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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.

23/12/54

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