Antiretroviral Therapy: A Case-Based Panel Discussion (Part I)

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IAS–USA

Michael S. Saag, MD Eric S. Daar, MD

Antiretroviral Therapy:A Case-Based Panel Discussion

(Part I)

MERGED: 03-21-13From MS Saag, MD and ES Daar, MD at San Francisco, CA: March 29, 2013, IAS-USA.

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From MS Saag, MD and ES Daar, MD at San Francisco, CA: March 29, 2013, IAS-USA.

Case 1

– 30 yo white man– Diagnosed on routine insurance

examination– PMHx remarkable for HTN, diet controlled– No medications– Understands treatment issues and wants

to begin therapy if you think it is appropriate

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Case 1b

– 30 yo white man– Diagnosed on admission to jail for

disorderly conduct– PMHx remarkable for HTN, diet controlled

and paranoid schizophrenia– Doesn’t take any medications and doesn’t

want to

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HIV Infected Cells

Uninfected Resting CD4+ Lymphocytes

Uninfected Activated CD4+ Lymphocytes

Antiretroviral Rx

Latently Infected CD4+ Lymphocytes

HIV virions

M Saag, UAB

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Effect on inflammation in predicting mortality higher in HIV disease than the general population (SOCA/SCOPE)

Hunt et al CROI 12

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T cell “activation” is lower in treated than untreated adults, but consistently higher than “normal”

Hunt et al JID 2003, PLoS ONE 2011 and unpublished

% C

D38

+HLA

DR

+C

D8+

T C

ells

0

20

40

60

80

HIVNegative(n=82)

Non-Controller

(n=65)

HAART(n=132)

P < 0.001

P < 0.001

HIV –(n=132)

HIV +ART

(n=65)

HIV +Untreated

(n=82)

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Permanent Loss of CD4 if Wait to Start• CD4-count increases on

sustained suppressive (<400 c/mL) ARV treatment (n=655) by baseline count– >350 cells/mm3:

CD4 counts return to near-normal levels

– ≤350 cells/mm3: CD4 counts significantly increased but plateau after 4 years below normal range

• Differences in CD4 counts associated with differences in morbidity and mortality

Median CD4 Counts Over 6 YearsStratified by Baseline CD4 Count

Moore RD, Keruly JC. Clin Infect Dis 2007;44:441-446.

900

800

700

500

500

400

300

200

100

00 1 2 3 4 5 6

Years After Starting HAARTC

D4

Cou

nt (c

ells

/mm

3 )

<200 201–350 >350


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HOPS Cohort: Resistance Development • Major mutations

50% less likely in pts starting with CD4+ >350 vs <200 cells/mm3, despite greater treatment exposure

1. Uy JP, et al. 4th IAS, Sydney 2007, #WEPEB017; 2. van Sighem B, et al. ibid, #WEPEB016

0-199 cells/mm3

200-349 cells/mm3

>350 cells/mm3

GT mutations and virologic failure1

Any mutation

(n=78)

NRTI mut. among

NRTI-exp(n=50)

NNRTI mut. among

NNRTI-exp(n=37)

PI mut. among PI-exp(n=48)

Patie

nts

(%)

p=0.076 p=0.007 p=0.051 p=0.103

0

10

20

30

40

50

50

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Most New Infections Transmitted by Persons who Do Not Know Their Status

~25% Unaware

of Infection

~75% Aware

of Infection

account for…

~54% New

Infections

~46% of New

Infections

Source: G. Marks et al. AIDS 2006From MS Saag, MD and ES Daar, MD at San Francisco, CA: March 29, 2013, IAS-USA.

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Reasons to Start Early:• The Biology• Association of Inflammation and Disease• Better Tolerated Medications Today• Randomized Controlled Trial Data• Cohort Data• Public Health• Common Sense!

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Relative Time on Treatment…

30 35 40 45 50 55 50 65 70AGE (years)

CD4 650/ul

CD4 500/ul

40 years on Rx

35 years on Rx

5 years

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Relative Time on Treatment…

30 35 40 45 50 55 50 65 70AGE (years)

CD4 650/ul

CD4 500/ul

40 years on Rx

35 years on Rx

5 years

HARM?

