hiv life cycle update arv and opportunistic infection · 2012-01-19 · 1 update arv and...
TRANSCRIPT
23/12/54
1
Update ARV and Opportunistic infection
Ploenchan Chetchotisakd, MD
Professor of Medicine
Division of Infectious Diseases
and Tropical Medicine
Faculty of Medicine
Khon Kaen University
HIV Life Cycle
Maturation
2. Membrane fusion & entry
9. Budding
3. Uncoating & reverse
transcription
4. Nuclear uptake 5. Integration
6. Transcription & RNA processing
7. Nuclear export 8. Translation
& Assembly
1. Receptor binding
Current ARV
NRTI NNRTI PI
AZT NVP ATV
ddI EFV
d4T
3TC
FTC
TDF RTV
ABC
Entry inhibitor Integrase inhibitor
Fusion inhibitor RAL
T20
CCR5 inhibitor
Maraviroc
FPV
NFV
TPV
IDV
LPV/r
DRV
ETV
RPV
Changing Guidelines for Initiation of Antiretroviral Therapy
CD4+ Counts, cells/mm3
1998 2001 2006 2008 2009
> 350 Offer if VL > 20,000
copies/mL
Consider if VL> 55,000 copies/mL
Consider if VL≥ 100,000 copies/mL
Consider in certain
groups*
Treat at 350-500; consider
for > 500†
200-350 Offer if VL > 20,000
copies/mL
Offer, but controversy
exists
Offer after discussion
with patient Treat Treat
< 200 or symptomatic
disease Treat Treat Treat Treat Treat
DHHS Guidelines 2011: When to Start
Asymptomatic Infection Recommendation
CD4+ cell count < 350 cells/mm3 Start HAART
CD4+ cell count 350-500 cells/mm3 Start HAART
CD4+ cell count > 500 cells/mm3 Panel divided
Clinical Conditions Favoring Initiation of Therapy Regardless of CD4+ Cell Count
History of AIDS-defining illness Certain acute opportunistic infections
Pregnancy HIVAN HBV coinfection when HBV treatment is indicated CD4+ count decline > 100 cells/mm3/yr HIV-1 RNA > 100,000 copies/mL Serodiscordant relationships
DHHS Guidelines. October, 2011.
IAS-USA 2010: Guidelines for When to Start ARV Therapy
Measure Recommendation
Specific conditions
ART recommended regardless of CD4 cell count
Symptomatic HIV disease
Pregnancy
High HIV-1 RNA Level (>100,000 copies/mL)
Rapid CD4 count decline (>100 cells/mm3 per year)
HIV-associated nephropathy
CD4 cell count ≤500 cells/mm3 ART recommended
CD4 cell count >500 cells/mm3 ART should be considered§
Thompson MA, et al. JAMA 2010;304(3):321-333; US Department of Health and Human Services Guidelines; Revised December 1, 2009. Available at: http://aidsinfo.nih.gov/contentfiles/AdultandAdolescentGL.pdf.
* Differs from 2009 DHHS guidelines § Unless patient is an elite controller (HIV-1 RNA <50 copies/mL) or has stable CD4 cell count and low-level viremia in the absence of ART
Active hepatitis B or C* virus co-infection
Active or high risk for cardiovascular disease*
Symptomatic primary HIV infection*
Risk for secondary HIV transmission is high*
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European AIDS Guidelines: 2011
R= Recommended, C= Considered, D=Deferred
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. Asian BMC 2010
CIPRAHT001: Early (CD4< 350) vs Standard (CD4<200) Therapy in Haiti
Early Antiretroviral therapy Initiated within 2 wks of enrolment
(n=408)
Standard Antiretroviral therapy Initiated when CD4 < 200 cells/mm3
Or upon development of AIDS-defining illness (n=408)
Treatment naive patients with CD4 200-350 and
No history of AIDS Defining illness
(n=816)
Study halted early 29 deaths report
Severe P. NEJM 2010;363:257-65
CIPRAHT001: Early (CD4< 350) vs Standard (CD4<200) Therapy in Haiti
Outcomes Early ARV N=408
Standard ARV N=408
Hazard ratio P-value
Death, n 6 23 4.0 .0011
Gastroenteritis 1 7
TB 0 5
Pneumonia 0 4
Cholangitis/sepsis 0 1
Other 5 6
Incident TB 18 36 2.0 .0125
Severe P. NEJM 2010;363:257-65
Early vs. standard antiretroviral therapy for HIV-infected adults in Haiti
Severe P. NEJM 2010;363:257-65.
