st trimester), TB and Hepatitis B)
• Safety in pregnancy
• Efficacy against HBV and less risk of hepatic toxicity with
EFV
• EFV is preferred NNRTI for people with HIV and TB
(pharmacological compatibility with TB drugs) and
Preferred 1st line regimen:
TDF + 3TC (or FTC) + EFV
Antiretroviral Pregnancy Registry: Birth Defects With First Trimester
Exposure
• Enrolls ~ 1500 women exposed to ART each yr (80% US)[1]
• 13,507 live births with follow-up data through July 2011
• Overall birth defect prevalence comparable to CDC population–based surveillance data: 2.8 per 100 live births vs 2.72
• No specific birth-defect patterns detected
• In separate small study, no growth or bone abnormalities in infants whose mothers took TDF in pregnancy[2]
1. The Antiretroviral Pregnancy Registry. 2. Vigano A, et al. Antivir Ther. 2011;16:1259-1266.
ART and Birth Defects in ANRS French Perinatal Cohort
• French national prospective multicenter cohort studying PMTCT strategies in HIV-positive women[1]
– N = 17,000 (~ 70% of HIV-positive women in France)
– 13,124 live births exposed to ART in utero
• In EFV first trimester–exposed infants, risk for neurologic (but not neural tube) defects but not for overall birth defects
• In ZDV first trimester–exposed infants, risk for both overall birth defects and heart defects
• Findings inconsistent with meta-analysis of studies of EFV use[2] in pregnancy and data from the US Antiretroviral Pregnancy Registry[3]
– Both indicate no risk of birth defect with EFV; APR shows no risk with ZDV
Defects With First Trimester Exposure, AOR (95% CI)
EFV (n = 372)
ZDV (n = 3267)
Overall birth defects
1.3 (0.9-1.9) P = .31
1.4 (1.1-1.8) P = .002
Specific organ system defects
3.2 (1.1-9.1) P = .03
2.5 (1.6-4.2) P = .001
1. Siubide J, et al. CROI 2013. Abstract 81. 2. Ford N, et al. AIDS. 2011;25:2301-2304.
3. Antiretroviral Pregnancy Registry. December 2012.
HBV/HIV COINFECTION HCV/HIV COINFECTION
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MONITORING HIV
Laboratory Monitoring Schedule: Entry into
care FU before ART
CD4 l Q 6 m
HIV RNA Optional
Hepatitis B profile l
Hepatitis C l
LFT l
CBC l Q 6 m
Lipid profile l
Fasting BS l
VDRL l
CXR l
Pap smear l
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10
RPV 25 mg QD +
TDF/FTC 300/200 mg QD
(n = 346)
EFV 600 mg QD + TDF/FTC 300/200 mg QD
(n = 344)
*THRIVE only. †Selected by investigator from ABC/3TC, TDF/FTC, ZDV/3TC.
Stratified by BL HIV-1 RNA < 100,000
vs ≥ 100,000 copies/mL, NRTI use*
Wk 96 final analysis
Wk 48 primary analysis
RPV 25 mg QD +
2 NRTIs†
(n = 340)
EFV 600 mg QD + 2 NRTIs†
(n = 338)
ECHO, THRIVE: Rilpivirine vs EFV in Treatment-Naive Patients
• Randomized, double-blind phase III trials
Cohen C, et al. AIDS 2010.
ECHO
(N = 690)
THRIVE
(N = 678)
Treatment-naive, HIV-1 RNA ≥ 5000 copies/mL,
no NNRTI RAMs, susceptible to NRTIs
ECHO and THRIVE: HIV-1 RNA < 50 c/mL With
EFV vs RPV
-12 -10 -8 -6 -4 -2 0 2 4 6 8 10 12
ECHO
Wk 48
Wk 96
THRIVE
Wk 48
Wk 96
Pooled
Wk 96
Favors EFV Favors RPV
Cohen CJ, et al. AIDS. 2013;27:939-950. Molina JM, et al. Lancet. 2011;378:238-246.
Cohen CJ, et al. Lancet. 2011;378:229-237.
Percent Difference (Noninferiority at 12% Margin)
-0.4%
-3.2%
3.5%
2.4%
-0.4% P < .0001
P < .0001
P = .0055
P < .0001
P < .0001
ITT-TLOVR. All patients received TDF/FTC.
