Antiretrovirals in the Management of HIV Infection: Case-Based, Panel Discussion

IAS–USA

Eric S. Daar, MDProfessor of Medicine

David Geffen School of Medicineat University of California Los Angeles

Antiretrovirals in the Management of HIV Infection: Case-Based, Panel Discussion

From ES Daar, MD, at Los Angeles, Ca: April 22, 2013, IAS-USA.

Slide 2 of 42


When to Start: 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

Adapted from Mike Saag

Slide 3 of 42


When to Start: 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

Slide 4 of 42


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

Hunt et al CROI 12

Slide 5 of 42


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Hunt et al JID 2003, PLoS ONE 2011 and unpublished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)

Slide 6 of 42

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 CD 4 Count

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

900

800

700

740

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


Slide 7 of 42


Reasons to Start Early:• The Biology• Association of Inflammation and Disease• Better Tolerated/Easier to Take

Medications• Randomized Controlled Trial Data• Cohort Data• Irreversible Damage• Public Health

Slide 8 of 42

Most New Infections Transmitted by Persons Who Do Not Know Their

Status~25%

Unaware of

Infection

~42% Aware

of Infection

account for…

~54% New

Infections

~46% of New

Infections

Source: G. Marks et al. AIDS 2006


Slide 9 of 42


HPTN 0521763 HIV discordant couples

(HIV+ partner CD4 350-550)

874 delayed HAART (CD4 250)

*96% reduction in HIV transmission to HIV-negative partner median follow-up 2 years

1 transmission* & 3 cases of

extrapulmonary TB

886 immediate HAART

All receiving HIV prevention services

27 transmissions*& 17 cases of

extrapulmonary TB

Slide 10 of 42


So ….what is the harm?

• Destruction of lymphoid tissue• Inflammation• Increased cardiovascular events• Increased incidence of certain

malignancies• Increased ‘aging’• Accelerated cognitive decline

Slide 11 of 42


When to Start Treatment

Clinical CategoryCD4 Count (cells/mm3)

HIV RNA(copies/mL)

2/13/13DHHS

Guidelines

2012IAS-USA

GuidelinesAIDS-defining illness or severe symptoms

Any value Any value Treat

Asymptomatic <500 Any value Treat

>500 Any value Treat

Pregnant women Any value Any value Treat

HIV-associated nephropathy


HIV/HBV coinfection when HBV treatment is indicated


DHHS. Available at: http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Revision February 2013; Thompson MA, et al. JAMA. 2012;308:387-402.

*Unless elite controller (HIV RNA <50 copies/mL) or has stable CD4 cell count and low-level viremia in absence of therapy. The IAS-USA guidelines also recommend initiating antiretroviral therapy in HIV-infected patients with active hepatitis C virus infection, active or high risk for cardiovascular disease, and symptomatic primary HIV infection.

Slide 12 of 42


When to Start: Case 2• 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

Slide 13 of 42


When to Start ARV with Complications• ARVs within 0-2 weeks of diagnosis

– Infections for which there is no specific treatment (e.g. dementia, cryptosporidium, microsporidium, PML) (AIII)

– Other OIs, e.g. PCP (AI)• Consider deferring therapy for crypto meningitis• Tuberculosis

– Within 2 weeks for CD4 <50 cells/uL (AI)– Within 2-4 weeks for severe symptoms with CD4 50-200

(BI) and >200 cells/uL (BIII)– Within 8-12 weeks for mild symptoms and 50-500

cells/uL (AI) and >500 cells/uL (BIII)– Meningitis 2 months (AI) in RLS, perhaps earlier in other

settings (CIII)DHHS. Available at: http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Revision February 2013; Thompson MA, et al. JAMA. 2012;308:387-402.

Slide 14 of 42


A 49 year old asymptomatic man presents to your clinic after recently being diagnosed with HIV• History of HTN with CrCl ~42 mL/min• HBsAb+, HCV antibody negative• CD4 cells repeatedly 700-420 cells/uL• Plasma HIV RNA 30-50,000 copies/mL• Not anxious to start antiretrovirals but willing

if you think it is necessary

Slide 15 of 42


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

Slide 16 of 42


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

74

80

100

CASTLE3

(ITT, NC=F)96 weeks

ATV/r300/100

QD

LPV/r400/100

BID

6874

0

20

40

74

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

74

80

100

Slide 17 of 42


ATV/r vs. EFVPrimary Endpoint

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

Slide 18 of 42


STARTMRK: RAL vs. EFV

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

ITT, NC=F

281 278 279 280 281 281 274 280 281 281 274 279282 282 282 281 282 282 281 281 282 282 282 279

Raltegravir 400 mg BIDEfavirenz 740 mg QHS

Number of Contributing Patients

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

0

20

40

74

80

100

Per

cent

age

of P

atien

ts w

ithHI

V RN

A Le

vels

<50

Cop

ies/

mL

86

82

81

79

42

69

76

67

71

61

CD4 Change: RAL +374 vs. EFV +312

Slide 19 of 42

From ES Daar, MD, at Los Angeles, Ca: April 22, 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)

Slide 20 of 42


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

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

Slide 21 of 42


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

Slide 22 of 42


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.