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So ….what is the harm?

• Destruction of Lymphoid Tissue• Inflammation• Increased Cardiovascular Events• Increased incidence of certain

malignancies• Increased ‘Aging’• Accelerated Cognitive Decline

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• Balance of data support starting Rx in ~ all individuals regardless of CD4+ T cell counts – Understanding of HIV pathogenesis– Cohort data – Public health implications– No randomized clinical trial data for higher

CD4 counts (START study is enrolling)• Waiting until RCT data could well lead to

harm that likely will not be reversible

Conclusions

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Case 2¨ 42 year old man diagnosed with HIV in 1999;

several OIs¨ Has ‘taken’ most existing antiretroviral drugs

available, on and off, for years¨ Currently on TDF / FTC / DRV / rit ¨ CD4 count is 33 /µL (nadir CD4 = 6)¨ CD4 count 3 months ago was 76 cells/µL¨ HIV RNA 128,000 c/mL (max VL 167,000)¨ Phenotype: Pan-sensitive

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Case 3¨ 34 yo woman is diagnosed with TB¨ As part of evaluation she is found to be HIV+¨ Initial lab values

— CD4 82 cells/µL— VL 76,000 c/mL

¨ No other significant medical condition¨ She is started on 4-drug anti-TB therapy

(including INH and rifabutin)¨ Virus is wild-type virus

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Case 1—30 yo white man—Diagnosed on routine insurance

examination—PMHx remarkable for HTN, diet controlled—No medications—Understands treatment issues and wants

to begin therapy if you think it is appropriate

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A 49 year old asymptomatic man presents to your clinic after recently being diagnosed with HIV

• History of HTN with CrCl ~75 mL/min• HBsAb+, HCV antibody negative• CD4 cells repeatedly 500-700 cells/uL• Plasma HIV RNA 30-50,000 copies/mL• Not anxious to start antiretrovirals but willing

if you think it is necessary

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Factors to consider in choosing first-line therapy

• Patient’s willingness to commit to therapy• Baseline resistance• Efficacy data• Tolerability• Convenience• Comorbid conditions• Consequences of failure (resistance)• Since the introduction of potent ARV therapy

preferred regimens all include NRTIs + third drug

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Boosted-Protease Inhibitors

Adapted from: 1. Eron J, et al. Lancet 2006; 368:476-482; 2. Mills A, et al. AIDS May 29, 2009 3. Molina J-M, et al. 48th ICAAC/46th IDSA , Washington, DC, 2008. Abst. H-1250d

ARTEMIS2

(ITT, TLOVR)96 weeks

LPV/r QD or

BID

DRV/r 800/100

QD

7971

n=343n=3460

20

40

50

80

100

CASTLE3

(ITT, NC=F)96 weeks

ATV/r300/100

QD

LPV/r400/100

BID

6874

0

20

40

50

80

100

n=443 n=440

KLEAN1

(ITT-E, TLOVR)48 weeks

LPV/r400/100

BID

FPV/r 700/100

BID

6665

N=444n=4340

20

40

50

80

100

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ATV/r vs. EFVPrimary Endpoint

Daar ES, et al. Ann Intern Med 2011; 154:445-456.

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STARTMRK: RAL vs. EFV

Rockstroh J, et al, 19th IAC; Washington, DC; July 22-27, 2012; Abst. LBPE19.

ITT, NC=F

281 278 279 280 281 281 250 280 281 281 250 279282 282 282 281 282 282 281 281 282 282 282 279

Raltegravir 400 mg BIDEfavirenz 500 mg QHS

Number of Contributing Patients

0 12 24 48 72 96 120 144 168 192 216 240Weeks

0

20

40

50

80

100

P

erce

ntag

e of

Pati

ents

with

HIV

RNA

Leve

ls <

50 C

opie

s/m

L86

82

81

79

75

69

76

67

71

61

CD4 Change: RAL +374 vs. EFV +312

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From MS Saag, MD and ES Daar, MD at San Francisco, CA: March 29, 2013, IAS-USA.Rimsky L, et al. 50th ICAAC 2010, Boston, MA. Abst. H-1810

84.3%82.3%

Pooled ECHO and THRIVE: Virologic Response (ITT-TLOVR)