ECHO/THRIVE: Rilpivirine vs Efavirenz in Treatment-Naive Patients
• D/C due to AE more common with EFV vs RPV: 8.5% vs 4.1%
• More virologic failures with RPV vs EFV: 14% vs 7.6%
– Difference due to more VF between Wks 0-48 at HIV-1 RNA > 100,000; VF similar Wks 48-96
– NRTI mutations more common with VF on RPV vs EFV
– Cross-resistance to ETR more common with RPV failure (E138K mutation)
100
80
60
40
20
0
HIV
-1 R
NA
< 5
0 c/
mL
(%)
78%
78%
RPV 25 mg QD (n = 686) EFV 600 mg QD (n = 682)
Wks
0 4 8 12 16 24 32 40 48 60 72 84 96 2
84%
82%
Cohen CJ, et al. AIDS. 2013;27:939-950. Molina JM, et al. Lancet. 2011;378:238-246.
Cohen CJ, et al. Lancet. 2011;378:229-237.
ECHO/THRIVE: Rilpivirine Noninferior to Efavirenz Through Wk 96
• More virologic failures with RPV vs EFV: 14% vs 8%
– Difference due to more failures between Wks 0-48; failures comparable between arms from Wks 48-96
– Development of NRTI mutations more common with RPV vs EFV
– E138K mutation with RPV → cross-resistance with ETR
• Discontinuation for AEs more common with EFV vs RPV: 9% vs 4%
RPV EFV
40
0
100
20
80 78 78
60
682 686 n =
Pooled Data
HIV
-1 R
NA
< 5
0 c
/mL
at
Wk 9
6
(IT
T-T
LO
VR
)
Cohen CJ, et al. AIDS. 2013;27:939-950.
ECHO/THRIVE Post Hoc Analysis: Wk 96 Efficacy by Baseline VL and CD4+ Count
Cohen CJ, et al. AIDS. 2013;27:939-950.
HIV
-1 R
NA
< 5
0 c
op
ies/m
L (
%)
By Baseline CD4+ Count
(cells/mm3)
84
71
≤ 100k
Rilpivirine Efavirenz
80 76
> 100k -
≤ 500k
5
6
71
< 50
69 75
50 -
< 200
81 79 85
79
200 -
< 350
≥ 350
By Baseline HIV-1 RNA
(copies/mL)
0
20
40
60
80
100
0
20
40
60
80
100
n = 368 329 249 270 n = 34 36 194 175 313 307 144 164
65
73
69 83
> 500k
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11
Pooled ECHO/THRIVE Analysis: Wk 96 Safety
Adverse Event, % Rilpivirine
(n = 686)
Efavirenz
(n = 682)
Most common adverse events of interest
Any neurologic
• Dizziness
Any psychiatric
• Abnormal dreams/nightmares
Rash (any type)
17
8
16
8
4
38*
27*
24*
13†
15*
Grade 2-4 laboratory abnormality
Total cholesterol
LDL-C
AST
ALT
7
7
6
6
22*
18*
10
11
Cohen CJ, et al. AIDS. 2013;27:939-950
*P < .0001 vs rilpivirine. †P = .0039 vs rilpivirine.
Open-Label STaR Trial: RPV/TDF/FTC Noninferior to EFV/TDF/FTC at Wk 48
• RPV/TDF/FTC noninferior to EFV/TDF/FTC in overall population and in pts with baseline HIV-1 RNA > 100,000 c/mL
– RPV/TDF/FTC superior to EFV/TDF/FTC in pts with baseline HIV-1 RNA ≤ 100,000 c/mL
Cohen C, et al. AIDS. 2014 Feb 6. [Epub ahead of print].
89
82
0
20
40
60
80
100
HIV
-1 R
NA
< 5
0 c
/mL (
%)
86
All Pts VL ≤ 100k
82
RPV/TDF/FTC (n = 394)
EFV/TDF/FTC (n = 392) Δ: 4.1%
(95% CI: -1.1 to 9.2)
80 82
VL > 100k
83 82
72 80
VL > 100k -
500k
VL > 500k
Δ : 7.2%
(95% CI: 1.1-13.4)
Δ : -1.8%
(95% CI: -11.1 to 7.5) Post Hoc Analysis
n/N = 338/
394
320/
392
231/
260
204/
250
107/
134
116/
142
81/
98
96/
117
26/
36
20/
25
Switching From EFV/TDF/FTC to RPV/TDF/FTC in Suppressed Patients
• Single-arm study of 50 patients virologically suppressed on EFV/TDF/FTC as first regimen for ≥ 3 mos
– No known resistance mutations to study meds
– Desiring to switch for intolerance of regimen
• 100% maintained HIV-1 RNA < 50 c/mL at Wk 12 after switch to RPV/TDF/FTC (primary endpoint)
• No events leading to discontinuation after switch
• RPV mean Ctrough within target range by 2 wks
Mills A, et al. HIV Clin Trials. 2013;14(5):216-23.