เร่ิมยาเม่ือ CD4 200-350 เซลล์/ลบ.มม
เร่ิมยาเม่ือ CD4 < 200 เซลล์/ลบ.มม
สปสช 6 กค. 2011
• อนุมัติให้เร่ิมการรักษาผู้ป่วยติดเชื้อ HIV เมื่อ CD4 < 350 cell/mm3 เมื่อผู้ป่วยมีความพร้อมและกรณีต่อไปน้ี 1. Coinfection with HBV or HCV
2. Age > 50 yr with DM, HT or DLD
3. HIV-associated nephropathy
4. Postpartum women who had CD4 < 350 during pregnancy
Note: any patients who have OI or TB can start ARV at any CD4 count
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Preferred First-line Regimens: 2011 DHHS Guidelines
Preferred regimens: those with optimal and durable efficacy, favorable tolerability and toxicity profile, and ease of use . (AI)
NNRTI based EFV* + TDF/FTC
Boosted PI based ATV/RTV** + TDF/FTC
DRV/RTV + TDF/FTC
Integrase inhibitor based RAL + TDF/FTC
Pregnancy AZT + 3TC + LPV/r
US Department of Health and Human Services. Available at: http://aidsinfo.nih.gov/Guidelines.
* Caution with pregnancy, ** should net be used in pt taking omiprazole>20mg/d
Alternate First-line Regimens: 2011 DHHS Guidelines
Alternate regimens: Regimens that are effective and tolerable but have potential disadvantages compared with preferred regimens. An alternative regimen may be the preferred regimen for some patients. (BI)
NNRTI based EFV + ABC/3TC (BI)
RPV/TDF/FTC (BI)
RPV+ ABC/3TC (BIII)
Boosted PI based ATV/RTV + ABC/3TC (BI)
DRV/RTV +ABC/3TC (BIII)
FPV/RTV + TDF/FTC or ABC/3TC (BI)
LPV/r + TDF/FTC or ABC/3TC (BI)
Integrase inhibitor based RAL + ABC/3TC (BI)
US Department of Health and Human Services. Available at: http://aidsinfo.nih.gov/Guidelines.
Acceptable First-line Regimens: 2011 DHHS Guidelines
Acceptable Regimens that may be selected for some patients but are less satisfactory than preferred or alternative regimens . (CI)
NNRTI based EFV + AZT/3TC
NVP + TDF/FTC or ABC/3TC or AZT/3TC
RPV + AZT/3TC
Boosted PI based ATV or ATV/r + ABC or AZT+3TC
DRV/RTV +AZT+3TC
FPV/r + AZT+3TC
LPV/r + AZT+3TC
Integrase inhibitor based RAL + AZT+3TC
CCR5 based MVC + AZT+ 3TC
MVC +TDF/FTC or ABC/3TC
US Department of Health and Human Services. Available at: http://aidsinfo.nih.gov/Guidelines.
Antiretroviral Components Not Recommended as
Part of an Antiretroviral Regimen
• ATV+IDV (AII)
• ddI +d4T (AII)
• ddI +TDF (AII)
• 2NNRTI (AI)
• EFV in 1st trimester (AIII)
• AZT +d4T (AII)
• FTC + 3TC (AIII)
• ETR + ATV/r, FPV/r , TPV/r (AII)
• ETR + unboosted PI (AII)
• Unboosted DRV, SQV, TPV (AII)
• NVP in ARV naïve (BI)
– Female CD4 > 250
– Male CD4 > 400
IAS-USA 2010: Guidelines for Initial ARV Regimens
Dual NRTI Key 3rd Drug
Re
com
me
nd
ed
TDF/FTC
EFV ATV/r DRV/r RAL
Alt
ern
ativ
e
ABC/3TC
LPV/r FPV/r MVC
Comparison to 2009 DHHS Guidelines: • “Recommended” therapies are the same as “Preferred” regimens • In addition to “Alternative” therapies listed, 2009 DHHS Guidelines “Alternative” and
“Acceptable” regimens include ZDV/3TC, ddI + 3TC, NVP, unboosted ATV, and SQV/r
+
Thompson MA, et al. JAMA 2010;304(3):321-333; US Department of Health and Human Services Guidelines; Revised December 1, 2009. Available at: http://aidsinfo.nih.gov/contentfiles/AdultandAdolescentGL.pdf.
Thompson MA, et al. JAMA. 2010;304;321-333.
European Guideline 2011
Recommended Regimens
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European Guideline 2011
Alternative Regimens
ACTG 5202: First-line Therapy With ABC/3TC vs TDF/FTC + EFV vs ATV/RTV
Daar E, et al. CROI 2010. Abstract 59LB.
Antiretroviral-naive patients with HIV-1 RNA
≥ 1000 copies/mL and any CD4+ cell count
(N = 1857)
TDF/FTC* 300/200 mg QD + EFV† 600 mg QD
(n = 464)
ABC/3TC* 600/300 mg QD + EFV† 600 mg QD
(n = 465)
Stratified by HIV-1 RNA < or ≥ 100,000 copies/mL
TDF/FTC* 300/200 QD + ATV/RTV† 300/100 mg QD
(n = 465)
ABC/3TC* 600/300 mg QD + ATV/RTV† 300/100 mg QD
(n = 463) *Double blind. †Open label.
Wk 96 primary endpoint
ACTG 5202: Virologic Failure With ATV/RTV vs EFV at Wk 96
Daar E, et al. CROI 2010. Abstract 59LB.
