Modifying Therapy in the Treatment-experienced Patient:When should it be done?

Professor of MedicineUNC Chapel Hill School of Medicine

Joseph J. Eron, Jr., MD

Disclosures

• Principal Investigator (Research Grants to University of North Carolina): GlaxoSmithKline/ViiV

• Ad hoc Consultant: Abbvie, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline/ViiV, Merck, Tibotec/Janssen, Tobira

• Data and Safety Monitoring Board: Vertex (Inactive 2/1/2014)

Treatment-experienced Patient

• Two broad categories– Suppressed HIV RNA; candidates for regimen modification

Convenience, tolerability, toxicity, cost– Virologic failure, usually in the context of poor medication

adherence Reestablish virologic suppression while avoiding complex or poorly

tolerated therapy (whenever possible)

Changing Therapy when HIV RNAIs Suppressed

Switching the regimen may improve safety, tolerability, convenience, or cost.

• Pro – My job as a clinician is to make sure each patient is on an optimal regimen weighing multiple factors

• Con – Any switch could lead to unanticipated toxicity, medication error, drug-drug interactions, and subsequent HIV RNA rebound

Regimen Switching with Virologic Suppression

• The vast majority of patients in care on ART have HIV RNA below the limit of detection– Example: 87% of Hopkins Cohort, 85% UNC Clinical Cohort

• Possible reasons to change treatment– Reduce pill burden and dosing frequency

– Enhance tolerability

– Decrease anticipated short-term or long-term toxicity

– Decrease food requirements

– Optimize treatment in anticipation of pregnancy

– Reduce costs

– Improve immunologic response (?)

Moore R, et al. Clin Infect Dis. 2011; 53:600-604.DHHS Guidelines 2014. Available at: http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Revision May 2014.

Disadvantages ofRegimen Switching

• A new agent may lead to new adverse event• Virologic rebound may lead to resistance

– Risk increased if previous resistance testing not done or unavailable or– Complete treatment history is not known

• Increased monitoring in the short term• What is said is not always what is heard

– Medication errors occur including DDI• Cost of new regimen may be higher

Candidates for Regimen Switching

• Optimal: Patients with no suspected drug-resistant virus• Selected patients with documented or suspected drug

resistance may also be candidates– Focus on those who changed regimens when

treatment options were much more limited Similar agents with better formulation, frequency, or potency; FDCs;

and dosing simplification

• Key is to review treatment history, treatment responses, tolerance, and resistance test results

• Maintaining virologic suppression a priority

DHHS Guidelines 2014. Available at: http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Revision May 2014.

SPIRIT: Switching from PI/r to Rilpivirine

Primary Endpoint:

• Noninferiority (12% margin) to PI + RTV + 2 NRTIs by FDA snapshot analysis HIV-1 RNA <50 c/mL at 24 weeks

Palella F, et al. 19th IAC; Washington, DC; July 22-27, 2012; Abst. TUAB0104.

RPV/FTC/TDF STRHIV-1 RNA <50 copies/mL

Stable PI/r + 2 NRTIs ≥ 6 months

On 1st or 2nd regimenNo prior NNRTIs

No known genotypic resistance to study ARVs

24 weeks 48 weeks

n=317

n=159

2:1

n=476

RPV/FTC/TDF STR

RPV/FTC/TDF STR

PI/r +2 NRTIs

89.3

2.5 8.20

102030405060708090

100

VirologicSuppression

VirologicFailure

No Data

FDA Snapshot at 48 Weeks

RPV/FTC/TDF

(Immediate switch, Day 1 to W24)

(delayed, Day 1 to W24)

(delayed switch, W24 to W48)

93.7

0.9 5.4

89.9

5 5

92.1

1.3 6.60

102030405060708090

100

Virologic Suppression(HIV-1 RNA <50

c/mL)

Virologic Failure No Data

Prop

ortio

n of

Sub

ject

s, P

erce

ntag

e FDA Snapshot at 24 Weeks

RPV/FTC/TDF

PI+RTV+2NRTIs

RPV/FTC/TDF 2

SPIRIT: Virologic Suppressionat Weeks 24 and 48

• 23/24 subjects with preexisting K103N maintain virologic suppression• Pretherapy VL NOT associated with rebound• Fewer adverse events on rilpivirine-based therapy• Lipid levels improved substantially• 3 patients on RPV failed with resistance

Fisher M, et al. HIV11; Glasgow, Scotland; November 11-15, 2012; Abst. P285.