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Rimsky L, et al. 50th ICAAC 2010, Boston, MA. Abst. H-1810

Pooled ECHO and THRIVE: Virologic Response (ITT-TLOVR)

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GS102 & GS103: EVG/COBI/TDF/FTC vs. EFV/TDF/FTC or ATV/RTV + TDF/FTC

Sax P, et al, Lancet 2012: 379::2439-48; DeJesus E, et al, Lancet 2012; 379: 2429-38

Randomized, Phase III, Double-blind, Double Dummy, Active-controlled, International Studies

Treatment Naïve HIV-1 RNA ≥5,000 c/mL

Any CD4 cell counteGFR ≥70 mL/min

48 weeks 192 weeks

GS 102~89% men

33% >105 c/mLCD4= ~385 c/uL

GS 103~90% men

~41% >105 c/mLCD4= ~370 c/uL

Quad QD

EFV/FTC/TDF Placebo QD

EFV/FTC/TDF QD

Quad Placebo QD

Quad QD

ATV/r +TDF/FTC Placebo QD

QUAD Placebo QD

ATV/r +TD/FTC QD

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Study 236-102: Primary Endpoint:HIV-1 RNA < 50 copies/mL

+3.6%, 95% CI 3.6 (-1.6% to +8.8%)

CD4+ change: Quad +239 vs. EFV +206 c/mm3 (p=0.009)No difference by baseline characteristics

Sax P, et al. 19th CROI; Seattle, WA; March 5-8, 2012. Abst. 101.

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Study 236-102:Common Adverse Events

Quad(n=348)

EFV/FTC/TDF(n=352)

Treatment Emergent Adverse Events in ≥ 10% of subjects (%)Diarrhea 23% 19%Nausea * 21% 14%Abnormal Dreams ^ 15% 27%Upper Respiratory Infection 14% 11%Headache 14% 9%Fatigue 12% 13%Insomnia * 9% 14%Depression 9% 11%Dizziness ^ 7% 24%Rash # 6% 12%

* p<0.05; ^ p<0.001; # p=0.009

Sax P, et al, Lancet 2012: 379::2439-48

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Study 236-103: ATV/r vs. TDF/FTC/COBI/EVG HIV-1 RNA < 50 c/mL

QUAD ATV/r

100908070505040302010

0Perc

ent w

ith H

IV R

NA

<50

c/m

L (IT

T, M

=F)

BL 2 4 8 12 16 24 32 40 48Week

Diff: 3.5% (95% CI: -1.0 to 8.0)

92%

88%

Changes in CD4+ count: Quad +207 vs. ATV/r +211 cells/mm3 (p=0.61)No difference by baseline characteristics

DeJesus E, et al, Lancet 2012; 379: 2429-38

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Study 236-103: Adverse Events

Adverse Events > 10% in Either Group

Discontinuation rates due to renal events were identical in both arms (0.3%)

Quad(n=353)

ATV/r + FTC/TDF(n=355)

Diarrhea 22% 27%

Nausea 20% 19%

Upper respiratory infection 15% 16%

Headache 15% 12%

Fatigue 14% 13%

Ocular icterus 1% 14%

DeJesus E, et al, Lancet 2012; 379: 2429-38

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TDF/FTC/EVG/COBI vs. EFV or ATV/r: Lipid changes

P =0.001P <0.001 P= 0.001 P =0.44 P =0.006

Conclusion: While some lipid fractions better with Quad than EFV or ATV/r, overall differences were modest and unlikely to be of clinical significance.

Sax P, et al, Lancet 2012: 379::2439-48; DeJesus E, et al, Lancet 2012; 379: 2429-38

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EVG/COBI/TDF/FTC vs. EFV or ATV/r: Creatinine Changes

Conclusion: Cobicistat is associated with reduced active secretion of creatinine in the renal tubules leading to initial rises in creatinine levels.Sax P, et al, Lancet 2012: 379::2439-48; DeJesus E, et al, Lancet 2012; 379: 2429-38

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A5202: Study Design

Stratified by screening HIV-1 RNA (< or ≥ 100,000 c/mL)

