1. ACTHIV 2018: A State-of-the-Science Conference for Frontline Health Professionals
ACTIVITY CODE TD342

2. Antiretroviral Medications: What you need to know
Jason J. Schafer, PharmD, MPH, BCPS, AAHIVP
Associate Professor, Department of Pharmacy Practice
Jefferson College of Pharmacy, Thomas Jefferson University

3. Learning Objectives Upon completion of this presentation, learners should be better able to:
Review the life cycle of HIV and the targets for antiretroviral therapy
Describe the mechanisms of action of antiretroviral medications for the treatment of HIV infection
Identify factors that influence the choice of antiretroviral therapy in treatment naïve patients

4. Faculty and Planning Committee Disclosures Please consult your program book.
I have received grant funding from Merck Pharmaceuticals for investigator initiated research
There will be no off-label/investigational uses discussed in this presentation.

5. What Antiretroviral Therapy to Start
A Moving Target
DHHS Guidelines Recommended Regimens
Protease inhibitor based
Darunavir + ritonavir + emtricitabine + TDF
Atazanavir + ritonavir + emtricitabine + TDF
Integrase inhibitor based
Raltegravir + emtricitabine + TDF
NNRTI based:
Efavirenz + emtricitabine + TDF
DHHS: Department of Health and Human Services, TDF: tenofovir disoproxil fumarate, NNRTI: non-nucleoside reverse transcriptase inhibitor

6. What Antiretroviral Therapy to Start
A Moving Target
DHHS Guidelines Recommended Regimens
Protease inhibitor based
Darunavir + ritonavir + emtricitabine + TDF
Integrase inhibitor based
Raltegravir + emtricitabine + TDF
Elvitegravir + cobicistat + emtricitabine + TDF or TAF
Dolutegravir + emtricitabine + TDF
Dolutegravir + abacavir + lamivudine
DHHS: Department of Health and Human Services, TDF: tenofovir disoproxil fumarate, TAF: tenofovir alafenamide

7. What Antiretroviral Therapy to Start
A Moving Target
DHHS Guidelines Recommended Regimens
Integrase inhibitor based
Raltegravir + emtricitabinea + TDF or TAFb
Elvitegravir + cobicistat + emtricitabinea + TDF or TAFb
Dolutegravir + emtricitabinea + TDF or TAFb
Dolutegravir + abacavir + lamivudinea
Bictegravir + emtricitabinea + TAFb
DHHS: Department of Health and Human Services, TDF: tenofovir disoproxil fumarate, TAF: tenofovir alafenamide
a Lamivudine may substitute for emtricitabine or vice versa.
b Tenofovir alafenamide (TAF) and tenofovir disoproxil fumarate (TDF) are two forms of tenofovir approved by the Food and Drug Administration. TAF has fewer bone and kidney toxicities than TDF, while TDF is associated with lower lipid levels. Safety, cost, and access are among the factors to consider when choosing between these drugs.
US DHHS. Guidelines for Use of Antiretroviral Agents in HIV-1−Infected Adults and Adolescents Accessed March, 2018.

8. HIV Life Cycle and Targets
CD4 receptor
CCR5 co-receptor
Glycoprotein 41
Reverse transcriptase enzyme
Nucleos(t)ide reverse transcriptase inhibitors
Non-nucleoside reverse transcriptase inhibitors
Integrase enzyme
Protease enzyme 1 2 3 4 5 6

9. Inhibiting Viral Entry
CD4 Receptor Antagonists, Co-Receptor Antagonists and Fusion Inhibitors
CD4 Receptor antagonist
Image adapted from: Moore JP, et al. Proc Natl Acad Sci U S A. 2003;100:

10. Inhibiting Viral Entry
CD4 Receptor Antagonists, Co-Receptor Antagonists and Fusion Inhibitors
Enfuvirtide
GP41 antagonist, subcutaneous injection
Not recommended as initial therapy
Maraviroc
CCR5 antagonist, tropism test required
Ibalizumab
Humanized monoclonal antibody
Binds to the extracellular domain of the CD4+ receptor
Heavily treatment experienced patients
Brand Name
Generic Name
Approval Date
Fuzeon
Enfuvirtide
2003
Selzentry
Maraviroc
2007
Trogarzo
Ibalizumab
2018