(Immediate switch, Day 1 to W48)

EVG/C/FTC/TDF: coformulated elvitegravir 150 mg, cobicistat 150 mg, emtricitabine 200 mg, tenofovir DF 300 mg. PI + RTV + FTC/TDF: ritonavir-boosted PI and emtricitabine/tenofovir DF.

Reasons subjects chose to enroll in study Desire to simplify current regimen 86% Concerned about long-term side effects of current regimen 12%

n =293

n =140

2:1

PI + RTV + FTC/TDF

EVG/C/FTC/TDFPI + RTV + FTC/TDF

Week 96Week 48

STRATEGY-PI StudyPI at Randomization

ATV 40%

DRV 40%

LPV 17%

FPV 3%

SQV <1%

STRATEGY-PI: Switch from PI/r to TDF/FTC/EVG/c

Arribas J, et al. 21st CROI; Boston, MA; March 3-6, 2014. Abst. 551LB.

* 6.7% (+0.4%, +13.7%) P=0.025 for superiority

No subject met the protocol-defined criteria for treatment-emergent resistance testing with virologic rebound ≥400 c/mL

Modest/significant improvement in diarrhea and bloating

STRATEGY-PI: Virologic Outcome at Week 48

Arribas J, et al. 21st CROI; Boston, MA; March 3-6, 2014. Abst. 551LB.

EVG/C/FTC/TDF(n=290)

PI + RTV + FTC/TDF (n=139)

Virologic success at week 48HIV-1 RNA <50 copies/mL* 272 (93.8%) 121 (87.1%)

Virologic failure (VF) at week 48 2 (0.7%) 2 (1.4%)HIV-1 RNA ≥ 50 copies/mL 2 1Discontinued study drug due to lack of efficacy 0 0Discontinued study drug due to other reasons and last available HIV-1 RNA ≥50 copies/mL

0 1

No virologic data in week 48 window 16 (5.5%) 16 (11.5%)Discontinued study drug due to AE 5 2Discontinued study drug due to other reasons and last available HIV-1 RNA <50 copies/mL

11 (3.7%) 14 (10.1%)

Missing data during window but on study drug 0 0

SPIRAL StudySwitch to RAL vs Continue PI/r

• Very low rates of VF• Patients with NRTI experience

• Similar success• ABC/3TC vs TDF/FTC

• Similar results • Improvement in lipids

• Including TC/HDL• Not in endothelial function

Martinez E, et al. AIDS. 2010. AIDS 2012, AHR 2013 and Masia, et al. J Antimicrob Chemother. 2013.

hsCRP IL-6 Insulin D-DimerChange after switch

from PI/r to RAL -40% -46% -26% -8%

P value <0.0001 <0.0001 <0.0001 0.018

Novel Strategies for Switch

• Simplification from 3-drug therapy to 2 drugs – PI/r plus 3TC alone

GARDEL study (in treatment naïve), AtLaS study

– PI/r plus integrase inhibitor

– Integrase inhibitor plus NNRTI Multiple small studies

♦ NVP plus raltegravir

♦ Etravirine plus raltegravir

• Beware of noncomparative studies– RAL plus maraviroc – stopped due to VF

• RPV plus DTG vs continued NNRTI plus 2NRTICahn P, et al. Lancet Infect Dis. 2014;14:572-580. Monteiro P, et al. J Antimicrob Chemother. 2014;69:742-748. Reliquet V, et al. Antivir Ther. 2014;19:117-123. Calin R, et al. Antivir Ther. 2012;17:1601-1604. Di Giambenedetto S, et al.J Antimicrob Chemother. 2013;68:1364-1372. van Lelyveld S, et al. Presented at: CROI. Atlanta, GA; March 3-6, 2013.

LATTE: Study Design

• Phase 2b randomized, multicenter, partially blind, dose-ranging study comparing S/GSK744 plus RPV to EFV plus NRTIs

Margolis D, et al. 14th EACS; Brussels, Belgium; October 16-19, 2013. Abst. PS7/1.

