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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
8/2/2014
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
ARV miracle
Before antiretroviral therapy,
September 2000
©Partners In Health
After antiretroviral therapy,
December 2000
©Partners In Health
8/2/2014
3
Intervention for human diseases: per-person survival gains (months)
Walensky R. JID 2006;194:11-9
Survival of Person with and without HIV infection
Population controls
Late HAART (2000-2005)
Early HAART (1997-1999)
Pre-HAART (1995-1996)
25 30 35 40 45 50 55 60 65 70 Age, y
1
0.75
0.5
0.25
0
Pro
bab
ility
of
Surv
ival
Lohse N. Ann Intern Med 2007;146:87-95
Survival of Patients with CD4 Counts
≥500 cells/mm3 for >5 Years is Similar
to the General Population
Standardized mortality ratio = mortality in HIV-infected patients / mortality in general population
APROCO and AQUITAINE cohorts
0
1
2
3
4
0 1 2 3 4 5 6 7
Sta
nd
ard
ised
mo
rtali
ty r
ati
o
Years with CD4+ count >500 cells/mm3
Lewden C et al. J Acquir Immune Defic Syndr 2007;46:72–77
NA-ACCORD: Increasing Life Expectancy in North American HIV+ Pts on HAART
• Analysis of 23,730 HIV+ pts in NA-ACCORD, on ART, with recent active data available
– Estimated life expectancy at age 20 yrs increased in later periods
Hogg R, et al. CROI 2012. Abstract 137.
Life Expectancy
at 20 Yrs of Age,
1996-2007, Yrs
NA-
ACCORD
US Life
Expectancy
Data After
Age 20
Sex
Male 41.3 55.3
Female 42.7 60.4
Race
Black 41.0 54.7
Hispanic 52.6 61.4
White 50.0 59.0
0
100
Life E
xpecta
ncy a
t
Age 2
0, Y
rs
20
40
60
80
2006-7 2003-5 2000-2 1996-9
34.4 36.9 43.1 47.1
Life Expectancy of HIV-Positive Patients
• Comparison of life expectancy of Athena cohort patients to general population (n=4174)
• Age at week 24, country of birth and stage B symptoms were associated with a higher risk of death
• Expected life years remaining at age 25 was 53.1 (44.9-59.5) for general population and 52.7 for asymptomatic HIV+ patients
• The modeled life expectancy of patient presenting at an older age and women were slightly lower that general population
Years of Life Remaining
General Population
Asymptomatic HIV+ Patients
0
10
20
30
40
50
60
70
80
90
20 30 40 50 60 70
Age at time of death
Remaining Life Years
Age at 24 weeks (years)
Years
liv
ed
van Sighem A, et al. 17th CROI; San Francisco, CA; February 16-19, 2010.
Frequency of Latently Infected CD4+ Cells as a Function of Time on HAART
Time on HAART (Years)
Fre
qu
en
cy
(pe
r 1
06
Re
stin
g C
D4
+ C
ell
s) t½ = 44.2 months
73.4 years
0.0001
0.001
0.01
0.1
1
10
100
1000
10,000
0 1 2 3 4 5 6 7 8
-
8/2/2014
4
ADHERENCE
Adherence to a PI-containing regimen correlates with HIV RNA response at 3 months
0
20
40
60
80
100
<70 70–80 80–90 90–95 >95
Pa
tien
ts
wit
h H
IV R
NA
<4
00
co
pie
s/m
L,
%
PI adherence, % (MEMScaps)
Peterson, et al. 6th Conference on Retroviruses and Opportunistic Infections; 1999; Chicago, IL.
What Degree of Adherence Is Needed?
Self-Administered (SAT) vs. Directly Observed Therapy (DOT) During Incarceration
0
10
20
30
40
50
60
70
80
90
100
% w
ith
VL
< 5
0 c
op
ies/m
L
w4 w8 w16 w24 w48 w64 w72 w80 w88
DOT <50
SAT <50
Fischl et al 8th CROI, 2001 abstract 528
p < 0.01
N = 50 in each group
WHEN TO START ARV?
Patient readiness
Commitment to Adherence
Life-long treatment
Likelihood of Achieving Normal CD4+ Cell Count on ART Depends on BL Level
1. Moore RD, et al. Clin Infect Dis. 2007;44:441-446
2. 2. Gras L, et al. J Acquir Immune Defic Syndr. 2007;45:183-192.
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
8/2/2014
5
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
R R R
R C C
EACS Guidelines 2011.
http://www.europeanaidsclinicalsociety.org/guidelinespdf/
C=consider, R= recommend, D=delay
When to Start: 2012 BHIVA Guidelines
CD4+ Cell Count Recommendation
CD4+ cell count < 350 cells/mm³ Start ART (1A)
CD4+ cell count 350-500 cells/mm³ Delay ART
Recommend to start ART
AIDS-defining illness
Pregnancy
HIV related co-morbidity (HIVAN)
HBV coinfection
HCV coinfection
Non-AIDS malignancy requiring chemotherapy
Serodiscordant couples
Primary HIV infection (neurological involvement, AIDS, confirmed CD4<350)
William I., HIV Medicine 2012, 13 (Suppl. 2), 1–85 4.