11. Blocking Reverse Transcription
Nucleoside Reverse Transcriptase Inhibitors
Mechanism of action
Structural analogues of nucleoside bases
Competitively bind to reverse transcriptase enzyme
Incorporate into DNA chain and terminate DNA synthesis
Image adapted from Clavel F. N Engl J Med 2004;350:

12. Blocking Reverse Transcription
Nucleoside Reverse Transcriptase Inhibitors
ABC/3TC, TAF/FTC, and TDF/FTC are the recommended NRTI combinations for use as initial therapy.
Recommendations are based on the potency, durability, toxicity, and convenience.
Safety is among the factors to consider when choosing between these drugs.
Brand Name
Generic Name
Approval Date
Epivir
Lamivudine (3TC)
1995
Ziagen
Abacavir (ABC)
1998
Epzicom
Abacavir/lamivudine
2004
Viread
Tenofovir disoproxil fumarate (TDF)
2001
Vemlidy
Tenofovir alafenamide (TAF)
2016
Emtriva
Emtricitabine (FTC)
2003
Truvada
TDF/emtricitabine
Descovy
TAF/emtricitabine

13. Blocking Reverse Transcription
Non-Nucleoside Reverse Transcriptase Inhibitors
Mechanism of action
Non-competitive binding to reverse transcriptase
Not analogues of nucleoside bases
Bind adjacent to the catalytic site of enzyme
Efavirenz
Image adapted from Clavel F. N Engl J Med 2004;350:

14. Blocking Reverse Transcription
Non-Nucleoside Reverse Transcriptase Inhibitors
Currently recommended as initial regimens only in certain clinical situations for the following reasons:
Low genetic barrier for resistance;
Efavirenz is less well tolerated than the recommended regimens; and
Virologic failure is more common with rilpivirine with high pretreatment viral loads (>100,000 copies/mL) or low CD4 counts (<200 cells/mm3)
Brand Name
Generic Name
Approval Date
Sustiva
Efavirenz
1998
Atripla*
Efavirenz, emtricitabine, TDF
2006
Edurant
Rilpivirine
2011
Intelence
Etravirine
2012
Complera*
Rilpivirine, emtricitabine, TDF
Odefsey*
Rilpivirine, emtricitabine, TAF
2016
*Single tablet regimens

15. Blocking Viral DNA Integration
Integrase Inhibitors
Mechanism of action:
Inhibit insertion of HIV DNA into human DNA following reverse transcription

16. Blocking Viral DNA Integration
Integrase Inhibitors
Recommended as initial treatment for most people with HIV
Agents are generally well tolerated
Reports of insomnia in some patients
Rare reports of depression and suicidal ideation, primarily in patients with a history of psychiatric illnesses
Often better tolerated than comparator agents in clinical trials
Brand Name
Generic Name
Approval Date
Isentress
Raltegravir
2007
Stribild*
Elvitegravir, cobicistat, TAF, and emtricitabine
2012
Tivicay
Dolutegravir
2013
Triumeq*
Dolutegravir, abacavir, lamivudine
2014
Genvoya*
2015
Biktarvy*
Bictegravir, TAF and emtricitabine
2018
*Single tablet regimens

17. Blocking The Production of Viral Proteins
Protease Inhibitors
Mechanism of Action
Bind to protease enzyme prevent cleavage of HIV polyproteins
1. The production of viral polypeptides from mRNA
2. Cleavage of polypeptides to form HIV proteins

18. Blocking The Production of Viral Proteins
Protease Inhibitors
Potent and durable in naive patients, with a high barrier to resistance
Useful for patients at risk for poor adherence
Less well tolerated than integrase inhibitors in clinical trials
All inhibit CYP3A4, which may lead to significant drug-drug interactions
Brand Name
Generic Name
Approval Date
Norvir
Ritonavir
1996
Kaletra
Lopinavir/ritonavir
2000
Reyataz
Atazanavir
2003
Prezista
Darunavir
2006
Evotaz
Atazanavir/cobicistat
2015
Prezcobix
Darunavir/cobicistat