Enrolled 2005-2007Followed through Sept 2009, 96 wks after last pt enrolled

HIV-1 RNA ≥1000 c/mLAny CD4+ count

> 16 years of age

ART-naïve N=1858

Randomized 1:1:1:1

TDF/FTC QD

ABC/3TC Placebo QD

EFV QD

ABC/3TC QD

TDF/FTC Placebo QD

EFV QD

TDF/FTC QD

ABC/3TC Placebo QD

ATV/rQD

ABC/3TC QD

TDF/FTC Placebo QD

ATV/rQD

A

B

C

D

Arm

ART-naïve 1857 enrolled

Randomized 1:1:1:1

TDF/FTC QD EFV QD

ABC/3TC QD

TDF/FTC Placebo QD

EFV QD

TDF/FTC QD

ABC/3TC Placebo QD

ATV/rQD

ABC/3TC QD

TDF/FTC Placebo QD

ATV/rQD

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No. at RiskABC-3TC 398 363 313 267 222 188 137 87 49 20TDF-FTC 399 361 321 284 236 204 150 104 65 23

A5202: Time to Virologic Failure in Patients with HIV RNA >100,000 c/mL

Sax PE, et al. NEJM 2009;361:2230-2240.

0

20

40

60

80

100

0 12 24 36 48 60 72 84 96 108Prob

abili

ty o

f No

Viro

logi

c Fa

ilure

(%)

Weeks since Randomization

P<0.001, log-rank testHazard ratio, 2.33 (95% CI, 1.46-3.72)

TDF-FTC (26 events)

ABC-3TC (57 events)

Probability of No Virologic Failure

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ABC/3TC vs. TDF/FTCLow Viral Load Stratum

Sax PE, et al. JID 2011: 204:1191-1201.

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HEAT: Virologic Failure by Baseline HIV-1 RNA (A5202 Efficacy Endpoint)

90 8787 90

0

20

40

60

80

100

<100,000 ≥100,000

ABC/3TC

Perc

ent w

ithou

t Viro

logi

c Fa

ilure

n = 188 155 140205

Pappa K, et al. 17th IAC, Mexico City, 2008. Abst. THAB0304.Young B, et al. 48th ICAAC/46th IDSA, Washington, DC, 2008. Abst. H-1233.

ABC/3TC TDF/FTC≥500,000 c/mL250,000 - <500,000 c/mL

100,000 - <250,000 c/mL<100,000 c/mL

41%

63%

18%

19%18%

4%22%

15%

0%

20%

40%

50%

80%

100%

Prop

ortio

n of

Sub

ject

s with

VF

~59%

~37%

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D:A:D Study: NRTIs and Risk of MI

Lundgren J, et al. 16th CROI, Montreal, Canada, 2009. Abst. 44LB. Sabin C, et al. Lancet 2008;371:1417-26.

ZDV ddI ddC d4T 3TC ABC TDF#PYFU: 138,109 74,407 29,676 95,320 152,009 53,300 39,157#MI: 523 331 148 405 554 221 139

1.9

1.5

1.2

1

0.8

0.6Recent Exposure*: yes/noCumulative Exposure: per year

**

Rela

tive

Risk

of M

I (95

% C

I)

Adjusting for eGFR does not change ABC MI finding:Adjusted RR 1.89; 95% CI (1.46 – 2.44; P=0.0001)

* Recent use=current or within the last 6 months. **Not shown (low number of patients currently on ddC)

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Concerns regarding NRTIs

• Many studies have not seen relationship between ABC and CV events

• TDF-associated with greater decline in bone mineral density

• TDF-associated with variable decline in renal function

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Preferred Regimens

• EFV/TDF/FTC• ATV/r + TDF/FTC• DRV/r (once daily) + TDF/FTC• RAL + TDF/FTC[Pregnant Women Only: LPV/r (twice daily) + ZDV/3TC]

AlternativeRegimens

• EFV + ABC/3TC• RPV + (TDF or ABC)/(FTC or 3TC)• ATV/r or DRV/r + ABC/3TC• FPV/r or LPV/r (qd or bid) ABC/3TC or TDF/FTC• RAL + ABC/3TC• EVG/COBI/TDF/FTC (9/18/12)