Summary of Changes in WHO Recommendations When to Start in Adults
TARGET POPULATION (ARV-NAIVE)
2010 ART GUIDELINES 2013 ART GUIDELINES
STRENGTH OF RECOMMENDATION
& QUALITY OF EVIDENCE
HIV+ ASYMPTOMATIC CD4 ≤350 cells/mm3
CD4 ≤500 cells/mm3
(CD4 ≤ 350 cells/mm3 as a priority)
Strong, moderate-quality evidence
HIV+ SYMPTOMATIC
WHO clinical stage 3 or 4 regardless of CD4 cell count
No change Strong, moderate-quality evidence
PREGNANT AND BREASTFEEDING WOMEN WITH HIV
CD4 ≤350 cells/mm3 or WHO clinical stage 3 or 4
Regardless of CD4 cell count or WHO clinical stage
Strong, moderate-quality evidence
HIV/TB CO-INFECTION
Presence of active TB disease, regardless of CD4 cell count
No change Strong, low-quality evidence
HIV/HBV CO-INFECTION
Evidence of chronic active HBV disease, regardless of CD4 cell count
Evidence of severe chronic HBV liver disease, regardless of CD4 cell count
Strong, low-quality evidence
HIV+ PARTNERS IN SD COUPLE
No recommendation established
Regardless of CD4 cell count or WHO clinical stage
Strong, high-quality evidence
2010 Thailand Guidelines: Initiation of ART in the Chronically HIV-Infected Patient
Clinical Category CD4 Recommendation
AIDS Any Treat
Symptomatic HIV Any Treat
Asymptomatic <350 Treat
Pregnancy Any Treat, D/C after delivery if CD4>350
Sungkanuparph S. BMC 2010
Thailand Guideline 2014?
WHO
(Treat CD4 < 500)
Conservative
(Optional for CD4 350-500)
DHHS
(Treat all CD4)
8/2/2014
6
When to start: 2014 Thailand Guideline
Conditions CD4 cell count
< 500 > 500
HIV infection regardless of symptoms and co-infection
Recommend
(AI: <350
AII: 350-500)
Recommend (BIII)
The following issue should be considered
• Asymptomatic: unclear individual benefit
but clear public health benefit
• As a priority, ART should be initiated in
patients with symptomatic or CD4 <500
• Patients should be willing and able to
commit to Tx, understand the benefit and
risks of Tx and importance of adherence.
Pts may choose to postpone.
• Providers may consider deferring Tx on
the basis of clinical and/or psychological
factors
Clinical conditions may have benefit with early ART (CD4> 500 cells/mm3)
Individual benefits Public Health benefits TB/HIV co-infection (AII) Serodiscordant couples (AI)
HBV/HIV co-infection with cirrhosis (AII) Pregnancy (AI)
HCV/HIV co-infection with cirrhosis (BII) TB/HIV co-infection
HIVAN Acute HIV infection
Acute/recent HIV infection (BII)
ชดสทธประโยชนส ำหรบกำรดแล
• การดแลรกษายาตานไวรสเอชไอว – Anti-retroviral Therapy (ART)
– Treatment of Opportunistic Infections (OIs)
– Treatment of Hyperlipidemia
• Laboratory Testing
• Voluntary Counseling & Testing
• Positive Prevention
Major Targets of Antiretroviral Agents
HIV
RNA
DNA
ds DNA
RT
Integrase
Transcription
Proviral DNA
Spliced mRNA
mRNA
Genomic RNA
Polyprotein
Protein
Protease
Protease Inhibitors SQV,RTV, IDV, NFV, APV, LPV/r, ATV
RT Inhibitors
NRTI: AZT, ddI,
ddC, d4T, 3TC, ABC, FTC
NNRTI: NVP, DLV, EFV
NTRTI: Tenofovir
1 2
3
4
5
6
Entry Inhibitors
CXCR4: AMD3100, T22
CCR5:Miraviric
Fusion gp41: T20
vpr
Integrase inhibitor RAL, EGV, DTG
Current ARV
NRTI NNRTI PI
AZT ATV
EFV
ABC
3TC RPV
FTC LPV/r
TDF RTV
d4T
Entry inhibitor Integrase inhibitor
Fusion inhibitor RAL
T20 EGV
DTG
CCR5 inhibitor
Maraviroc
FPV
NFV
TPV
IDV
DRV
ETR
ddI
NVP
Antiretroviral therapy
• HAART: Highly Active Anti-Retroviral Therapy
• cART: Combined Antiviral Therapy
– 2 NRTI + 1NNRTI
– 2 NRTI + bPI
– 2 NRTI + Integrase inhibitor
8/2/2014
7
HAART or cART NNRTI based regimens
3TC or FTC
d4T or AZT
ddI or ABC or TDF
EFV
RPV
NVP
ARV components Not recommended as initial therapy
ARV Reasons
ABC/ddI Insufficient data in treatment naïve pts
ABC/TDF Insufficient data in treatment naïve pts
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
8/2/2014
8
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.