19. What Antiretroviral Therapy to Start
How to Choose?
DHHS Guidelines Recommended Regimens
Integrase inhibitor based
Raltegravir + emtricitabinea + TDF or TAFb
Elvitegravir + cobicistat + emtricitabinea + TDF or TAFb
Dolutegravir + emtricitabinea + TDF or TAFb
Dolutegravir + abacavir + lamivudinea
Bictegravir + emtricitabinea + TAFb
DHHS: Department of Health and Human Services, TDF: tenofovir disoproxil fumarate, TAF: tenofovir alafenamide
a Lamivudine may substitute for emtricitabine or vice versa.
b Tenofovir alafenamide (TAF) and tenofovir disoproxil fumarate (TDF) are two forms of tenofovir approved by the Food and Drug Administration. TAF has fewer bone and kidney toxicities than TDF, while TDF is associated with lower lipid levels. Safety, cost, and access are among the factors to consider when choosing between these drugs.
US DHHS. Guidelines for Use of Antiretroviral Agents in HIV-1−Infected Adults and Adolescents Accessed March, 2018.

20. What Antiretroviral Therapy to Start
Influential Factors for the Treatment Naïve Patient
Efficacy
Safety/Tolerability
Convenience/Pill Size
Drug-Drug Interactions
Comorbidities/Co-infections
Resistance/Resistance Barrier
Pregnancy

21. Audience Response Question 1: Why are integrase inhibitor based regimens recommended ahead of comparators?
A. They more often lead to virologic suppression B. They have fewer drug interactions C. They are comparably effective, but have better tolerability D. They have a higher barrier to HIV resistance

23. Antiretroviral Therapy Selection
Integrase Inhibitors and the Comparators – Efficacy and Tolerability
Study
Integrase Agent
Comparator(s)
Follow-up (Wks)
Efficacy
STARTMRK
Raltegravir
Efavirenz
192 Weeks
Raltegravir superior to efavirenz
ACTG 5257
Darunavir/ritonavir
Atazanavir/ritonavir
96 Weeks
Raltegravir superior to darunavir/ritonavir
Raltegravir superior to atazanavir/ritonavir
GS-102
Elvitegravir/cobicistat
144 Weeks
Elvitegravir non-inferior to efavirenz
GS-103
Elvitegravir non-inferior to atazanavir
WAVES
48 Weeks
Elvitegravir superior to atazanavir/ritonavir
SINGLE
Dolutegravir
Dolutegravir superior to efavirenz
FLAMINGO
Dolutegravir superior to darunavir/ritonavir
GS-US
Bictegravir
Bictegravir non-inferior to dolutegravir
GS-US

24. Choosing Between The Integrase Inhibitors

25. Audience Response Question 2: Which of the following medications has a significant interaction with all integrase inhibitors?
A. Omeprazole B. Simvastatin C. Metformin D. Multivitamins

27. Antiretroviral Therapy Selection
Choosing Between The Integrase Inhibitors – Drug-Drug Interactions
Absorption
INSTIs are not negatively impacted by the concurrent use of proton pump inhibitors or H2-blockers
INSTs are negatively impacted by divalent and trivalent cations in antacids and multivitamins through chelation interactions
Metabolism
Raltegravir has the least interactions
Dolutegravir and bictegravir have some CYP3A4 metabolism and therefore few drug interactions
Elvitegravir has many interactions due to CYP3A4 metabolism and cobicistat boosting
Drug
Recommendation with Al, Mg Containing Antacids
Raltegravir
Do not co-administer with Al-Mg antacids
Elvitegravir
Separate by ≥ 2 hours
Dolutegravir
Administer DOL 2 hours prior or 6 hours after antacid
Bictegravair
Drug
Substrate
Inhibits
Induces
Raltegravir
UGT
Elvitegravir/Cobi
3A4
3A4, Pgp, MATE-1
2C9
Dolutegravir
UGT, 3A4
MATE-1, OCT-2
Bictegravir

