HIV Treatment Update

Anton Pozniak

Consultant Physician,

Director of HIV Services

Chelsea and Westminster Hospital, London

Guidelines

Nuke sparing

Nukes

Efavirenz placement as the gold standard ARV

Role of PIs

STRs

Switching

Second Line

Choosing the best Regimen

Evolution of Better Treatments DHHS panel criteria for regimen selection

Preferred regimens (studied in RCTs)

– Optimal and durable virologic efficacy

– Favourable tolerability and toxicity profiles

– Ease of use

DHHS Guidelines for the Use of Antiretroviral

Agents in HIV-1-Infected Adults and Adolescents.

March 27, 2012. Available at:

http://www.aidsinfo.nih.gov/Guidelines

Summary of key randomized clinical trials in ARV-naïve patients

1. Molina J-M, et al. Lancet 2011;478: 238–246; 2. Cohen CJ, et al. Lancet 2011; 378:229–237; 3. Daar E, et al. Ann Intern Med 2011;154:445–456; 4. Ortiz R, et al. AIDS 2008;22:1389–1397; 5. Lennox JL, et al. Lancet 2009;374:796−806; 6. Riddler SA, et al. N Engl J Med 2006;358:2095−2106; 7. Molina J-M, et al. Lancet 2008;372:646–655

EFV vs.

NNRTI 2NN, ECHO1,

THRIVE2

vs. PI ACTG 52023

ACTG

51426

vs. INI

STARTMRK5

ATV/r vs.

NNRTI ACTG 52023

vs. PI

CASTle

ACTG5257

DRV/r vs. PI

ARTEMIS4

ACTG5257

RAL vs.

NNRTI STARTMRK5

NNRTI = non-nucleoside reverse transcriptase inhibitor; PI = protease inhibitor; INI = integrase inhibitor.

EVG/c vs.

NNRTI QUAD102

vs. PI

QUAD103

DTG vs.

NNRTI Single

vs. INI

Spring

vs. PI

Flamingo

vs. INI

QUAD103

vs. INI

Spring

vs.

PI / NRTI

ACTG5257 NEAT001

vs. INI

ACTG5257

Comparison of International

Guidelines 2014 Regimen DHHS IAS EACS

EFV/TDF/FTC Recommended Recommended Recommended

DRV/r + TDF/FTC Recommended Recommended Recommended

ATV/r + TDF/FTC Recommended Recommended Recommended

RAL + TDF/FTC Recommended Recommended Recommended

EVG/c+TDF/FTC Recommended Recommended Recommended

DTG + ABC/3TC

DTG + TDF/3TC Recommended Recommended -

US Department of Health and Human Services Guidelines; Revised January 10, 2011 Available at: http://aidsinfo.nih.gov/contentfiles/AdultandAdolescentGL.pdf; Thompson MA, et al. JAMA 2010;304(3):321-333; www.eacs.eu.

DO WE STILL NEED NUKES?

TOLERABILITY AND TOXICITY

NUKES ASSOCIATED WITH

CVS, RENAL AND BONE PROBLEMS

NRTI-sparing regimens 7 randomised trials of PI/r + RAL versus PI/r + 2NRTIs

HIV RNA <50 copies/mL (switch = failure endpoint)

Overall, in 7 randomised trials of 1266 patients, PI/r + raltegravir showed HIV RNA suppression rates 10% lower than PI/r + 2NRTIs (p=0.008). However there was evidence for heterogeneity between the trials (p=0.03).

Favours 3-drug treatment

Favours 2-drug treatment

If we still need Nukes

We need to sort out the ABC CV question

D:A:D: current abacavir use associated with 98% increase in acute MI risk

Sabin, C et al. CROI 2014. Abstract 747LB.