Slide 23 of 42


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=0.009Sax P, et al, Lancet 2012: 379::2439-48

Slide 24 of 42


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

QUAD ATV/r

100908070745040302010

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

Slide 25 of 42


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

Slide 26 of 42


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

Slide 27 of 42


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

Slide 28 of 42


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

Slide 29 of 42


No. at RiskABC-3TC 398 363 313 267 222 188 137 87 49 20TDF-FTC 399 361 321 284 236 204 174 104 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

Slide 30 of 42


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

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

Slide 31 of 42


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 Fai

lure

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%

74%

80%

100%

Prop

ortio

n of

Sub

ject

s with

VF

~59%

~37%

Slide 32 of 42


Concerns regarding NRTIs

• Conflicting results regarding relationship between ABC and CV events

• TDF-associated with greater decline in bone mineral density

• TDF-associated with variable decline in renal function

Slide 33 of 42


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

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

Slide 34 of 42


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)

Slide 35 of 42


A 45 year old African American woman presents to your clinic having been diagnosed with HIV and severe thrush/onychomycosis• Clinically stable on fluconazole• History mild depression, diabetes, HTN and

dyslipidemia on ACE, metformin, atorvastatin• Laboratories

– HBsAg and HCV antibody negative– AST/ALT- 42/82 IU/mL, CrCl~70 mL/min (relatively stable),

HgbA1C=7.1%, UA- 3+ proteinuria– CD4= 78 cells/uL, HIV-RNA= 219,000 copies/mL– HIV genotype- WT

• Ready to start antiretrovirals if recommended with no specific concerns regarding various adverse events but would prefer simple regimen

Slide 36 of 42


Patient starts TDF/FTC/EFV, TMP/SMX and continues other meds. At 2 months CD4 190 cells/uL, HIV RNA 220 copies/mL, but patient has increasing depression and persistent neurologic symptoms thought to be associated with EFV. CrCl is repeatedly ~70 mL/min. She is seeing psych and on antidepressants.

A 45 year old African American woman• H/O depression, DM, HTN, dyslipidemia, CKD• CrCl- 70 mL/min with proteinuria• CD4 nadir= 78 cells/uL and BL HIV RNA 212,000 copies/mL

Slide 37 of 42


Switch TDF/FTC + EFV to RPV (N=49)

Mills A, et al. 51st ICAAC; Chicago, IL; September 17-20, 2011. Abst. H2-794c.

RPV mean Ctrough in ECHO/THRIVE

Slide 38 of 42


Patient switched to TDF/FTC + ATV/r and continued other meds. After 4 months neurologic symptoms resolved, CD4 250 cells/uL, HIV RNA <40 copies/mL but patient CrCl has gradually declined (now off TMP/SMX) to 40-45 mL/min with no change in other labs or UA (glucosuria and proteinuria).

A 45 year old African American woman• H/O depression, DM, HTN, dyslipidemia, CKD• CrCl- 40-45 mL/min with proteinuria (HLA-B5701-negative)• CD4 nadir= 78 cells/uL and BL HIV RNA 212,000 copies/mL

Slide 39 of 42


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 95,320 153,009 53,300 39,157#MI: 533 331 148 405 554 221 139

1.9

1.5

1.2

1

0.8

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

**

Rel

ativ

e R

isk

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)

Slide 40 of 42


VA Case Registry: Use of ABC or TDF in Last Regimen and Risk of MI

Bedimo R, et al. Clin Inf Dis. 2011;53:84-91.

Unadjusted HR of AMI for each PY of exposure to each one of the categories

Adjusted for estimated GFR prior to regimen onset (by MDRD method)

ABC TDF Both ABC and TDF

Haz

ard

ratio

0.20.40.60.81.01.21.41.61.82.02.2

NRTI in Last Regimen During Observation Period

Slide 41 of 42


Cumulative Exposure to ARVs and Risk of CKD

Cockcroft-Gault (n=225)MDRD (n=274)CKD-EPI (n=258)INSIGHT def (n=129)Censoring ATVCensoring TDFCensoring boosted PI

Tenofovir

Indinavir

Atazanavir

Lopinavir/r

0.9 1.4Mocroft A, et al. AIDS. 2010; 53:1667-78

Slide 42 of 42


A5202: ABC/3TC vs. TDF/FTCMedian Change in Creatinine Clearance

ABC/3TC

ATV/r

ABC/3TC

TDF/FTC

TDF/FTC

EFVN= 191 173 217 191 186 157 200 178

Wk 48, p<0.001Wk 96, p<0.001

Wk 48, p=0.83Wk 96, p=0.14

Week 96Week 48

p-values: ABC/3TC vs. TDF/FTC

Cha

nge

in C

alcu

late

d C

reat

inin

e C

lear

ance

, (m

L/m

in)

>25% decr(%): 3 2 7 6 2 3 1 3Daar ES, et al. Ann Intern Med 2011; 154:445-456.

Documents

Antiretrovirals in the Management of HIV Infection: Case-Based, Panel Discussion