Defects/Live Births, n ( > 200 First Trimester
Exposures)
Prevalence, % (95% CI)
NRTIs ABC ddI FTC 3TC d4T TDF ZDV
25/781 19/409 18/764
122/3966 19/799
27/1219 120/3699
3.2 (2.1-4.7) 4.6 (2.8-7.2) 2.4 (1.4-3.7) 3.1 (2.6-3.7) 2.4 (1.4-3.7) 2.2 (1.5-3.2) 3.2 (2.7-3.9)
PIs ATV IDV LPV NFV RTV
12/576 6/285
18/816 46/1196 35/1567
2.1 (1.1-3.6) 2.1 (0.8-4.5) 2.2 (1.3-3.5) 3.8 (2.8-5.1) 2.2 (1.6-3.1)
NNRTIs EFV NVP
17/644
26/1002
2.6 (1.5-4.2) 2.6 (1.7-3.8)
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
8/2/2014
9
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
8/2/2014
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
8/2/2014
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
• Emtricitabine (200mg) • Tenofovir (TDF 300mg OD)
– Renal toxicity – Fanconi syndrome, hypokalemia, hypophosphatemia – Lactic acidosis – Bone lost early
• Abacavir (ABC 300mg BID or 600mg OD) – Hypersensitivity (HLA-B 5701) in 3-5%, – no re-challenge – Lactic acidosis
Drug Specific Toxicities
• Stavudine (d4T 30mg BID) – Neuropathy – Lipoatrophy – Dyslipidemia: hypertriglyceridemia – Hepatitis – Lactic acidosis – Ascending motor weakness: "ascending neuromuscular weakness", some associated with elevated lactate levels resemble Guillain Barré syndrome one case of myositis
Management of d4T side effects
• Lipoatrophy: use low dose of d4T
– change to AZT or TDF
• Dyslipidemia: change to AZT or TDF
• Peripheral neuropathy: change to AZT or TDF
• Pancreatitis: D/C medication change to AZT
• Lactic acidosis: D/C medication
Asymptomatic Symptomatic
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13
Drug Specific Toxicities
• Zidovudine (AZT 200-300mg BID) – 5% grade III/IV nausea – Anemia/leucopenia – Headache – Myopathy – Lactic acidosis – Fat atrophy – Blue nails
• Management – Start AZT in healthy patients – Follow CBC both short term and long term – If anemia change to TDF or ddI or d4T
Drug Specific Toxicities • Didanosine (ddI BW< 60 kg, 250mg, BW>60kg, 400
mg OD ac) – Diarrhea (sachet > tablet with buffer >enteric coat), need
to be taken on empty stomach
– Nausea, diarrhea
– Pancreatitis (rare)
– Neuropathy especially with d4T
– Lactic acidosis especially with d4T, contraindicate used with d4T in pregnancy
Drug Specific Toxicities
• Indinavir (IDV 400-800/r100 BID) – GI: N/V, hyperbilirubinemia
– Skin disorders: alopecia, dry skin, toenail
– Nephrolithiasis
– Renal dysfunction
– Lipodystrophy Metabolic complications • Lipid abnormalities
• Insulin resistance
• Osteopenia
– Need to monitor FBS BUN Cr UA q 6 mo.
Lopinavir/ritonavir
Advantages Disadvantages
Coformulated GI side effect with diarrhea, nausea
Once or twice daily dosing in treatment naive
Once-daily dosing not recommended in pregnant women
No food restriction Lower drug exposure in pregnant women- may need dose increase in 3rd trimester
Recommended PI in pregnant women
Greater CD4 cell count increase than EFV
Metabolic Complications
Dysregulation In glucose
metabolism
Body fat redistribution
Lipid abnormalities
Bone Mitochondrial Toxicity
Lipoatrophy facial fat pads lost
legs, buttocks, arms prominent subcutaneous veins pseudocachexia
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14
Lipoatrophy: Risk Factors
• Almost certainly interrelated
• Antiretroviral therapy
– Thymidine analogue exposure (d4T > AZT)
– EFV used
• Host factors
– Age
• HIV disease factors
– Duration of illness
– Severity of illness: AIDS, low CD4+ cell count
• Possibly due to mitochondrial toxicity
• Associated with NRTIs (especially d4T, ddI, AZT)
• Clinical presentation variable: have high index of suspicion
• Lactate >2-5 mmol/dL plus symptoms
• Treatment: discontinue ARVs, supportive care
ARV-Associated Adverse Effects: Lactic Acidosis/Hepatic Steatosis
Risk factors for hyperlactatemia
• Use of d4T + ddI
• Use of either d4T, ddI or AZT
• ddI + hydroxyurea
• ddI + ribavirin
• Treatment > 6 months
• Female gender
• Pregnancy
• Decreased CCr <70 ml/min
• Obesity
• High baseline body mass index
Management of hyperlactatemia
– Hyperlactatemia • lactate >5-10 mmol/l: nucleside analogues
withdrawal • Tenofovir, abacavir, 3TC regimens
– 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
• Persistent immune activation
• Loss of regenerative potential of immune system
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ทำนควรท ำอยำงไรในผปวยทมVirus suppress แต CD4 ไมเพม (Immune-Virologic Discordance )?
