1. Modifying Therapy in the Treatment-experienced Patient: When should it be done?
Joseph J. Eron, Jr., MD
Professor of Medicine
UNC Chapel Hill School of Medicine

2. 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)

3. 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)

4. Changing Therapy when HIV RNA Is 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

5. 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:
DHHS Guidelines Available at: Revision May 2014.

6. Disadvantages of Regimen 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

7. 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
Slide: Candidates for Regimen Simplification
Candidates for regimen simplification include:
No suspected drug-resistant virus.
Selected patients with documented or suspected drug resistance. Patients on regimens that were selected when treatment options were limited. For such patients it is important to review treatment history, treatment responses, tolerance, and resistance test results, as well as consider expert consultation.1
Reference
Panel on Antiretroviral Guidelines for Adult and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. February 12, 2013; Available at:
DHHS Guidelines Available at: Revision May 2014.

8. SPIRIT: Switching from PI/r to Rilpivirine
RPV/FTC/TDF STR
HIV-1 RNA <50 copies/mL
Stable PI/r + 2 NRTIs
≥ 6 months
On 1st or 2nd regimen
No prior NNRTIs
No known genotypic resistance to study ARVs
24 weeks weeks
n=317
n=159
2:1
n=476
PI/r
+2 NRTIs
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. 8

9. SPIRIT: Virologic Suppression at Weeks 24 and 48
(Immediate switch, Day 1 to W24)
(delayed, Day 1 to W24)
(delayed switch, W24 to W48)
(Immediate switch, Day 1 to W48)
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.

10. STRATEGY-PI: Switch from PI/r to TDF/FTC/EVG/c
CORE_Efficacy_Safety_Feb-14_SLB.ppt
4/22/2017
STRATEGY-PI: Switch from PI/r to TDF/FTC/EVG/c
n =293
n =140
2:1
PI + RTV + FTC/TDF
EVG/C/FTC/TDF
Week 96
Week 48
STRATEGY-PI Study
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%
Arribas J, et al. 21st CROI; Boston, MA; March 3-6, Abst. 551LB.
Gilead 10

11. STRATEGY-PI: Virologic Outcome at Week 48
EVG/C/FTC/TDF
(n=290)
PI + RTV + FTC/TDF
(n=139)
Virologic success at week 48
HIV-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 1
Discontinued study drug due to lack of efficacy
Discontinued study drug due to other reasons and last available HIV-1 RNA ≥50 copies/mL
No virologic data in week 48 window
16 (5.5%)
16 (11.5%)
Discontinued study drug due to AE 5
Discontinued 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
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
* 6.7% (+0.4%, +13.7%) P=0.025 for superiority
Arribas J, et al. 21st CROI; Boston, MA; March 3-6, Abst. 551LB.

12. SPIRAL Study Switch 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
hsCRP
IL-6
Insulin
D-Dimer
Change after switch from PI/r to RAL
-40%
-46%
-26%
-8%
P value
<0.0001
0.018
Martinez E, et al. AIDS AIDS 2012, AHR 2013 and Masia, et al. J Antimicrob Chemother

13. 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 2NRTI
Cahn P, et al. Lancet Infect Dis. 2014;14: Monteiro P, et al. J Antimicrob Chemother. 2014;69:
Reliquet V, et al. Antivir Ther. 2014;19: Calin R, et al. Antivir Ther. 2012;17: Di Giambenedetto S, et al.
J Antimicrob Chemother. 2013;68: van Lelyveld S, et al. Presented at: CROI. Atlanta, GA; March 3-6, 2013.

14. Oral maintenance phase** stratified by VL and NRTI
LATTE: Study Design
Phase 2b randomized, multicenter, partially blind, dose-ranging study comparing S/GSK744 plus RPV to EFV plus NRTIs
mg + 2 NRTIs*
mg + 2 NRTIs*
Oral induction phase
mg + 2 NRTIs*
Oral maintenance phase**
mg + RPV 25 mg
HIV ART-naïve
HIV RNA >1,000 c/mL
1:1:1:1 Randomization
stratified by VL and NRTI
mg + RPV 25 mg
mg + RPV 25 mg 24 16 20 48 96 72
EFV 600 mg + 2 NRTIs*
Week D1
*ABC/3TC or TDF/FTC
**Patients on NRTI: If week 20 VL <50 c/mL - simplify to 744/RPV at week 24
Margolis D, et al. 14th EACS; Brussels, Belgium; October 16-19, Abst. PS7/1.

15. Median (IQR) change from baseline CD4+ cell count (cells/mm3)
Two-drug RPV Maintained Suppression Comparable to EFV-based Therapy
744 overall response W24
87%
744 overall response W48
82%
Induction Phase
Maintenance Phase
Proportion, %
EFV response W24
74%
EFV response W48
71%
Median (IQR) change from baseline CD4+ cell count (cells/mm3)
Week 48
744 overall
+219 (141,343)
EFV
+227 (134,369) BL 2 4 8 12 16 24 26 28 32 36 40 48
Week
Margolis D, et al. CROI 2014; Boston, MA. Abstract 91LB.

16. Long-acting Injectable Study
LATTE 2
Rilpivirine LA plus 744 LA monthly or every other month vs
Oral NRTI
Margolis D, et al. 14th EACS; Brussels, Belgium; October 16-19, 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.

17. Treatment Experienced Patient with Virologic Failure
Selected Factors Associated with Virologic Failure
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
DHHS Guidelines Available at: Revision May 2014.

18. 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 Available at: Revision May 2014.

19. Second-line: LPV/RTV + RAL vs LPV/RTV + NRTIs after First-line VF
Randomized, open-label, international, multicenter trial
Week 48 primary endpoint
Stratified by clinical site, baseline HIV-1 RNA
(≤ or > 100,000 copies/mL)
Lopinavir/ritonavir 400/100 mg BID + Raltegravir 400 mg BID (n=270)
HIV-infected patients with virologic failure on first-line regimen of 2 NRTIs + NNRTI
(n=541)
TDF + FTC/3TC: 46%
AZT + FTC/3TC: 18%
For more detailed information about this study go to:
Lopinavir/ritonavir 400/100 mg BID NRTIs QD or BID (n=271)
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
Boyd MA, et al. Lancet. 2013;381:

20. Second-line Study: Results
P-value=0.59
80.8% (76.1 – 85.5)
82.6% (78.1 – 87.1)
Percent Patients
Boyd M, et al. 20th CROI; Atlanta, GA; March 3-6, Abst. 180LB.

21. 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

22. 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.