Plasma Concentrations of
RPV (Ctrough) or EFV (Any Time)
Mean
Co
ncen
trati
on
(ng
/mL
)
Wks After Switch
200
0 160
0 120
0 800
400
120
80
40
0 0 2 4 6 8 10 12
EFV concentration
RPV Ctrough
RPV mean Ctrough in
ECHO/THRIVE
RPV/TDF/FTC Indications
• DHHS guidelines 2013[2]
– RPV is not recommended in patients with pretreatment HIV-1 RNA > 100,000 copies/mL
– Higher rate of virologic failures reported in patients with pre-ART CD4+ count < 200 cells/mm3 who were treated with RPV + 2 NRTIs
1. RPV/TDF/FTC [package insert]. June 2013. 2. DHHS Guidelines. February 2013.
[1]
COMMON SIDE EFFECTS AND MANAGEMENT
Efavirenz
• Advantage
– Long track record
– High efficacy
– Convenience
– Forgiving of missed dose
• Disadvantage
– CNS adverse effects
– Risk of resistance with treatment interruption
– Lower CD4+ cell count increase than with other drug classes
– Lipids
– Vitamin D?
8/2/2014
12
Ripilvirine
• Advantage
– Once daily
– Small pill
– Less lipids
– Less CNS side effects
– Low cost
• Disadvantage
– Less effective in HIV RNA > 100,000 c/mL
– High failure rate in CD4 <200 cells/mm3
Nevirapine
Advantages Disadvantages
No food effect Higher incidence of rash (SJS, TEN)
Less lipid effects than EFV Higher incidence of hepatotoxicity
Contraindicated in pts with moderate or severe hepatic impairment (Child Pugh B or C)
Higher risk of hepatotoxicity in treatment naïve with high CD4
Less clinical data than EFV
NVP should not be initiated in adult women or men with CD4+ cell counts > 250 cells/mm3 and 400 cells/mm3, respectively, unless the benefit outweighs the risk
250 Symptomatic Hepatic Events
0.9%
11.0%
Women
CD
4+
Co
un
t at
Init
iati
on
of
The
rap
y
400
300
200
100
500
Symptomatic Hepatic Events
1.2%
6.3%
Men
Viramune [package insert]. January 2005.
Risk of NVP Hepatotoxicity by CD4+ Count and Sex
0
400
300
200
100
500
0
Drug Specific Toxicities
• Lamivudine (300mg OD or 3TC 150mg BID) – Lactic acidosis
– Lactic acidosis • nucleside analogues withdrawal • treatment of metabolic acidosis • Cofactors (thiamine, riboflavin, L-carnitine) • antioxidants (vitamin C and E, co-enzyme Q10)
ARV-Associated Adverse Effects: Hyperlipidemia
• Elevations in total cholesterol, LDL, and triglycerides
• Associated with all PIs (except ATV), d4T, EFV
• Mechanism unknown
• Consequences uncertain: concern for cardiovascular events, pancreatitis
• Monitor: Chol, Trig, HDL, LDL q 6mo
• Treatment: consider ARV switch; lipid-lowering agents (caution with PI + certain statins)
• Insulin resistance, hyperglycemia, and diabetes associated with all PIs, cARV, thymidine (d4T, AZT) especially with chronic use
• Mechanism not well understood
– Insulin resistance, relative insulin deficiency
• Consider regular screening via fasting glucose
ARV-Associated Adverse Effects: Hyperglycemia
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15
ARV and Mitochondial toxicity
Lactic acidosis and Lipoatrphy
Lipohypertrophy
IDV, RTV any bPIs ATV
d4T ddI AZT 3TC FTC ABC TDF
TREATMENT FAILURE
CD4
HIV-RNA
Time
ARV failure
Criteria for failure
Virological failure
Immunological failure
Clinical failure
Clinical failure • Occurrence or recurrence of HIV- related events (after at least 3 months
on ART, except pulmonary TB), • excluding immune reconstitution syndrome • Late • Unreliable: some patients demonstrate discordant responses in virologic, immunologic and clinical parameters
Important of percentage of CD4
White blood cell 8000
% lymphocyte 40% 40%
Absolute lymphocyte 3200
%CD4 10% 10%
Absolute CD4 cell 320
4000
1600
160
Factors associated with immunologic failure
• CD4 < 200/mm3 when starting ART