Pat
ien
ts W
ith
ou
t V
iro
logi
c Fa
ilu
re (%
)
ATV/RTV
EFV
ABC/3TC TDF/FTC
100
80
60
40
20
0
85.3 89.0 89.8
83.4
• Similar time to virologic failure with ATV/RTV vs EFV when combined with either ABC/3TC or TDF/FTC in overall population analysis – With ABC/3TC, HR: 1.13 (95%
CI: 0.82-1.56)
– With TDF/FTC, HR: 1.01 (95% CI: 0.70-1.46)
ACTG 5202: Virologic Failure With ABC/3TC vs TDF/FTC
Daar E, et al. CROI 2010. Abstract 59LB.
Pati
ents
Wit
ho
ut
Vir
olo
gic
Failu
re (
%)
ATV/RTV EFV
100
80
60
40
20
0
90.3 87.4 89.2 88.3
ABC/3TC
TDF/FTC
Virologic Failure Free at 96 Wks for Pts With Screening VL < 100,000 copies/mL
In pts with screening VL < 100,000 c/mL
• Similar time to virologic failure with ABC/3TC vs TDF/FTC regardless of ATV/RTV or EFV
– With ATV/RTV, HR: 1.26 (0.76-2.05)
– With EFV, HR: 1.23; (0.77-1.96)
In pts with screening VL ≥ 100,000 c/mL
• Shorter time to VF with ABC/3TC vs. TDF/FTC with either EFV or ATV/RTV
– With EFV, HR: 2.22 (1.19-4.14)
– With ATV/RTV, HR: 2.46 (1.20-5.05)
ACTG 5202: Shorter Time to VF in Patients With High HIV-1 RNA Receiving ABC/3TC
Outcome, n ABC/3TC
(n = 398)
TDF/FTC
(n = 399)
Virologic failure (VF), total 57 26
Early VF with no previous
suppression to VL< 200
19 9
Late VF with no previous
suppression to VL< 200
9 2
Late VF with previous
suppression to VL< 200
29 15
• Similar proportions in each arm with VL < 50 at Wk 48 (P = .20) by ITT (switching NRTIs failure)
• Post hoc analysis: for subjects achieving 2 VL < 50 on ART, no significant difference in risk of rebound between arms (P = .247)
Sax PE, et al. N Engl J Med. 2009;361:2230-2240.
0.0
0.2
0.4
0.6
0.8
1.0
0 4 16 24
Wks From Randomization
Pro
bab
ility
of
Rem
ain
ing
Free
of
Vir
olo
gic
Failu
re
36 48 60 72 84 96 108
ABC/3TC (57 events)
TDF/FTC (26 events)
Log rank P = .0003 HR: 2.33 (95% CI: 1.46-3.72)
Metabolic Substudy of ACTG 5202: Lumbar Spine and Hip BMD Changes (ITT)
McComsey G, et al. CROI 2010. Abstract 106LB.
P = .025 P = .004
Comparison of ABC/3TC vs TDF/FTC Comparison of EFV vs ATV/RTV
Mea
n ∆
in B
MD
Fro
m B
L to
Wk
96
(%
)
-4.0
-3.0
-2.0
0
TDF/FTC ABC/3TC
-1.0
Difference: 2.0%
Lumbar Spine Hip
n = 101 97 99 96
P = .59 P = .035
Mea
n ∆
in B
MD
Fro
m B
L to
Wk
96
(%
)
-4.0
-3.0
-2.0
0
ATV/RTV EFV
-1.0
Lumbar Spine Hip
n = 107 91 105 90
Difference: 1.5%
Difference : 1.5% Difference: 0.3%
• Initial loss in BMD in all arms stabilized after Wk 48
• No significant differences in fracture rates between arms
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Metabolic Substudy of ACTG 5202: Limb Fat Changes
McComsey G, et al. CROI 2010. Abstract 106LB.
• Similar absolute and % increases in limb fat with ABC/3TC and TDF/FTC in ITT analysis (P > 0.1)
– In as-treated analysis, greater increase in limb fat with ABC/3TC vs TDF/FTC (difference: 1 kg; P = .023)
• Greater absolute and % increases in limb and trunk fat with ATV/RTV vs EFV in ITT and as-treated analyses (P < .05)
Limb Fat Primary Endpoint
ABC/3TC + EFV TDF/FTC + EFV
TDF/FTC + ATV/RTV ABC/3TC + ATV/RTV
≥ 1
0%
Lim
b F
at L
oss
Fr
om
BL
to W
k 9
6 (
%)
0
20
60
80
40
n =
18.9
53
14.3
56
16.3
49
15.6
45
100
P = NS
Regimen
Boosted PIs in ARV-Naive Pts: Virologic Suppression at Wk 48
0
10
20
30
40
50
60
70
80
90
100
This slide is an illustration only and not meant to be a cross-study comparison. *P < .05 between LPV/RTV QD and DRV/RTV QD; no other significant differences in any comparisons above. †Use of LPV/RTV BID or QD was not randomized and was dependent on site and pt preference. ‡SGC or tablet until Wk 8; tablet after Wk 8.