A. เปลยนสตรยา ARV
B. ปรบสตรยา ARV
C. Intensification with Integrase inhibitor
D. Intesification with CCR5 inhibitor
E. ยงไมมขอสรป
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
Resistance: M184V (82.1%, K65R (6.7%), ≥3 TAMS (33.3%), ≥4 TAMS (11.3%)
Proportion of Patients with Virological Suppression at 48 Weeks (M=F)
Bunupuradah T, et al. Antivir Ther. 2012;17:1351-61.
SECOND-LINE: LPV/RTV + RAL vs LPV/RTV + NRTIs After First-line VF
• Randomized, open-label, international, multicenter trial
Second line Study group. Lancet. 2013;381:2091-9.
Lopinavir/Ritonavir 400/100 mg BID +
Raltegravir 400 mg BID
(n = 270)
Lopinavir/Ritonavir 400/100 mg BID +
2-3 NRTIs QD or BID
(n = 271)
HIV-infected pts with
virologic failure on first-
line regimen of 2 NRTIs + NNRTI
(N = 541)
Stratified by clinical site,
baseline HIV-1 RNA
(≤ or > 100,000 copies/mL)
Wk 48
primary endpoint
8/2/2014
18
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
0.75
0.80
0.85
0.90
0.95
1.00
Surv
ival
Months Postrandomization
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
Intensive phase of TB
treatment
Post-TB treatment Continuation phase of TB treatment
Early ART Sequential ART
SAPiT: Increased Survival With Concurrent HIV and TB Treatment
Abdool Karim SS, et al. CROI 2009. Abstract 36a.
8/2/2014
21
Abdool Karim S, et al. CROI 2011. Abstract 39LB.
SAPiT: Early vs Late ART Initiation During Integrated TB/ART Therapy
• Early integrated: ART started within 4 wks of starting TB Rx
• Late integrated: ART started within 4 wks of completing TB Rx intensive phase
• 68% lower AIDS/death rate with early integrated Rx in patients with CD4+ counts < 50 cells/mm3
IRIS (per 100 Person-Yrs) Early Integrated Rx Late Integrated Rx IRR (95% CI) P Value
CD4+ < 50 cells/mm3 46.8 (n = 37) 9.9 (n = 35) 4.7 (1.5-19.6) .01
CD4+ ≥ 50 cells/mm3 15.8 (n = 177) 7.2 (n = 180) 2.2 ( 1.1-4.5) .02
AIDS/Death in Patients With CD4+ < 50 cells/mm3
Post-TB treatment Continuation
phase of TB
Rx
Intensive phase of TB
Rx
Surv
ival
Pro
bability
Early integrated therapy
Late integrated therapy
IRR: 0.32 (95% CI: 0.07-1.13;
P = .06)
18 0 6 12
1.0
0.9
0.8
0.7
0.6
0.5
Mos of Follow-up
Early events/# at risk
Late events/# at risk 0/37
0/35
2/33
7/27
4/31
9/24
4/29
10/21
Post-TB treatment Continuation
phase of TB
Rx
Intensive phase of TB
Rx
Early integrated therapy
Late integrated therapy
IRR: 1.51 (95% CI: 0.61-3.95;
P = .34)
18 0 6 12 0/177
0/180
8/149
4/48
10/137
7/129
14/121
9/121
AIDS/Death in Patients With CD4+ ≥ 50 cells/mm3
STRIDE Study (ACTG 5221): Immediate vs Early ART Initiation in TB Patients
Havlir D, et al. CROI 2011. Abstract 38.
Immediate ART*
Begun within 2 wks after TB therapy† initiation
(n = 405)
Early ART*
Begun 8-12 wks after TB therapy† initiation
(n = 401)
HIV-infected patients,
confirmed/suspected TB,
CD4+ count
< 250 cells/mm3
(N = 806)
Stratified by CD4+ cell count
< or ≥ 50 cells/mm3
Wk 48
*ART comprised EFV, FTC, and TDF. †TB therapy comprised standard rifampicin-based regimen.
Outcome, % Immediate (n = 405)
Early (n = 401)
95% CI for Difference
P Value
Deaths or new AIDS-defining events by Wk 48
Overall population 12.9 16.1 -1.8 to 8.1 .45
CD4+ cell count < 50 cells/mm3 15.5 26.6 1.5 to 20.5 .02
CD4+ cell count ≥ 50 cells/mm3 11.5 10.3 -6.7 to 4.3 .67
TB IRIS 11 5 .002
CAMELIA: ART Initiation at Wk 2 vs Wk 8 of TB Therapy in HIV-Coinfected Patients
• WHO 2010 guidelines recommend to[1]
– Initiate HAART in all HIV-infected patients with TB, regardless of CD4+ cell count
– Initiate TB therapy before HAART, with HAART added as soon as possible
• CAMELIA: randomized, open-label trial of HIV-infected patients with newly-diagnosed AFB-positive TB and CD4+ cell count ≤ 200 cells/mm3 [2]