• Older age
• Coinfection (e.g. HCV)
• Medication both ARV (AZT, TDF+ddI) and other medication
Immunological failure • Immunological failure: no acceptable definition
– CD4 increase < 50 cells/mm3 after 1 year of treatment – CD4 drop > 30% from maximum value or > 3% – CD4 drop down below baseline – CD4 <350 cells/mm3 after 4-7 years of HAART
Risk of AIDS and non-AIDS complication are increase especially with CD4 < 200 cells/mm3
• No consensus recommendation for immunological failure
In clinically stable patients with suppressed viral load, CD4 count can be monitored every 6–12 months
DHHS Guideline 2011
Frequent CD4+ Count Monitoring Not Necessary for Pts With CD4+ > 300
• Retrospective review of VA laboratory database of > 25,000 paired VL and CD4+ counts from 1821 unique pts (1998 -2011)
• Eligible pts had “sequences”: consecutive VL/CD4+ pairs with
– VL < 200 copies/mL
– CD4+ count > 200 cells/mm3
– %CD4+ > 14
– < 390 days between CD4+ counts
• Analysis of pts with sequences (n = 846) who experienced CD4+ “dips” < 200 during periods of virologic suppression (n = 61)
– 24 with clinical causes of lymphopenia
• Virologically suppressed pts with CD4+ > 300 extremely unlikely to have CD4+ count dip < 200
• CD4+ testing may be undertaken less frequently in these pts
Gale H, et al. AIDS 2012. Abstract WEPDB0101.
Pro
ba
bilit
y
Viral Suppression (Yrs)
0 1 2 3 4 5 6 0.5
0.6
0.7
0.8
0.9
1.0
≥ 350 300-349 250-299 200-249
Probability of Maintaining CD4+ > 200 During Viral Suppression
CD4+ Count
เกณฑกำรวนจฉย virological failure ของไทยขอใดถกตอง?
A. Viral load > 50 c/mL after ART for 24 wk
B. Viral load > 400 c/mL after ART for 24 wk
C. Viral load > 1000 c/mL after ART for 24 wk
D. Viral load > 2000 c/mL after ART for 24 wk
E. Viral load > 5000 c/mL after ART for 24 wk
Virologic Definitions • Virologic suppression: A confirmed HIV RNA level
below the limit of assay detection (e.g., <48 copies/mL).
• Virologic failure: The inability to achieve or maintain suppression of viral replication (to an HIV RNA level <200 copies/mL).
• Incomplete virologic response: Two consecutive plasma HIV RNA levels >200 copies/mL after 24 weeks on an ARV regimen.
DHHS Guideline 2011
Virologic Definitions • Virologic rebound: Confirmed detectable HIV RNA (to
>200 copies/mL) after virologic suppression.
• Persistent low-level viremia: Confirmed detectable HIV RNA levels that are <1,000 copies/mL (typically < 200 c/mL).
• Virologic blip: After virologic suppression, an isolated detectable HIV RNA level that is followed by a return to virologic suppression (typically < 400 c/mL)
DHHS Guideline 2011
8/2/2014
17
Expected Goal
Limit of detection
Virological suppressed
Vir
al lo
ad Immunological response
CD4
Virological response
40 copies/mL
Virological suppressed
Vir
al lo
ad
Virological Blip
Virological rebound
Persistent low level viremia
Virologic failure
1000 copies/mL
Stopping drugs with different half-lives may lead to periods of monotherapy
0 24 48 36 12
Time (hours)
Dru
g co
nce
ntr
atio
n
Last dose Day 1 Day 2
Zone of potential replication
MONOTHERAPY
Taylor S, et al., 11th CROI, San Francisco, February 2004, #131
HIV STAR study • Randomized, open-label, multicenter trial
Lopinavir/Ritonavir 400/100 mg BID
monotherapy
(n = 100)
Lopinavir/Ritonavir 400/100 mg BID +
TDF+ 3TC
(n = 100)
HIV-infected pts with
virologic failure on
first-line regimen of 2
NRTIs + NNRTI
(N = 200)
Stratified by clinical site,
baseline HIV-1 RNA
(≤ or > 100,000 copies/mL)
and CD4 < 100 or >100
Wk 48
primary endpoint
Bunupuradah T, et al. Antivir Ther. 2012;17:1351-61.