Pts
Wit
h H
IV-1
RN
A
< 5
0 c
op
ies/
mL
(%)
1. Eron J Jr, et al. Lancet. 2006;368:476-482. 2. Walmsley SL, et al. J. Infect Dis. 2009;50:367-374. 3. Molina JM, et al. Lancet. 2008;372:646-655. 4. Ortiz R, et al. AIDS. 2008;22:1389-1397.
440 443
CASTLE[4] (ITT)
NRTIs: TDF/FTC
ATV/RTV 300/100
QD
LPV/RTV 400/100
BID
76 78 78*
KLEAN[1] (ITT-E, TLOVR)
NRTIs: ABC/3TC
GEMINI[2] (ITT)
NRTIs: TDF/FTC
ARTEMIS[3] (ITT)
NRTIs: TDF/FTC
65
FPV/RTV 700/100
BID
LPV/RTV 400/100
BID
66
LPV/RTV†
400/100 BID or
800/200 QD
DRV/RTV 800/100
QD
84*
434 444 343
65
SQV/RTV 1000/100
BID
LPV/RTV 400/100
BID
170 167
64
346 n =
Lipid Changes From BL to Wk 48
This slide is an illustration only and not meant to be a cross-study comparison. 1. Eron J Jr, et al. Lancet. 2006;368:476-482. 2. Walmsley SL, et al. J. Infect Dis. 2009;50:367-374. 3. Nelson M, et al. Inter Congress on Drug Therapy in HIV Infection 2008. Abstract P127. 4. Reprinted from The Lancet, v 372, Molina JM, et al, pp 646-655.
66
FPV/RTV LPV/RTV
39 33
29 23
39 41
TC LDL HDL TG
Med
ian
Ch
ange
(%
)
0
10
20
30
40
50
60
70 60
KLEAN[1]
17 20 18 20
29 26
12
47
P = .0022
LPV/RTV SQV/RTV
GEMINI[2]
DRV/RTV LPV/RTV
P < .001
P < .001
ARTEMIS[3] P < .0001
ATV/RTV LPV/RTV
12
24
12 15
27 32
13
51
P < .0001
CASTLE[4]
TC LDL HDL TG
Med
ian
Ch
ange
(%
)
0
10
20
30
40
50
60
70
TC LDL HDL TG
Med
ian
Ch
ange
(%
)
0
10
20
30
40
50
60
70
TC LDL HDL TG
Med
ian
Ch
ange
(%
)
0
10
20
30
40
50
60
70
12.4 19.8
12.6 12.5 9.8
19.4
6.8
57.6
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, THRIVE: Rilpivirine vs EFV in Treatment-Naive Patients
HIV-1 RNA < 50 copies/mL (ITT-TLOVR) at Wk 48
*P < .0001 for noninferiority at -12% margin.
RPV EFV
Cohen C, et al. AIDS 2010. Abstract THLBB206. Cohen C, et al. Glasgow 2010. Abstract O48.
HIV-1 RNA < 50 copies/mL at Wk 48 by BL VL
40
0
100
20
80
82.3 84.3*
60
682 686 n =
ECHO THRIVE Pooled
Pati
en
ts (
%)
82.8 82.9* 81.7 85.6*
338 340 344 346 -3.6 (-9.8 to +2.5)
6.6 (1.6-11.5)
> 100,000 copies/mL
125/ 165
121/ 153
246/ 318
149/ 181
136/ 171
285/ 352
77 81 79 80 76 82
Pati
en
ts (
%)
40
0
100
20
80
60
Pooled THRIVE ECHO
≤ 100,000 copies/mL
162/ 181
170/ 187
332/ 368
136/ 163
140/ 167
276/ 330
90 83
91 84
90 84
Pati
en
ts (
%)
40
0
100
20
80
60
ECHO THRIVE Pooled
ECHO, THRIVE: Treatment Failure, Resistance, and Adverse Events at Wk 48
Wk 48 Outcome RPV EFV
VF with resistance data, n 62 28
No NNRTI or NRTI RAMs, % 29 43
1 emergent NNRTI RAM, % 63 54
Most frequent NNRTI RAM E138K K103N
1 emergent NRTI RAMs, % 68 32
Most frequent NRTI RAM M184I M184V
Treatment Failure in ECHO and THRIVE
Resistance at VF
6
0
15
3
12
9
4.8
346 n =
VF
9.0
682 686
6.7
AE
2.0
682 686
Pati
ents
(%
)
Wk 48 Outcome, % RPV EFV P Value
DC for AE 3 8 .0005
Most Common AEs of Interest, %
Any neurologic AE 17 38 < .0001
Any psychiatric AE 15 23 .0002
Any rash 3 14 < .0001
RPV
EFV Self-Reported Adherence RPV
(n = 627)
EFV
(n = 587)
> 95% 88 88
> 90% - 95% 78 75
< 90% 51 59
HIV-1 RNA < 50 copies/mL (ITT-TLOVR) by Adherence Level
AEs and Discontinuation
Cohen C, et al. AIDS 2010. Abstract THLBB206. Cohen C, et al. Glasgow 2010. Abstract O48.