• Compared HAART initiation (d4T + 3TC + EFV) at
– Wk 2 (n = 332) vs
– Wk 8 (n = 329) of TB therapy
• All patients received standard TB therapy for 6 mos
• Baseline median CD4 25 cells/mm3 and HIV RNA 5.6 log10 c/mL
1. WHO. Available at: http://www.who.int/hiv/pub/arv/adult/en.
2. Blanc FX, et al. AIDS 2010. Abstract THLBB206.
CAMELIA: Survival With Early vs Late Therapy in TB-Coinfected Patients
• Significantly higher incidence of IRIS with early vs late HAART
– 4.03 vs 1.44 per 100 person-mos, respectively (P < .0001)
Blanc FX, et al. AIDS 2010. Abstract THLBB206.
Wk Survival Probability, % (95% CI)
P Early Arm Late Arm
50 86.1
(81.8-89.4) 80.7
(76.0-84.6) .07
100 82.6
(78.0-86.4) 73.0
(67.7-77.6) .006
150 82.0
(77.2-85.9) 70.2
(64.5-75.2) .002
Factor Multivariate Adjusted HR (95% CI)
P
Late therapy 1.52 (1.12-2.05) .007
BMI ≤ 16 1.68 (1.07-2.63) .01
Karnofsky score ≤ 40
4.96 (2.42-10.16) < .001`
Pulmonary + extrapulmonary TB
2.26 (1.62-3.16) < .001
NTM 2.84 (1.13-7.13) < .001
MDR-TB 8.02 (4.00-16.07) < .001
Factors Independently Associated With Mortality Survival Probability, Early vs Late Therapy
Log rank P = .0042
Wks From TB Treatment Initiation
Pro
babili
ty o
f S
urv
ival 1.00
0.90
0.80
0.70
0.60
Early arm
Late arm
0 50 100 150 200 250
กำรเรมยำตำนไวรสขณะทผปวยก ำลงไดยำวณโรค • เรมยำตำนไวรสในผปวยเอชไอวทกรำยทก ำลงรบกำรรกษำวณโรค
• ระยะเวลำเรมยำตำนไวรสทเหมำะสม
ปรมาณเมดเลอดขาว CD4 ค าแนะน าการเรมยาตานไวรสหลงเรมยาวณโรค
<50 cells/mm3 เรมภายใน 2 สปดาห*
>50 cells/mm3 ถาอาการวณโรครนแรง** เรมภายใน 2 สปดาห
ถาอาการวณโรคไมรนแรง เรมภายใน 2-8 สปดาห
*ถาผ ปวยทนตอยาวณโรคได **อาการวณโรครนแรง ไดแก วณโรคแพรกระจาย น าหนกตวนอย(BMI<16) ซด (Hb <10 g/dL.) และ Karnofski score <40
กรณวนจฉยวณโรคเยอหมสมองพจารณารอเรมยาตานไวรสหลงรกษาวณโรคแลวนาน 2 สปดาห
กำรเรมยำตำนไวรสขณะทผปวยก ำลงไดยำวณโรค
• กรณทไมม rifampicin ในสตรยำรกษำวณโรคใหพจำรณำเรมสตรยำตำนไวรสตำมปกต
• กรณทใช rifampicin ในสตรยำรกษำวณโรคใหพจำรณำดงน 1. EFV ในขนำด 600 มก.ตอวน
2. NVP 200 มก.วนละ 2 ครงโดยไมตอง lead-in 3. RAL ขนำด 400 มก.วนละ 2 ครง
• กรณทม rifabutin แทนการใช rifampicin
1. ใชรวมกบ efavirenz ใหเพมขนาดยา rifabutin เปน 450 มก.ตอวน
2. ใชรวมกบ boosted protease inhibitor ใหลดขนาดยา rifabutin เหลอ 150 มก.ตอวน 3 ครงตอสปดาห
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กำรเรมยำวณโรคขณะทผปวยก ำลงไดยำตำนไวรส
• กรณผปวยก ำลงไดยำตำนไวรสสตร NNRTIs ทง EFV และ NVP ใหสตรยำวณโรคตำมปกต
• กรณผปวยก ำลงไดยำตำนไวรสสตรทม PI ใหพจำรณำดงน
1. ปรบยำ PI เปนสตรทม NNRTIs (พจำรณำยำ EFV กอน NVP) หรอ integrase inhibitor
(ไดแก raltegravir) เปนสวนประกอบแทน และใหสตรยำวณโรคตำมปกต ทงนตรวจสอบและ
ควรระวงวำผปวยไมเคยมประวตดอยำหรอแพยำทก ำลงจะเปลยน
2. ถำไมสำมำรถใช NNRTIs และ integrase inhibitor ได ใหพจำรณำปรบสตรยำวณโรคเปน
2IEZ+quinolone/10-16IE+quinolone อำจพจำรณำเพม streptomycin ในชวง 2 เดอนแรก
ACTG A5164: Immediate vs Deferred ART in Patients With Acute OIs
Zolopa A, et al. CROI 2008. Abstract 142.