5 4 3

2

1

0.7

Adjusted relative rate of MI

in pts currently receiving ABC

Overall Pre-3/08 Post-3/08

1.98

(1.72–2.29)

1.97

(1.68–2.33)

1.97

(1.43–2.72)

No current ABC

Events/PYs 600/295,642 425/169,417 175/126,225

Rate/100 PYs 0.20

(0.19-0.22)

0.25

(0.23-0.28)

0.14

(0.12-0.16)

Current ABC

Events/PYs 341/71,917 247/40,833 94/31,084

Rate/100 PYs 0.47

(0.42-0.52)

0.61

(0.53-0.68)

0.30

(0.24-0.36)

TDF and Bone loss ACTG 5280: high-dose vitamin D and calcium

attenuate bone loss in TDF patients

Randomised, double-blind trial in patients initiating TDF/FTC/EFV with baseline vitamin D 10–75ng/mL

– Vitamin D3 4,000 IU/day plus calcium carbonate 1,000 IU/da

Decline in BMD from baseline to

week 48

Overton, ET et al. CROI 2014. Abstract 133

Lower and upper edges of box indicate 25th and 75th

percentiles; lines inside box indicate median

5

0

-5

-10

-15 Total

hip Lumbar spine

-1.46

-3.19 -1.41

-2.91

P<0.001 P=0.085

Change in B

MD

(%

)

Placebo Vitamin D/calcium

IS IT TIME TO MOVE ON FROM EFAVIRENZ?

Why is EFV no longer so gold?

Has been ‘beaten’ by the integrase inhibitors

Non-inferior to other STRs (Stribild ▼ and Eviplera ▼) – But the latter have less toxicity

Baseline resistance increased in MSM

NNRTI resistance develops in about half of the failures

The toxicity is not acceptable now?

PI, important points to consider

and indication are outlined at the

end of this presentation

SINGLE Trial: DTG vs EFV in Naive Week 48 efficacy results

ABC/3TC/DTG TDF/FTC/EFV600

Ref: Dolutegravir FDA prescribing information

HIV RNA <50 88%

HIV RNA <50 81%

VF: 5%

VF: 6%

DC Adverse Events: 2% DC Adverse

Events: 10%

DC Other =5% DC Other:3%

STARTMRK: Efficacy of RAL vs EFV

Durability…. Long term side effects

RAL is BID vs QD (EFV) but fewer adverse events (52% vs 80%)

Rockstroh JK, et al. J Acquir Immune Dis Syndr. 2013;63:77-85.

ITT, NC = F

281 278 279 280 281 281 277 280 281 281 277 279

282 282 282 281 282 282 281 281 282 282 282 279

RAL 400 mg BID

EFV 600 mg QHS

Pts at Risk, n

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

0

20

40

60

80

100

HIV

-1 R

NA

< 5

0 c

/mL

(%

)

86

82

81

79

75

69

76

67

71

61

CD4+ gain:

+374

+312

Efavirenz tolerability But do the neuropsychiatric symptoms matter?

In the short-term – For the majority of patients probably not…

In the long-term if neuropsychiatric symptoms persist – Then…?

Efavirenz tolerability Persistence of neuropsychiatric symptoms in

randomised controlled trials

1. Zolopa, A et al. HIV-11 2012; Glasgow.

O424

2. Gazzard, B et al. AIDS 2011;25:2249-2258

• Most EFV-associated

neuropsychiatric symptoms are mild

and transient, occurring during the

first 2-4 weeks

• In some patients, neuropsychiatric

symptoms can be long-lasting and

may persist for up to two years after

starting EFV1,2

Risk of suicidality increased in patients treated with EFV-containing regimens

Treatment with EFV is associated with increased risk of suicidality – Absolute risk is small

Risk of attempted or completed suicide also associated with EFV – HR: 2.58; 95% CI: 0.94 to 7.06;

P=0.06

EFV is also associated with increased risk of death from injury, substance use or unknown causes – Careful attention should be paid to

cause of death in all clinical trials

HR: 2.28 (95% CI 1.27-4.10; P = .006)

47 events/5817

PY (8.08/1000 PY)

