8/2/2014

1

HIV: Antiretroviral Therapy

Ploenchan Chetchotisakd, MD

Professor of Medicine

Division of Infectious Diseases

and Tropical Medicine

Department of Medicine

Faculty of Medicine

Khon Kaen University

Based on Thai Guideline, Asymptomatic HIV จะเรมยาตานไวรสเมอใด?

A. CD4 > 500

B. CD4 < 500

C. CD4 < 350

D. CD4 < 200

E. เมอใดกไดเมอผปวยพรอม

Lab ใดบางทตองตรวจในผปวย newly diagnosed HIV?

A. CD4

B. Viral load

C. HBs Ag

D. HCV Ab

E. VDRL

F. CXR

G. LFT

H. Pap smear in women

I. Lipid profiles

จงจบคยา ARV วาอยในกลมใด

1. AZT

2. TDF

3. 3TC, FTC

4. NVP

5. IDV

6. RTV

7. ddI

8. d4T

9. EFV

10. LPV

A. NRTI

B. NNRTI

C. PI

ยาคใดทไมใชรวมกน

A. AZT+d4T

B. AZT+3TC

C. AZT+TDF

D. ddI + d4T

E. FTC+3TC

F. TDF +ddI

G. TDF+3TC

จงจบค ARV และ side effect

A. AZT

B. d4T

C. TDF

D. NVP

E. EFV

F. LPV/r

G. IDV/r

1. CNS side effect

2. Nephrolithiasis

3. Lipoatrophy

4. Diarrhea

5. Anemia

6. Fanconi syndrome

7. Hepatitis and rash

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2

จงจบค fixed combination ARV

A. d4T+3TC+NVP

B. AZT+3TC+NVP

C. AZT+3TC

D. d4T+3TC

E. TDF+FTC

F. LPV+RTV

G. TDF+FTC+EFV

1. Zilarvir

2. GPO VIR-S

3. Lopinavir

4. Lastavir

5. Atripla, Teevir

6. Truvada, Ricovir EM

7. GPO VIR-Z

GENERAL KNOWLEDGE OF HIV

9

Deaths per 100 Person-Years

0

5

10

15

20

25

30

35

40

1995 1996 1997 1998 1999 2000 2001

De

ath

s p

er

10

0 p

ers

on

-ye

ars

0

25

50

75

100 Pe

rce

nta

ge

of p

atie

nt-d

ays

on

AR

T

DEATHS

USE OF ART

Mortality vs. ART utilization

Palella F et al. 8thCROI 2001; abstract 268b.

AIDS Mortality Rates: 1996-2001

EuroSIDA EuroSIDA November 2000

Durability of clinical effect of HAART: Incidence of AIDS and death 1994-2000

0

5

10

15

20

25

30

35

9/94-

3/95

3/95-

9/95

9/95-

3/96

3/96-

9/96

9/96-

3/97

3/97-

9/97

9/97-

3/98

3/98-

9/98

9/98-

3/99

3/99-

9/99

>9/99

Calendar period

Incid

en

ce (

per

100 P

YF

U)

0

20

40

60

80

100Deaths

AIDS

% on HAART

0

5

10

15

20

25

30

35

40

82 84 86 88 90 92 94 96 98*

De

ath

s p

er

10

0,0

00

Po

pu

lati

on

Unintentional

injuryCancer

Heart disease

Suicide

HIV infection

Homicide

Chronic liver

diseaseStroke

Diabetes*Preliminary 1998 data

Trends in Annual Rates of Death from Leading Causes of Death Among Persons 25-44 Years Old, USA, 1982-1998

National Center for Health Statistics National Vital Statistics System

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

-

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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

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European Guideline 2013 Condition Current CD4 count

350-500 >500

Asymptomatic HIV C C

To reduce transmission of HIV C C

Symptomatic HIV disease R R

Primary HIV infection C C

Pregnancy R R

HIV associated condition HIVAN Neurocognitive impairment Hodgkin’s lymphoma HPV associated cancers Non-AIDS defining cancers Autoimmune diseases High risk for CVD or history of CVD

R R R R C C C

R R R R C C C

Chronic viral hepatitis HBV requiring treatment HCV for which anti-HCV treatment is being considered or given HCV which anti-HCV treatment not feasible

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

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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

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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

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MONITORING HIV

Laboratory Monitoring Schedule: Entry into

care FU before ART

CD4 l Q 6 m

HIV RNA Optional

Hepatitis B profile l

Hepatitis C l

LFT l

CBC l Q 6 m

Lipid profile l

Fasting BS l

VDRL l

CXR l

Pap smear l

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10

RPV 25 mg QD +

TDF/FTC 300/200 mg QD

(n = 346)

EFV 600 mg QD + TDF/FTC 300/200 mg QD

(n = 344)

*THRIVE only. †Selected by investigator from ABC/3TC, TDF/FTC, ZDV/3TC.