Immediate Antiretroviral Therapy (initiation within 48 hours of randomization and
within 14 days of starting OI treatment) (n = 141)
Deferred Antiretroviral Therapy (initiation between Weeks 4 and 32)
(n = 141)
HIV-infected patients receiving treatment
for presumed or confirmed acute
OI/BI*
(N = 282)
Stratified by CD4+ cell count < or 50 cells/mm3, PCP, BI, or other OI
48 weeks
48 weeks
*Patients with TB excluded.
ACTG A5164: Improved Outcomes With Immediate ART During Acute OI
• 92% treatment naive
– Median baseline CD4+ cell count 29 cells/mm3; HIV-1 RNA 5.07 log10 copies/mL
• OIs with effective antimicrobial therapy only: PCP, bacterial infections, cryptococcal disease, MAC, toxoplasmosis
• Median duration from start of OI treatment to initiation of HAART
– Immediate group: 12 days
– Deferred group: 45 days Week 48 virologic outcomes similar between groups
Safety and incidence of IRIS similar between groups
Zolopa A, et al. CROI 2008. Abstract 142.
Pat
ien
ts P
rogr
ess
ing
to A
IDS
or
De
ath
at
We
ek
48
(%
)
100
80
60
40
20
0
14.2
24.1
Immediate Deferred
P = .035
COAT: Early vs Delayed ART in Tx-Naive Pts With Cryptococcal Meningitis
• Optimal timing of ART initiation after diagnosis of CM remains uncertain
– Early ART associated with increased mortality in recent trials in resource-limited settings[1,2]
– Earlier study showed improved outcomes with immediate vs delayed ART during acute OIs[3]
• COAT study compared 26-wk survival in tx-naive pts with first episode of CM who received early vs deferred ART initiation[4]
1. Makadzange AT, et al. Clin Infect Dis. 2010;50:1532-1538. 2. Bisson GP, et al. Clin Infect
Dis. 2013; [Epub ahead of print]. 3. Zolopa A, et al. PLoS One. 2009;4:e5575. 4. Boulware
D, et al. CROI 2013. Abstract 144.
ART-naive, HIV-infected pts
with first episode of CM;
study entry at 7-11 days after initiation of antifungal therapy
(N = 177)
Early ART Initiation ART started < 48 hrs after study entry,
before hospital discharge
(n = 88)
Deferred ART Initiation
ART started ≥ 4 wks after study entry,
after hospital discharge (outpatient) (n = 89)
Stratified by treatment site and
mental status (altered vs not)
1. Boulware D, et al. CROI 2013. Abstract 144. 2. Weisner D, et al. CROI 2013. Abstract 861.
COAT: Increased Mortality With Early ART During CM Induction Therapy
• Significantly lower 6-mo OS with early vs deferred ART[1]
– Enrollment halted early by NIAID Africa DSMB
• Mortality associated with
– Altered mental status at study entry (Glasgow Coma Scale score < 15; HR: 3.0; P = .05)
– Patients with CSF WBC counts < 5 cells/mm3 at randomization (HR: 3.3; P = .01)
• In separate analysis of COAT data, reduced interferon gamma secretion associated with increased risk of IRIS or death[2]
– Multivariate analysis of death or CM-IRIS risk: OR per 2-fold increase 0.806 (95% CI: 0.684-0.958; P = .014)
1.
0
0.
8
0.
6
0.
4
Su
rviv
al P
rob
ab
ilit
y
0 1 2 4 6 8 1
0 1
2 Mos From Randomization
OS
Deferred ART
Early ART
70%
55%
P = .03
n =
n =
8
9
88
7
1
54
6
5
51
6
0
47
6
0
47
5
8
45
5
7
44
โรคตดเชอฉวยโอกำสอนๆ
• Primary prophylaxis ส ำหรบปองกน cryptococcosis, penicilliosis, histoplasmosis และกำรตดเชอ MAC ในผปวยตดเชอเอชไอวทมขอบงชนน อำจพจำรณำใหเฉพำะในรำยทไมสำมำรถเรมกำรรกษำดวยยำตำนไวรสไดเรว (optional)
• กำรเรมยำตำนไวรสขณะรกษำ OIs อนๆ – เรม ART หลงรกษำ OIs แลว 2-4 สปดำห ยกเวน Cryptococcal meningitis ใหเรม 4-6
สปดำหหลงกำรรกษำ CM
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Time to Initiate ART in patients with OIs (after starting OI treatment)
Conditions Time of initiation ART
TB
CD4 <50 CD4 >50
Within 2 wk
Severe* Non severe
Within 2 wk 2-8 wk
Crypto 4-6 wk
PCP/MAC/Other OI 2-4 wk
*Severe: Disseminated TB, BMI <16, Hb < 10, Karnofski <40
CMV/PML/Cryptosporidiosis ASAP
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HIV PREVENTION
PrEP Trials Have Shown Efficacy in MSM, Heterosexual Men and Women, and IDUs
Trial Population/Setting Intervention HIV Infections, n Reduction in HIV Infection Rate,
% (95% CI) PrEP Placebo
iPrEX[1] (N = 2499)
MSM, transgender women, 11 sites in US, South America,
Africa, Thailand
TDF/FTC 36 64 44 (15-63)
Partners PrEP[2] (N = 4747)
Serodiscordant couples in Africa
TDF 17 52
67 (44-81)
TDF/FTC 13 75 (55-87)
TDF2[3]
(N = 1219) Heterosexual males and
females in Botswana TDF/FTC 9 24 62 (21-83)
Thai IDU[4] (N = 2413)
Volunteers from 17 drug treatment centers in Thailand
TDF 17 33 49 (10-72)