AcceptableRegimens

• EFV or RPV + ZDV/3TC• NVP + TDF/FTC or ZDV/3TC or ABC/3TC• ATV + (ABC or ZDV)/3TC• ATV/r, DRV/r, LPV/r, FPV/r , RAL + ZDV/3TC• MVC + ZDV or ABC/3TC• SQV/r + TDF/FTC or ABC/3TC or ZDV/3TC (with caution)

DHHS Guidelines for Adolescents/Adults: What to Start

DHHS Guidelines. Available at: http://aidsinfo.nih.gov/contentfiles/lvguidelines/adultandadolescentgl.pdf . Revision March 27,

2012.

http://aidsinfo.nih.gov/contentfiles/lvguidelines/adultandadolescentgl.pdf

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ART: What to StartIAS–USA Recommendations, 2012

Thompson MA, et al. JAMA. 2012;308(4):387-402

Component Recommended Regimens

NNRTI plus nRTIs

• Efavirenz/tenofovir/emtricitabine (AIa)• Efavirenz plus abacavir/lamivudine (AIa)

in HLA-B*5701-negative patients with baseline plasma HIV-1 RNA <100,000 copies/mL

PI/r plus nRTIs

• Darunavir/r plus tenofovir/emtricitabine (AIa)• Atazanavir/r plus tenofovir/emtricitabine (AIa)• Atazanavir/r plus abacavir/lamivudine (AIa)

in patients with plasma HIV-1 RNA <100,000 copies/mL

InSTI plus nRTIs • Raltegravir plus tenofovir/emtricitabine (AIa)

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Your Patient• 43 year old man found to be HIV

infected• HIV VL 56,000 c/ml• CD4 count 340 cells/ul• Seropositive for HBV

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Initial Evaluation• Physical exam: normal; no

hepatosplenomegaly• Initial laboratory studies

–ALT 1.7 x ULN, bilirubin normal–Platelet count: 150,000–HCV Ab negative–HBV DNA 6.1 x 105 IU/mL–HBsAg+ / HBeAg+

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FDA Approved Therapies First Line Therapy Year

Peginterferon alfa-2a 2005

Entecavir 2005

Tenofovir 2008Second Line Therapy Year

Adefovir dipivoxil 2002

Telbivudine 2006Third Line Therapy Year

Lamivudine 1998Available at http://www.accessdata.fda.gov/scripts/cder/drugsatfda/ Accessed 02/18/10.CLDF HBV Advisory Board

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ResponseHBeAg- Patients

(Study 102)HBeAg+ Patients

(Study 103)

Year 5 Year 6 Year 5 Year 6

HBV DNA < 400 copies/mLIntent-to-treat*, % (n/N)

83(291/350)

81(281/345)

65(150/248)

63(157/251)

HBV DNA < 400 copies/mLOn treatment†, % (n/N)

99(292/295)

99.6(283/284)

97(170/175)

99(167/169)

♦ 80% of 585 patients entering the open-label phase remained on study at year 6; 73% of enrolled patients remained on study

♦ HBeAg loss/seroconversion rates of 50% and 37%, respectively, through 6 years♦ 11% of HBeAg+ patients had confirmed HBsAg loss (8% with seroconversion)♦ No resistance to TDF was detected through 6 years

TDF: Virologic Suppression at Year 6

Marcellin P, et al. AASLD 2012; Boston. #374.

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Months

33%

HBsAg Loss Occurred in 33% of HBeAg+ Pts Treated With 5 Years of ETV

• HCC developed at yearly rate of 2.5% despite good viral suppression

Conclusions:• Long-term ETV monotherapy efficiently suppressed HBV replication in

naïve HBV patients• High rates of HBsAg loss can also be seen with this therapy

Lampertico P, et al. 63rd AASLD; Boston, MA; November 9-13, 2012; Abst. 366.

Patients at risk 72 70 65 54 48 41 35 28 19 8 3

HBsAg Loss in HBeAg-positive Patients

Antiretroviral Therapy: A Case-Based Panel Discussion (Part I)

Documents

md eric

ms saag

es daar

hiv case

hiv disease

hiv artn

hiv untreatedn

hiv infected cellsuninfected