15 events/4099

PY (3.66/1000 PY)

Mollan, K et al. IDWeek 2013. Abstract

40032

EFV

EFV-free

0.05

0.04

0.03

0.02

0.01

0

Pro

babili

ty

192 0 24 48 72 96 120 144 168

Weeks to suicidality

Multivariate analysis of factors associated with suicidality in

ACTG clinical trials

Variable HR (95% CI) P value

Randomly assigned EFV 2.15 (1.20-3.87) 0.01

Age category, yrs

<30

30-44

≥45

2.82 (1.25-6.34)

1.69 (0.81-3.55)

1.00 (reference)

0.04

Hx IDU 2.18 (1.11-4.30) 0.02

Psychiatric hx or

psychoactive rx

3.90 (2.23-6.82) <0.001

Using Real World Data to Assess the Risk of Suicidality among Patients Initiating an Efavirenz versus an Efavirenz-Free

Antiretroviral Regimen

.Nkhoma E et al IDWeek 2014. October 8-12, 2014, Philadelphia. Abstract 818

Dose Reduction of EFV ENCORE1: 400-mg EFV non-inferior to 600-mg EFV With

TDF/FTC for Initial ART

Randomized, double-blind, placebo-controlled, non-inferiority phase III trial Part of ongoing effort to identify ARVs effective at lower doses (and

cost)

No significant difference in SAEs between treatment arms More pts with study drug-related AEs for EFV 600 mg vs EFV 400

mg (47.2% vs 36.8%; p=0.008) More pts discontinued EFV 600 mg due to AE vs EFV 400 mg

(1.9% vs 5.8%; p=0.010)

Puls, R et al. IAS 2013. Abstract WELBB01

EFV 400 mg + placebo +

TDF/FTC 300/200 mg

(n = 324)

EFV 600 mg + TDF/FTC 300/200 mg

(n = 312)

ART-naive pts,

CD4+ 50-500 cells/mm3,

HIV-1 RNA > 1000 copies/mL

(n=636)

Week 48 Stratified by clinical site and

HIV-1 RNA at screening

(< 100,000 or ≥ 100,000 copies/mL)

*EFV administered as 200-mg tablets.

HIV-1 RNA < 200 c/mL

at Week 48 (%)

NC=F

90.0

85.8

Starting another NNRTI

STaR Study Multicenter, international, randomized, open-label, Phase 3b, 96-week study

RPV/FTC/TDF

STR

EFV/FTC/TDF

STR

ARV-naive HIV-1 RNA ≥2500 c/mL Sensitivity to EFV, FTC, RPV, TDF (N=786)

Stratified by HIV RNA (≤ or >100,000 c/mL)

n=394

n=392

96 Weeks

Primary endpoint: Efficacy of the 2 STRs by proportion with HIV-1 RNA <50 c/mL at

Week 48 (Snapshot analysis); non-inferiority margin of 12%

Secondary endpoints: Safety and efficacy of the 2 STRs by proportion with

HIV-1 RNA <50 c/mL at Week 96 (Snapshot analysis)

Change in CD4 cell count at Weeks 48 and 96

Genotype/phenotype resistance at time of virologic failure

48 Weeks

Primary Endpoint

STaR

Virologic Outcomes by Snapshot Analysis and CD4 Change at Weeks 48 & 96

86

8 6

82

5 13

78

9 13

72

6

22

0

10

20

30

40

50

60

70

80

90

100

Virologic Success Virologic Failure No Data in Window

RPV/FTC/TDF W48 EFV/FTC/TDF W48

RPV/FTC/TDF W96 EFV/FTC/TDF W96

4.1 -1.1 9.2

W48 W96 W48 W96 W48 W96

-0.6 5.5 11.5 W96

W48

0 -12% 12%

Mean CD4 count change (cells/mm3) Week 48: RPV/FTC/TDF +200 vs. EFV/FTC/TDF +191 (p=0.37) Week 96: RPV/FTC/TDF +278 vs. EFV/FTC/TDF +259 (p=0.17)