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6
Riplivirine
• Once-daily dosing
• Coformulated with TDF/FTC (Endurance)
• Compared with EFV:
- Fewer discontinuations for CNS adverse effects
- Fewer lipid effects
- Fewer rashes
Riplivirine
• More virologic failures in patients with pretreatment HIV RNA >100,000 copies/mL than with EFV-based regimen
• More NNRTI- and 3TC-associated mutations at virological failure than with regimen containing EFV + two NRTIs
• Food requirement
• Absorption depends on lower gastric pH, caution with H2 blocker and antacid
• Contraindicated with PPIs
• RPV-associated depression reported
• Use RPV with caution when coadministered with a drug having a known risk of torsades de pointes.
Thailand ARV regimens 2010
NRTI NNRTI
Preferred AZT+3TC TDF+FTC/3TC
NVP EFV
Alternative ABC+3TC d4T+3TC ddI+3TC
PI
Preferred LPV/r
Alternative ATV/r DRV/r SQV/r
If patients Cannot
Tolerate NNRTI
Sungkanuparph S. Asian BMC 2010
• TDF: Caution in abnormal creatinine clearance and elderly patients.
• TDF +3TC/FTC is recommended in HBV co-infection.
• ABC: hypersensitivity reactions and should not be used with NVP.
• d4T: replaced with other NRTI after 6-12
• EFV: cannot be used in the first trimester of pregnancy.
• NVP: should be used in caution in females with CD4+ >250 cells/mm3
AZT VS. TDF AZT/3TC VS. TDF/FTC (TDF+3TC)
Relative Potency of Approved NRTIs
1. Eron JJ, et al. N Engl J Med. 1995;333:1662-1669. 2. Riddler SA, et al. Antiviral Res. 1995;27: 189-203. 3. Katzenstein DA, et al. N Engl J Med. 1996;335:1091-1098. 4. Rousseau F, et al. J Infect Dis. 2003;188:1652-1658. 5. Staszewski S, et al. AIDS. 1998;12:F197-F202. 6. Louie M, et al. AIDS. 2003;17:1151-1156. 7. Rousseau FS, et al. J Antimicrob Chemother. 2001;48:507-513.
HIV
RN
A D
eclin
e
(lo
g 10
cop
ies/
mL)
-2.0
-1.5
-1.0
-0.5
0.0
AZT[1] d4T[2] ddI[3] 3TC[4] ABC[5] TDF[6] FTC[7]
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Efficacy of Select EFV-Based Regimens (< 400 c/mL TLOVR, 48 wks)
Bartlett JA, et al. HIV Clin Trials. 2007;8:221-226.
50 55 60 65 70 75 80 85 (%)
EPV-20001
EPV-20001
DMP-006
CNA-30021
CNA-30024
CNA-30021
CNA-30024
GS-934
GS-903
FTC-301 A
GS-903
GS-934
(n = 276)
(n = 278)
(n = 422)
(n = 384)
(n = 325)
(n = 386)
(n = 324)
(n = 243)
(n = 299)
(n = 286)
(n = 301)
(n = 244)
ZDV BID + 3TC BID
ZDV BID + 3TC QD
ZDV BID + 3TC BID
ABC QD + 3TC QD
ZDV BID + 3TC BID
ABC BID + 3TC QD
ABC BID + 3TC BID
ZDV/3TC BID
TDF QD + 3TC BID
ddl QD + FTC QD
d4T BID + 3TC BID
TDF QD + FTC QD
63 65
61 67
65 69
64 71
69 71
65 72
69 73
70 73
76 79
78 81
79 82
80 84
Indicates the TLOVR response rate at < 50 copies/mL
38
Study 934: 96 weeks
Proportion with HIV-RNA <50 c/mL (TLOVR)
0
1 0
2 0
3 0
4 0
5 0
6 0
7 0
8 0
9 0
B L 8 1 6 2 4 3 2 4 0 4 8 6 0 7 2 8 4 9 6
Weeks
TDF+FTC+EFV (n = 232) 67%*
AZT+3TC+EFV (n = 231) 61%*
Re
spo
nd
er (
% o
f P
atie
nts
)
Pozniak A.L., et al. JAIDS 2006; 43(5):535-540
Gallant JE et al. NEJM 2006; 354:251-60
48-week TLOVR results: HIV RNA <50 c/mL 80% FTC+TDF+EFV (n = 244) vs 70% AZT+3TC+EFV (n = 243)
39
Study 934: ZDV/3TC vs TDF + FTC
Pozniak AL et al. JAIDS. 2006;43:535-540.