*ABC/3TC or TDF/FTC

**Patients on 744 + NRTI: If week 20 VL <50 c/mL - simplify to 744/RPV at week 24

HIV ART-naïveHIV RNA >1,000 c/mL

1:1:1:1 Randomization

stratified by VL and NRTI

744 30 mg + 2 NRTIs*

744 10 mg + 2 NRTIs*

Oral induction phase

744 60 mg + 2 NRTIs*

Oral maintenance phase**

744 10 mg + RPV 25 mg

744 30 mg + RPV 25 mg

744 60 mg + RPV 25 mg

2416 20 48 9672

EFV 600 mg + 2 NRTIs*

WeekD1

744 overall response W4882%

744 overall response W2487%

0

20

40

60

80

100

744 10 mg (N=60) 744 30 mg (N=60) 744 60 mg (N=61)EFV 600 mg (N=62)

Two-drug 744 + RPV Maintained Suppression Comparable to EFV-based Therapy

Margolis D, et al. CROI 2014; Boston, MA. Abstract 91LB.

Week

EFV response W4871%

EFV response W2474%

Prop

ortio

n, %

242 4 8 12 16 4032 48362628BL

Induction Phase Maintenance Phase

Median (IQR) change from baseline CD4+ cell count

(cells/mm3)Week 48

744 overall +219 (141,343)EFV +227 (134,369)

Long-acting Injectable Study

LATTE 2

• Rilpivirine LA plus 744 LA monthly or every other month vs• Oral 744 + 2NRTI

Margolis D, et al. 14th EACS; Brussels, Belgium; October 16-19, 2013. Abst. PS7/1; Margolis D, et al. CROI 2014; Boston, MA. Abstract 91LB; Levin J. Presented at 21st Conference on Retroviruses and Opportunistic Infections. Boston, MA. March 3 - 6, 2014.

Treatment Experienced Patientwith Virologic Failure

DHHS Guidelines 2014. Available at: http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Revision May 2014.

Patient factors ART factors

Higher baseline HIV RNA Side effects and toxicities

Lower nadir CD4 cell count Suboptimal pharmacokinetics

Prior AIDS diagnosis Food/fasting requirements

Substance use, depression Drug-drug interactions

Presence of drug-resistant virus Suboptimal virologic potency

Prior treatment failure Prescription errors

Suboptimal ART adherence/missed clinic appointments

Selected Factors Associated with Virologic Failure

Virologic Failure: Next Steps

• Assess patient’s past medication history, adherence, and potential medication intolerance, previous resistance tests

• Order drug resistance test– For patients on an integrase inhibitor, specific testing for integrase inhibitor resistance should

be performed if available

• The goal of ART is to reestablish virologic suppression– At least 2 (preferably 3) fully active drugs as part of new regimen

Eron Corollary: 3 fully active drugs – may increase complexity, decrease tolerability, and increase cost – partially active drugs likely contribute

DHHS Guidelines 2014. Available at: http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Revision May 2014.

Second-line: LPV/RTV + RAL vs LPV/RTV + NRTIs after First-line VF

Boyd MA, et al. Lancet. 2013;381:2091-2099.

Randomized, open-label, international, multicenter trial

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 patients with virologic failure on first-line regimen of 2 NRTIs +

NNRTI(n=541) TDF + FTC/3TC: 46% AZT + FTC/3TC: 18%

Stratified by clinical site, baseline HIV-1 RNA

(≤ or > 100,000 copies/mL)

Week 48 primary endpoint

Of 492 participants with baseline GRT:− 89% had ≥1 N(t)RTI resistance mutation− 60% had M184V plus 1 or more additional N(t)RTI mutations

Second-line Study: Results

0

20

40

60

80

100

0 12 24 36 48Week

HIV RNA <200 copies/mL (ITT)

LPV/r + 2-3N(t)RTI LPV/r + RAL

Boyd M, et al. 20th CROI; Atlanta, GA; March 3-6, 2013. Abst. 180LB.

P-value=0.59

80.8% (76.1 – 85.5)

82.6% (78.1 – 87.1)

Perc

ent P

atie

nts

Therapy for Later Treatment Failure

• Adherence remains the most common cause• For patients who initiated therapy in the ART era – multiclass,

high-level resistance is rare• Resistance testing is critical

– Use at least 2 fully active drugs if possible– Partially active drugs likely add benefit

– NRTI may not be necessary– Knowledge of a drug’s barrier to resistance and activity against resistant virus

is essential

Modifying Antiretroviral Therapy in Treatment-experienced Patients: Summary

• Patients with HIV RNA suppression– Goals include: simplify, improve tolerability, reduce toxicity, sustain virologic

suppression– Need: Treatment history, resistance data, clear patient understanding and

follow-up• Patients with virologic failure

– Adherence must be addressed– Resistance testing is critical– At least 2 fully active agents – most patients have several options– Full suppression is the goal.