1. Grant RM, et al. N Engl J Med. 2010;363: 2587-2599. 2. Baeten JM, et al. N Engl J Med.
2012;367:399-410. 3. Thigpen MC, et al. N Engl J Med. 2012;367:423-434. 4. Choopanya K, et al.
Lancet. 2013;381:2083-2090.
Adherence Is a Key Determinant of PrEP Trial Outcomes
Study Detection of TFV in Plasma, %
HIV Seroconverters HIV Uninfected
iPrEx[1] 51
Partners PrEP[2]
(TDF/FTC arm) 81
Thai IDU[3] 67
In the large iPrEx, Partners PrEP, and Thai IDU studies,
TFV was detected in blood samples of the majority of subjects who
remained HIV uninfected during the study
1. Grant RM, et al. N Engl J Med. 2010;363:2587-2599. 2. Baeten JM, et al. N Engl J Med.
2012;367:399-410. 3. Choopanya K, et al. Lancet. 2013;381:2083-2090.
Adherence Is a Key Determinant of PrEP Trial Outcomes
Study Detection of TFV in Plasma, %
HIV Seroconverters HIV Uninfected
iPrEx[1] 9 51
Partners PrEP[2]
(TDF/FTC arm) 25 81
Thai IDU[3] 39 67
By contrast, TFV was detected in only a minority of subjects who
acquired HIV, arguing that adherence to taking the study
medication was related to remaining HIV uninfected
1. Grant RM, et al. N Engl J Med. 2010;363:2587-2599. 2. Baeten JM, et al. N Engl J Med.
2012;367:399-410. 3. Choopanya K, et al. Lancet. 2013;381:2083-2090.
This difference in TFV detection translated into a
relative risk reduction of acquiring HIV:
iPrEx: 92% (95% CI: 40% to 99%; P < .001)
Partners PrEP TDF/FTC: 90% (95% CI: 56% to 98%; P = .002)
Thai IDU: 70% (95% CI: 2% to 91%; P = .04)
PrEP (Like ART) Works When Taken
2 additional trials of PrEP (FEM-PrEP and VOICE), both conducted
among high-risk African women, did not demonstrate protection against
HIV; in both trials, PrEP adherence was very low (< 30%)
Study Blood Samples With TFV Detected, %
HIV Protection Efficacy in Randomized
Comparison,%
Partners PrEP[1] 81 75
TDF2[2] 80 62
iPrEx[3] 51 44
Thai IDU[4] 67 49
FEM-PrEP[5] and VOICE[6] < 30 No HIV protection
1. Baeten JM, et al. N Engl J Med. 2012;367:399-410. 2. Thigpen MC, et al. N Engl J Med.
2012;367:423-434. 3. Grant RM, et al. N Engl J Med. 2010;363:2587-2599. 4. Choopanya K, et al.
Lancet. 2013;381: 2083-2090. 5. Van Damme L, et al. N Engl J Med. 2012;367:411-422. 6. Marrazzo
J, et al. CROI 2013. Abstract 26LB.
PrEP Trials to Date: Negative Study
1. Van Damme L et al. N Engl J Med 2012;367:411-422. 2. http://www.mtnstopshiv.org/node/2003
Trial Population/Setting Intervention Comments
FEM-PrEP1
(N = 2120)
High-risk women in Africa
Daily oral TDF/FTC
Equal numbers of infections in active and control arms Study stopped for lack
of efficacy
VOICE2
(N = 5029)
Women in Uganda, South Africa and
Zimbabwe
Daily TDF gel Daily oral TDF Daily oral TDF/FTC
None proved to be effective TDF gel and TDF arms
were discontinued
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Male circumcision
2400 BC
Effect of male circumcision on HIV Randomized control
trial study Population and Intervention No. of incidence HIV infection % Reduction in HIV
incidence
Intervention Control
ANRS 1265 trial 1
Orange Farm South Africa
Stopped early on April 30, 2005
Mean follow up 18.1 months
3128 uncircumcised, HIV-neg 18-24 year-old, reside in orange farm and surrounding area
1546 immediate circumcision 1582 Delayed circumcision at end of follow up
20
(0.85 cases per
100 person-year)
49
(2.1 cases per
100 person-year)
60% (95%CI, 32-76)-ITT analysis
76% (95%CI, 56-86)-per-protocol analysis
Rakai, Uganda2
Stopped early on December 12, 2006
Total follow-up time 24 months
4996 uncircumcised, HIV neg, 15-49 year-old
2474 immediate circumcision 2522 delayed circumcision for 24 months
22
(0.66 cases per
100 person-years)
45
(1.33 cases per
100 person-years)
51% (95%CI, 16-72 P = 0.006) - mITT
55% (95%CI 22-75 P= 0.002) – as-treated
Kisuma, Kenya 3
Stopped early on December 12, 2006
Median length of follow-up 24 months
2784 uncircumcised men, 18-24 year-old
1391 immediate circumcision 1393 delayed circumcision for 24 months
22
(2.1 % 2 year
incidence 95%CI,2.1-3.0)
47
(4.2 % 2 year
incidence 95%CI,3.0-5.4
p= 0.0065 )
53% (95%CI,22-72) - ITT
60% (95%CI,32-77) - Adjust for non-adherence and exclude sero-positive at enrolment
1. Auvert B et al. PLoS 2005;2:1112-1122, 2. Gray RH et al. Lancet 2007;369:657-66, 3.Bailey RC et al. Lancet 2007;369:643-56
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HIV CURE
US Timothy Ray Brown, also known as “The Berlin Patient”, the first man to cure AIDS CCR5 Delta32/Delta32 Transplant
Hütter G. N Engl J Med 2009;360:692-8.