Me
an
Ch
an
ge
Fro
m B
ase
lin
e (
mg
/d
L)
0 4 16 24 32 48 60 72 84 96
-10
0
10
20
30
40
50
Study Week
TDF + FTC + EFV
ZDV/3TC + EFV
Triglycerides Fasting LDL
P =0.12
TDF + FTC + EFV
ZDV/3TC + EFV
P =0.067
Mean Change Lipid Profile
Gilead 903/934: Mean (95% CI) limb fat
Campo et al. IAC 2008
GS903E: TDF and Bone Loss Over 7 Yrs
• GS903E[1]: ongoing, open-label extension phase of randomized, double-blind phase III study GS903[2]
– d4T vs TDF, both + 3TC and EFV
– After 144 wks, all participants continued on TDF
• Bone loss in spine (-2.2%) and hip (-2.8%) in Wks 24-48; stabilized by Wk 144 1. Cassetti I, et al. IAC 2008. Abstract TUPE0057.
2. Gallant J, et al. JAMA. 2004; 292:191-201.
8
6
4
2
0
-2
-4
-6
-8
% C
han
ge in
BM
D
Yr 1 2 3 4 5 6 7
Spine Hip
-1.5%
-2.6%
Spine n = 86 85 86 86 80 76 69 71 Hip n = 86 85 84 86 81 76 70 71
Gilead 903/934: 3 year median estimated GFR
Gallant et al. IAC 2008
23/12/54
8
TDF and Renal Function in Initial HAART
• GFR decreases similar in pts receiving TDF vs other NRTIs during first 2 yrs of therapy in retrospective analysis of pts from Hopkins cohort[1]
– Older age, lower CD4+ count, hypertension, use of boosted PI independently associated with higher risk of 25% decline in GFR by multivariate analysis (P < .05)
• Philadelphia clinic cohort observed no association between TDF and renal function decline over 2 yrs, regardless of concomitant PI vs NNRTI[2]
1. Moore R, et al. ICAAC/IDSA 2008. Abstract 2297. 2. Short WR, et al. ICAAC/IDSA 2008. Abstract 2298. Graphics reproduced with permission.
Days
0
25
50
75
100
0 100 500 600 300
TDF
Other NRTI
700 200 400
GFR decline ≥ 25%
GFR decline ≥ 50%
Pts
(%
)
100
80
60
40
20
0
Pts
(%
)
> 25% GFR Decline
> 50% GFR Decline
TDF + boosted PI Other NRTI + boosted PI TDF + NNRTI Other NRTI + NNRTI
*P < .01 vs NNRTI †P < .05 vs NNRTI
27.1* 25.1*
15.3 13.7 5.8† 4.0 2.1 3.1
TDF used in Thai patients
• Retrospective study at Bamrasnaradura ID institute
• 130 cases changed to TDF – 45% NVP based – 37% EFV based – 18% PI based
• eGFR baseline 103 ml/min/1.73m2 decrease to 100 at 306 months (p<0.001)
• Retrospective at Chonburi Hosp.
• 405 cases – 29.3% had eGFR a 25%
decreased – Median time 28 months
• Risk Factors – Low body weight – Low BMI – Based line GFR – PI used – Nephrotoxic drug
Manosuthi W. Southeast Asian J Trop Med Public Health 2011;42:643-50. Chaisiri K. Curr HIV Res 2010; 8:504-9.
Switching from d4T/3TC to TDF/3TC in Thai patients
28 cases 34 cases
Manosuthi W. AIDS Res Ther 2010;7:37
All Patients No TAMs 1 or 2 TAMs
≥ 3 TAMs With M41L or L210W
≥ 3 TAMs, no M41L or L210W
Me
an D
AV
G2
4 (l
og 1
0 c/
mL)
n = 222 n = 42 n = 57 n = 68 n = 55
* * *
†
* -1.0
-0.9
-0.8
-0.7
-0.6
-0.5
-0.4
-0.3
-0.2
-0.1
0
0.1
Tenofovir Resistance and Virologic Response
*P < .0001 vs placebo †P = .013 vs placebo
Miller M, et al J Infect Dis. 2004;189:837-846.