Favours EFV/FTC/TDF

Favours RPV/FTC/TDF

Virologic Outcomes

% o

f S

ub

jec

ts

STaR All Grades Treatment-Emergent Adverse Events of Importance*

through Week 96

*Prespecified evaluation for common adverse events included in the US Prescribing Information and EMA SmPC for efavirenz, rilpivirine, COMPLERA/EVIPLERA and ATRIPLA®

†One suicide occurred in the EFV/FTC/TDF arm, Day 36 of study

RPV/FTC/TDF

n=394

EFV/FTC/TDF

n=392

Nervous System Events, n (%) 107 (27%) 186 (47%) p< 0.001

Dizziness 27 (7%) 90 (23%)

Headache 56 (14%) 62 (16%)

Somnolence 10 (3%) 30 (8%)

Psychiatric Events†, n (%) 111 (28%) 192 (49%) p< 0.001

Abnormal Dreams 23 (6%) 101 (26%)

Anxiety 28 (7%) 37 (9%)

Depression 36 (9%) 47 (12%)

Insomnia 45 (11%) 59 (15%)

Rash Events, overall, n (%) 62 (16%) 95 (24%) p=0.003

Rash 31 (8%) 52 (13%)

Events >5%

of subjects

Role for PI/r as first line therapy

ACTG 5257: Study Design

• Primary Endpoints*

• Time to HIV-1 RNA >1000 c/mL wk 16 to before wk 24, or >200 c/mL at or after wk 24 (VF)

• Time to discontinuation of randomized component for toxicity (TF)

• Pre-planned Composite Endpoint • The earlier occurrence of either VF or TF in a given participant

Landovitz L, et al. 21st CROI; Boston, MA; March 3-6, 2014. Abst. 85.

HIV-infected patients, ≥18 yr, with no previous ART,

VL ≥ 1,000 c/mL at U.S. Sites

(N=1,809)

ATV 300 mg QD + RTV 100 mg

QD + FTC/TDF 200/300 mg QD

(N=605)

RAL 400 mg BID +

FTC/TDF 200/300 mg QD

(N=603)

DRV 800 mg QD + RTV 100 mg

QD + FTC/TDF 200/300 mg QD

(N=601)

Randomized 1:1:1 to Open Label Therapy

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

A5260s metabolic substudy participation, cardiovascular risk

Proportion VL ≤50 copies/mL ITT, regardless of ART change ITT, off-ART=failure (SNAPSHOT)

24 48 96 144

ATV/r 83% 90% 88% 90%

RAL 90% 92% 94% 94%

DRV/r 83% 88% 89% 90%

24 48 96 144

ATV/r 70% 73% 63% 62%

RAL 84% 83% 80% 76%

DRV/r 77% 77% 73% 71%

ACTG 5257:

Toxicity Associated Discontinuation

ATV/r

(N=605)

RAL

(N=603)

DRV/r

(N=601)

Any Toxicity Discontinuation 95 (16%) 8 (1%) 32 (5%)

Gastrointestinal Toxicity 25 2 14

Jaundice/Hyperbilirubinemia 47 0 0

Other Hepatic Toxicity 4 1 5

Skin Toxicity 7 2 5

Metabolic Toxicity 6 0 2

Renal Toxicity (All Nephrolithiasis) 4 0 0

Abnormal Chem/Heme (Excl. LFTs) 0 0 2

Other Toxicity 2 3 4

Landovitz L, et al. 21st CROI; Boston, MA; March 3-6, 2014. Abst. 85.