Allers K. Blood 2011;117:2791-9.
Clinical Course and HIV-1 Viremia in berlin man
Hütter G. N Engl J Med 2009;360:692-8.
Very Early Triple-Drug ART Elicits “Functional Cure” in HIV-Infected Child
• Infant born to untreated HIV-infected mother at 35 wks’ gestation via spontaneous vaginal delivery[1]
– Maternal HIV infection identified during labor via ELISA and Western blot
– Infant HIV infection confirmed via HIV-1 DNA PCR, HIV-1 RNA analysis of 2 separate samples at 30 and 31 hrs of age[2]
• ZDV/3TC + NVP (at therapeutic dose) initiated at 31 hrs of age, continued for 7 days
• ZDV/3TC + LPV/RTV continued from 7 days to 18 mos of age
– HIV-1 RNA undetectable by Day 30 – Mother removed patient from care at 18 mos of age
1. Persaud D, et al. N Engl J Med 2013;369:1828-35. 2. DHHS Pediatric Guidelines. 2012.
“Functional Cure” Child: Standard HIV-1 Assays Undetectable to Age 26 Mos
• Assessments at Mos 24 and 26
– Western blot negative
– No HIV-specific CD8+ or CD4+ T-cell responses
– Standard HIV-1 RNA and HIV-1 DNA undetectable
– By ultrasensitive assays
• Mo 24: HIV-1 RNA 1 c/mL; HIV-1 DNA < 2.7 c/million PBMCs
• Mo 26: HIV-1 DNA 4 c/million PBMCs
• Clinical trials of exposed infants treated with ART recommended
Persaud D, et al. N Engl J Med 2013;369:1828-35.
• ART regimens: ZDV/3TC + NVP (31 hours – 7 days)
• ZDV/3TC + LPV/RTV (7 days – 18 months)
• Plasma VL on ART displayed typical biphasic decay from baseline VL 19,812 c/mL
– VL undetectable by < 30d of age
– VL remained undetectable though > 80d of age
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Detection of Human Immunodeficiency VirusType 1 (HIV-1) Infection in the Child.
Persaud D, et al. N Engl J Med 2013;369:1828-35.
HIV controller(HIC) and post treatment controller (PTC)
• HIC < 1% of HIV who spontaneously control viremia to undetectable levels (without ARV)
• PTC: interrupting a prolonged antiretroviral therapy initiated close to primary HIV infection are able to control viremia afterwards.
Sa´ez-Cirion A. PLOS Pathogens 2013;9:e1003211
14 PTCs CD4 and viral load
Sa´ez-Cirion A. PLOS Pathogens 2013;9:e1003211
Early Treatment of Pts With Acute HIV Infection Restricts Seeding of
Reservoirs RV254/SEARCH 010: ongoing, prospective, open-label
study of subjects seeking voluntary HIV testing (n = 75 with Fiebig stage I-III acute infection)
• Before ART, HIV reservoir seeding limited
– Integrated HIV-1 DNA undetectable in PBMCs (92%) and sigmoid colon (88%) of most Fiebig I pts
– Lower infection frequencies of central memory CD4+ T cells vs other memory cells
• After ART, decline in HIV reservoir size
– Integrated HIV-1 DNA undetectable in PBMCs in 90% of pts at 1 yr
– Reservoir primarily in transitional and effector memory CD4+ T cells
Suggests very early ART may prevent seeding of reservoirs
Fiebig Stages Fiebig I: RNA+, p24 neg, 3rd-gen ELISA neg
– Would not be detected by 4th-gen ELISA
Fiebig II: RNA+, p24+, 3rd-gen ELISA neg
Fiebig III: 3rd-gen ELISA+, WB neg
Ananworanich J, et al. CROI 2013. Abstract 47.
Thank you for your attention