Response rate in patients with ≥ 3 TAMs with M41L or L210W was significantly lower than all other groups
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 d4T or ddI or TDF
Drug Specific Toxicities
• Tenofovir (300mg OD) – Potential for renal impairment
– Fanconi syndrome and acute renal insufficiency, rare report
– Potential for decrease in bone mineral density
– Lactic acidosis
• Management
– Monitor renal function and UA
– Adjust dose according to renal function
23/12/54
9
Fanconi syndrome
• Proximal tubule dysfunction
– Nephrogenic DI: polyurea, malaise
– Hypokalemia
– Hypophosphatemia
– Glycosuria
– Mild proteinuria
NRTI adjustment for renal failure
ARV Normal dose >50-90 10-50 <10
AZT 300 q12h 300 q 12h 300 q 12h 100 q 8h
ddI 125-200 q 12h Buffered tabs
200 q 12h 200 q 24h < 60 kg:100 q 24h >60 kg:150 q24h
400 q 24h Enteric coat tabs
400 q 24h 125-200 q 24h Do not use EC tabs
3TC 300 q 24 300 q 24h 50-150 q 24h 25-50 q 24h
d4T 30-40 q12 h 100% 50% q12-24h <60 kg: 15 q 24h >60 kg: 20 q 24h
TDF 300 q 24h 300 q 24 h 30-49: 300 q48h 10-29:300 q 72-96h
No data
Sanford guide to antimicrobial therapy 2010
AZT/3TC
Advantage Disadvantage
• Coformulated (ZDV/3TC and ZDV/3TC/ABC) • No food effect (although better tolerated with food) • Preferred dual NRTI in pregnant women
• Bone marrow suppression, especially anemia and neutropenia • GI intolerance, headache • Mitochondrial toxicity, including lipoatrophy, lactic acidosis, hepatic steatosis • Inferior to TDF/FTC in combination with EFV • Less CD4 increase compared with ABC/3TC • Twice-daily dosing
TDF/FTC Advantage Disadvantage
•Better virologic responses than with ZDV/3TC • Better virologic responses than with ABC/3TC in patients with baseline HIV RNA >100,000 copies/mL in ACTG 5202 study; however, this was not seen in the HEAT study. • Active against HBV; recommended dual- NRTI for HBV/HIV coinfection • Once-daily dosing • No food effect • Coformulated (TDF/FTC, EFV/TDF/FTC and RPV/TDF/FTC) • No cumulative TAM-mediated resistance
• Potential for renal impairment, including rare reports of Fanconi syndrome and acute renal insufficiency • Early virologic failure of NVP + TDF + (FTC or 3TC) in small clinical trials • Potential for decrease in bone mineral density
EFV VS. NVP
2NN Study: NVP vs EFV vs NVP+EFV Treatment success and failure
van Leth H, et al. Lancet 2004
* Success: only significant
difference EFV vs NVP+EFV
(p<0.001)
Change therapy
Disease progression
Virologic failure
Success
Failure component:
whichever comes first
% p
atients
29.1
11.4
56.4 56.3 62.3 46.9
18.9 15.3 16.3
22.0 20.0 34.5
100
75
50
25
0 NVP QD NVP BID EFV* NVP+EFV*
2 deaths attributed to NVP (toxic hepatitis, Stevens-Johnson leading to MRSA sepsis)
1 death attributed to d4T (lactic acidosis)
Coadministration of NVP and EFV not advisable due to enhanced toxicity
n=220 n=387 n=400 n=209
23/12/54
10
EFV
Advantage Disadvantage
• Virologic responses equivalent or superior to all comparators to date • Once-daily dosing • Coformulated with TDF/FTC
• Neuropsychiatric side effects • Teratogenic in nonhuman primates. Several cases of neural tube defect reported in infants of women exposed to EFV in the first trimester of pregnancy. EFV use should be avoided in women with potential for pregnancy and is contraindicated in the first trimester. • Dyslipidemia
NVP Advantage Disadvantage
• No food effect • Fewer lipid effects than EFV • Once-daily dosing with extended-release tablet formulation • Safe in pregnant women
• Higher incidence of rash, including rare but serious HSRs (SJS, TEN), than with other NNRTIs • Higher incidence of hepatotoxicity, including serious and even fatal cases of hepatic necrosis, than with other NNRTIs • Contraindicated in patients with moderate or severe (Child-Pugh B or C) • Some data suggest that ART-naive patients with high pre-NVP CD4 counts (>250 cells/mm3 for females, >400 cells/mm3 for males) are at higher risk of symptomatic hepatic events.
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
NVP 200 mg BID* + TDF/FTC (n = 188)
NVP 400 mg QD* + TDF/FTC (n = 188)
Antiretroviral-naive pts with MDRD
≥ 50 mL/min; CD4+ count < 400 (males) or < 250 cells/mm³ (females)
(N = 569)
ATV/RTV 300/100 mg + TDF/FTC (n = 193)
Wk 48 primary endpoint
*Preceded by 2-wk lead-in dose of NVP 200 mg daily.
Stratified by HIV-1 RNA ≤ or > 100,000 copies/mL and CD4+ count < or ≥ 50 cells/mm³
Soriano V, et al. IAS 2009. Abstract LBPEB07.
ARTEN: Wk 48 Response to NVP vs ATV/RTV in Naive Pts
ARTEN: Wk 48 Response to NVP vs ATV/RTV in Naive Pts
• NVP either once daily or twice daily noninferior to ATV/RTV at Wk 48
• Rates of AEs similar overall but higher rate of discontinuation due to toxicity in NVP arms (13.6% vs 3.6%)
HIV
-1 R
NA
< 5
0 c/
mL
at W
k 48
(%
)
40
0
100
20
80
Any NVP
65.3 66.8
60
P = .63
ITT, NC = F
NVP QD
NVP BID
67.0 66.5
Outcome at
Wk 48, %
NVP QD
(n = 188)
NVP BID
(n = 188)
ATV/RTV
(n = 193)
Virologic failure 11.2 12.8 14.0
• Investigator-
defined
virologic failure
5.9 11.2 1.6
• No confirmed
response at
Wk 48
5.3 1.6 12.4
Soriano V, et al. IAS 2009. Abstract LBPEB07.