Stratified by BL HIV-1 RNA < 100,000

vs ≥ 100,000 copies/mL, NRTI use*

Wk 96 final analysis

Wk 48 primary analysis

RPV 25 mg QD +

2 NRTIs†

(n = 340)

EFV 600 mg QD + 2 NRTIs†

(n = 338)

ECHO, THRIVE: Rilpivirine vs EFV in Treatment-Naive Patients

• Randomized, double-blind phase III trials

Cohen C, et al. AIDS 2010.

ECHO

(N = 690)

THRIVE

(N = 678)

Treatment-naive, HIV-1 RNA ≥ 5000 copies/mL,

no NNRTI RAMs, susceptible to NRTIs

ECHO and THRIVE: HIV-1 RNA < 50 c/mL With

EFV vs RPV

-12 -10 -8 -6 -4 -2 0 2 4 6 8 10 12

ECHO

Wk 48

Wk 96

THRIVE

Wk 48

Wk 96

Pooled

Wk 96

Favors EFV Favors RPV

Cohen CJ, et al. AIDS. 2013;27:939-950. Molina JM, et al. Lancet. 2011;378:238-246.

Cohen CJ, et al. Lancet. 2011;378:229-237.

Percent Difference (Noninferiority at 12% Margin)

-0.4%

-3.2%

3.5%

2.4%

-0.4% P < .0001

P < .0001

P = .0055

P < .0001

P < .0001

ITT-TLOVR. All patients received TDF/FTC.

ECHO/THRIVE: Rilpivirine vs Efavirenz in Treatment-Naive Patients

• D/C due to AE more common with EFV vs RPV: 8.5% vs 4.1%

• More virologic failures with RPV vs EFV: 14% vs 7.6%

– Difference due to more VF between Wks 0-48 at HIV-1 RNA > 100,000; VF similar Wks 48-96

– NRTI mutations more common with VF on RPV vs EFV

– Cross-resistance to ETR more common with RPV failure (E138K mutation)

100

80

60

40

20

0

HIV

-1 R

NA

< 5

0 c/

mL

(%)

78%

78%

RPV 25 mg QD (n = 686) EFV 600 mg QD (n = 682)

Wks

0 4 8 12 16 24 32 40 48 60 72 84 96 2

84%

82%

Cohen CJ, et al. AIDS. 2013;27:939-950. Molina JM, et al. Lancet. 2011;378:238-246.

Cohen CJ, et al. Lancet. 2011;378:229-237.

ECHO/THRIVE: Rilpivirine Noninferior to Efavirenz Through Wk 96

• More virologic failures with RPV vs EFV: 14% vs 8%

– Difference due to more failures between Wks 0-48; failures comparable between arms from Wks 48-96

– Development of NRTI mutations more common with RPV vs EFV

– E138K mutation with RPV → cross-resistance with ETR

• Discontinuation for AEs more common with EFV vs RPV: 9% vs 4%

RPV EFV

40

0

100

20

80 78 78

60

682 686 n =

Pooled Data

HIV

-1 R

NA

< 5

0 c

/mL

at

Wk 9

6

(IT

T-T

LO

VR

)

Cohen CJ, et al. AIDS. 2013;27:939-950.

ECHO/THRIVE Post Hoc Analysis: Wk 96 Efficacy by Baseline VL and CD4+ Count

Cohen CJ, et al. AIDS. 2013;27:939-950.

HIV

-1 R

NA

< 5

0 c

op

ies/m

L (

%)

By Baseline CD4+ Count

(cells/mm3)

84

71

≤ 100k

Rilpivirine Efavirenz

80 76

> 100k -

≤ 500k

5

6

71

< 50

69 75

50 -

< 200

81 79 85

79

200 -

< 350

≥ 350

By Baseline HIV-1 RNA

(copies/mL)

0

20

40

60

80

100

0

20

40

60

80

100

n = 368 329 249 270 n = 34 36 194 175 313 307 144 164

65

73

69 83

> 500k

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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

8/2/2014

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

8/2/2014

16

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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22

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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23

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

8/2/2014

24

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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26

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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27

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