0 TDF+FTC

1 RAL

0 RAL+FTC

0 RAL+FTC+TDF

1 TDF+FTC

1 RAL

0 RAL+FTC

0 RAL+FTC+TDF

Resistance to Study Agents None to boosted PIs

75/94 VF

Available

RAL

99/115 VF

Available

9 Any Resistance

(1.5%)

18 Any Resistance

(3%)

4 Any Resistance

(<1%)

2 TDF 0 TDF 0 TDF

5 FTC 7 FTC 3 FTC

0 TDF+FTC

ATV/r DRV/r

295 Virologic Failures 1 Baseline Missing

56 VF Failed to Amplify

1809 Participants

1 RAL

7 RAL+FTC

3 RAL+FTC+TDF

65/85 VF

Available

Which Patient for Boosted PIs?

Considerations in Favor

• Effective across HIV-1 RNA, CD4+ strata[1,2]

• Few CNS adverse events[1,2]

• Little/no emergence of resistance at VF[1,2]

• Preferred agents in pregnancy3

• Low risk for new resistance to develop in those with transmitted resistance or those with poor adherence

Considerations Against

• No coformulations with NRTIs (yet)

• Variable lipid effects[1,2]

• Concerns about renal function (greatest concern when ATV/RTV combined with TDF)[1,4]

• Drug–drug interactions with other drugs metabolized by CYP system[5,6]

• Hyperbilirubinemia with ATV[1,5]

1. Molina JM, et al. Lancet. 2008;372:646-655. 2. Ortiz R, et al. AIDS. 2008;22:1389-1397. 3. DHHS Perinatal Guidelines. July 2012. 4. Mocroft A, et al. AIDS. 2010;24:1667-1678. 5. Atazanavir [package insert]. 6. Darunavir [package insert].

The single pill?

Many regimens are single tablet currently all with 3TC/FTC in backbone

PI, important points to consider

and indication are outlined at the

end of this presentation

Atripla

EFV/FTC/TDF

Eviplera▼ RPV/FTC/TDF

Stribild▼

Elvitegravir/cobicistat/FTC/TDF

Triumeq DTG/ABC/3TC

29

More STRs on the Way!

30

31

FDCs/STRs-issues not for everyone

Cannot adjust the doses – Important in renal disease and with DDIs

Some may be too big to make

Co-packaging vs single pill

Does differing half lives matter if you stop?

All have FTC/3TC at present

STR cross resistance – 184V is a multidrug resistant mutation to all current and proposed

STR!

Where is the data re significant difference

Patented so more expensive

What about

Switches Due to Toxicity

27%

14%

12%12%

9%

8%

18% CNSSE

GI

CVDRisk

Hepatotoxicity

Metabolic

RenalToxicity

Other

Boyle A et al, HIV11 2012, Oral 312.

•923 regimens switched over 18 months affecting 12% (n=722/6211) •Predicted annual switch rate of 8%

•Half switches for toxicity

Many switch options if undetectable

• Need a reason to switch!

• Must check treatment history and prior resistance tests

Recent trials

• PI/r to rilpivirine plus TDF/ FTC

• PI/r to Stribild

• NNRTI to Stribild

SECOND-LINE TREATMENT SWITCH FOR VIROLOGICAL

FAILURE

SECOND-LINE: Noninferiority of LPV/RTV + RAL vs LPV/RTV + NRTIs in Pts With First-Line VF

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/m

L (%

) 82.6

80.8

P = .59

Humphries A, et al. CROI 2013. Abstract 180LB. Graphic used with permission.

EARNEST: Second-line LPV/RTV-Based ART After Initial NNRTI Failure Clinical Outcomes at Wk 96

*“Good disease control” at Wk 96 defined as pt alive, no new WHO4 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

60 64

56

86 86

61

74 73

44

PI/NRTI PI/RAL PI mono

Pat

ien

ts (

%)

Conclusion

Modern HAART is highly effective but.....

Need to maintain lifelong well tolerated therapy

is Efavirenz going to remain first line treatment of choice

What will be the role of PI/r and integrase?

STRs are becoming a standard of care in Naives

Switching because of toxicity is common

Second Line therapy –can you move to a second regimen without resistance testing

38