ATV/ RTV
n = 376 193 188 188 OPPORTUNISTIC INFECTIONS
23/12/54
11
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. N Engl J Med. 2010 Feb 25;362(8):697-706 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
8/1494/48
10/1377/129
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.
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12
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
bab
ility
of
Surv
ival
1.00
0.90
0.80
0.70
0.60
Early arm Late arm
0 50 100 150 200 250
DHHS 2011: Indications for initiation of ART in patients with HIV and TB
CD4 count
Recommendation
<200 Start ART 2-4 weeks after the initiation of TB treatment (AI)
200-500 Prefer 2-4 weeks, or within 8 weeks after the initiation of TB treatment (AIII)
>500 Within 8 weeks after TB therapy (BIII)
DHHS Guideline 2011
IRIS may occur after initiation of ART. Both ART and TB treatment should be continued while managing IRIS (AIII).
Indications for initiation of ART in patients with HIV and TB
CD4 count
Recommendation
<200 Start ART 2-8 weeks after the initiation of TB treatment
200-350 Start ART 2 months after the initiation of TB treatment
>350 Defer and follow up CD4 every 6 months
Thai Guideline 2010
Prednisolone vs. placebo in TB IRIS symptom score in week 2 and 4
• RCT trial for non fatal IRIS
• Prednisolone – 1.5mg/kg/dx2wk
– 0.75mg/kg/dx2wk
Meintjes G. AIDS 2010, 24:2381–2390
ACTG A5164: Immediate vs Deferred ART in Patients With Acute OIs
Zolopa A, et al. PLoS One 2009;4:e5575
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
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
Zolopa A, et al. PLoS One 2009;4:e5575
23/12/54
13
Early ART Decreases Survival in HIV+ Patients With Cryptococcal Meningitis
Makadzange AT, et al. CID 2010
• HIV-infected African patients diagnosed with cryptococcal meningitis randomized to receive 10 wks of fluconazole 800 mg QD + ART (n = 26) or fluconazole alone (n = 28)
– After 10 wks, all patients received fluconazole 200 mg QD + ART
• After 2 yrs of follow-up: 23 deaths in early ART group (87% mortality rate) vs 9 deaths in delayed ART group (37% mortality rate) (P = .002)
• Median survival, early ART vs delayed ART: 35 vs 274 days (P = .028)
0.00
0.25
0.50
0.75
1.00
0 200 400 600 800
Time to Death (in Days)
Delayed ART Early ART
P = .028
Surv
ival
AIDS defining illness in Thailand Sep1984-Feb2004
http://epid.moph.go.th
Percentage
Primary Prophylaxis of Cryptococcosis in Thailand
Recommended
•CD4 < 100 /mm3
•No sign/symptom of cryptococcal disease
•Negative serum crypto Ag (if available)
Regimen
– Fluconazole 400 mg weekly
Discontinuation of primary prophylaxis – On ART with CD4> 100 /mm for 3 months
Thailand National Guidelines on HIV/AIDS 2010
Primary prophylaxis of cryptococcal disease with fluconazole in HIV +ve Ugandan: RCT
double blind study
Primary outcomes
Placebo N=759
Fluconazole N=760
Unadjusted log-rank test
(p value)
Adjusted HR (95%CI)
Cryptococcal disease
18 1 15.3 (p=.0001)
18.7 (2.5-140.7)
Death 93 96 0.05 (P=0.82)
0.96 (0.72-1.27)
Parkes-Ratanshi R. Lancet Infect Dis 2011;11:933-41
WHO guideline
WHO RAPID ADVISE, December 2011
WHO guideline WHO RAPID ADVISE, December 2011
23/12/54
14
What is the recommended as preferred regimen in initial induction therapy for CM in Thai guidelines?
A. Ampho B .7 mg/kg/d + 5FC 100 mg/d
B. Ampho B .7 mg/kg/d
C. Ampho B .7 mg/kg/d + Fluconazole 400 mg/d
D. Ampho B .7 mg/kg/d + Fluconazole 800 mg/d
E. Fluconazole 800-1200 mg/d
Treatment of Cryptococcosis in Thailand
• Induction Phase Recommend
– Ampho B 1 mg/kg/d – Amopho B .7 mg/kg/d + Fluconazole 800 mg/d
Alternative – Fluconazole 800-1200mg/d in Cryptococcosis without
meningitis
• Consolidation Phase Maintenance Phase Recommend Recommend – Fluconazole 800 mg/d Fluconazole 200 mg/d Alternative Alternative – Itraconazole 400mg/d Itraconazole 200mg/d
Ampho + Fluconazole for CM: Phase II study
Pappas P. CID 2009; 48:1775–83
41.3
71.7 71.7
AmB
27.1
72.9 75.0
80.5
53.7
78.0
AmB+Flu 400 AmB+Flu 800
Overall (MITT)
Day 14 Day 42 Day 70 Day 14 Day 42 Day 70 Day 14 Day 42 Day 70
100
90
80
70
60
50
40
30
20
10
0
Su
cc
es
sfu
l o
utc
om
es
%
Thank you for your attention