HIV STAR Study: LPV/r With or Without TDF + 3TC Following Failure of First-line NNRTI
200 Patients who failed first-line NNRTI-containing randomized to LPV/r BID monotherapy or LPV/r BID + TDF + 3TC
SECOND-LINE: Noninferiority of LPV/RTV + RAL vs LPV/RTV + NRTIs
• Pooled pt data from ACTG A5142, A5202, A5208 of those failing first-line boosted PI regimens found 131/200 (66%) remained on same regimen[2]
– Various regimen changes: n = 69
– HIV-1 RNA < 400 c/mL at Wk 24 similar between pts who maintained same regimen and those who switched
– Pts with highest resuppression rates were those with higher CD4+ counts at regimen change and those who had ever responded to first regimen
• Suggests better adherence
0
20
40
80
100
Wk
LPV/RTV + RAL
LPV/RTV + 2-3 NRTIs
60
0 12 24 36 48
HIV
-1 R
NA
< 2
00 c
/mL (
%)
• Similar high levels of virologic suppression with each strategy in primary mITT analysis[1]
82.6
80.8
P = .59
1. Secondline study group. Lancet. 2013;381:2091-9.
2. Zheng Y, et al. CROI 2013. Abstract 558.
EARNEST: Second-Line LPV/RTV-Based ART After Initial NNRTI Failure
• Randomized, controlled, open-label, phase III trial
• Baseline demographics (medians): HIV-1 RNA 69,782 copies/mL; CD4+ 71 cells/mm3; time on ART, 4 yrs
Paton N, et al. IAS 2013. Abstract WELBB02.
WHO World Health Organization.
*Including clinical, CD4+ cell count (viral load confirmed), or virologic criteria. †Selected by physician according to local standard of care.
HIV-infected adults and
adolescents, received
first-line NNRTI-based ART > 12 mos, > 90%
adherence in previous
mo,
treatment failure by WHO
(2010) criteria* (N = 1277)
LPV/RTV + 2-3 NRTIs†
(n = 426)
LPV/RTV + RAL (n = 433)
LPV/RTV + RAL (n = 418)
Wk 144 Wk 12
LPV/RTV monotherapy (n = 418)
EARNEST: Clinical Outcomes at Wk 96
• “Good disease control” at Wk 96 defined as pt alive, no new WHO 4 events from Wks 0-96, and CD4+ cell count > 250 cells/mm3, and HIV-1 RNA < 10,000 copies/mL or > 10,000 copies/mL without PI resistance mutations
Paton N, et al. IAS 2013. Abstract WELBB02.
100
80
60
40
20
0 Good Disease
Control HIV-1 RNA
< 400 copies/mL
HIV-1 RNA
< 50 copies/mL
PI/NRTI
PI/RAL
PI Mono 60 64
56
86 86
61
74 73
44
VACCINATION IN HIV PATIENTS
8/2/2014
19
ARV IN PATIENTS WITH OI
8/2/2014
20
SAPiT: Optimal Time to Initiate ART in HIV/TB-Coinfected Patients
Early ART ART initiated during intensive or
continuation phase of TB therapy (n = 429)
Sequential ART
ART initiated after TB therapy
completed
(n = 213)
HIV-infected patients diagnosed with TB and
CD4+ cell count < 500 cells/mm3
(N = 642)
Primary endpoint: all-cause mortality
Abdool Karim SS, et al. CROI 2009. Abstract 36a.
Significantly Improved Outcomes With Integrated HIV and TB Treatment
Outcome, % Early ART Sequential ART
HIV-1 RNA <1000 copies/mL at 12 mos 91.0* 80.0
TB treatment successful 78.4 73.3
Incidence of IRIS 12.1*† 3.8†
Mortality in MDR-TB patients 20 71
• 56% lower rate of death associated with concurrent ART and TB treatment (early ART)
• Mortality: HR: 0.44 (95% CI: 0.25-0.79; P = .003)
– Early ART: 5.4/100 person-yrs
– Sequential ART: 12.1/100 person-yrs
Abdool Karim SS, et al. CROI 2009. Abstract 36a.
*P < .05
†Note: 83% early ART vs 62% sequential ART patients had initiated ART—data provisional. 0.70