28. Antiretroviral Therapy Selection
Choosing Between The Integrase Inhibitors – Boosting
Cobicistat and low-dose ritonavir are used to increase bioavailability and prolong t½ of elvitegravir and protease inhibitors
Activity primarily via Pgp inhibition and CYP 3A4 inhibition in the liver and GI tract
Achieves higher and sustained troughs that limit the possibility of suboptimal levels

29. Antiretroviral Therapy Selection
Choosing Between The Integrase Inhibitors – Drug-Drug Interactions
Elimination
Cobicistat is an inhibitor of MATE-1 and therefore, inhibit active tubular secretion of creatinine
SCr increases by ~10% within 1-2 weeks and plateaus
Dolutegravir is an inhibitor of OCT2 and MATE-1 and can also inhibit active tubular secretion of creatinine
Metformin is eliminated through OCT2 and MATE-1
AUC increase of 79% with dolutegravir
AUC increase of 39% with bictegravir
Dofetilide is eliminated through OCT2 and MATE-1
Contraindicated with dolutegravir and bictegravir
Dolutegravir
Bictegravir
Dolutegravir
Bictegravir Cobicistat

30. Antiretroviral Therapy Selection
Choosing Between NRTIs – TDF or TAF?
Tenofovir disoproxil fumarate (TDF) is a prodrug converted to tenofovir in the plasma and then enters the HIV target cell.
TDF can lead to diminished renal function and losses in bone mineral density (BMD)
Tenofovir alafenamide (TAF) is a prodrug with 91% less circulating plasma tenofovir
TAF reduces the risk of kidney injury and BMD losses in comparison to TDF
Image adapted from Babusis D, et al. Mol Pharm. 2013;10(2):102:

31. Antiretroviral Therapy Selection
Choosing Between NRTIs –Abacavir Hypersensitivity
Incidence = 5-8%
Onset - within 6 weeks of initiating treatment
Multi-organ system syndrome with symptoms from ≥ 2 of the following:
Fever, rash, GI (nausea, vomiting, diarrhea or abdominal pain), malaise/fatigue, respiratory (cough or dyspnea)
Can be fatal upon re-challenge
HLA-B*5701 test has a 100% negative predictive value
Mallal, et al. N Engl J Med 2008;358:568-79

32. Antiretroviral Therapy Selection
Choosing Between NRTIs –Abacavir and Cardiovascular Disease Risk
Study
Study Design
Event (n)
Patients (n)
Abacavir Effect
Risk of MI (95% CI)
D:A:D
Cohort
MI (387)
22,625
Yes
1.70 ( )
D:A:D 2013
MI (493)
32,663
1.47
SMART
RCT
MI (19)
2,752
4.30 ( )
Danish
MI (67)
2,952
2.00 ( ) VA
CV event (501)
10,931
1.64 ( )
NA-ACCORD
MI (301)
16,733
1.33
Swiss
CVD event (350)
11,625
3.36 ( )
Swiss HIV Cohort
CVD event (365)
11,856
2.06 ( )

33. Antiretroviral Therapy Selection
Choosing Between NRTIs –Abacavir and Cardiovascular Disease Risk
Study
Study Design
Event (n)
Patients (n)
Abacavir Effect
Risk of MI (95% CI)
French Database CC
MI (289)
74,958
No*
1.27 ( )
ALLRT/ACTG
Cohort
MI (36)
5,056 No
0.70 ( )
GSK
Meta-analysis of RCTs
MI (27)
14,174
0.17 ( )
VA Case Registry
MI (278)
19,424
1.18 ( )
FDA
MI (24)
9,868
1.02 ( )
*Without adjustment for cocaine use OR: 2.01 ( )

34. Antiretroviral Therapy Selection
Choosing Between NRTIs –Abacavir and Cardiovascular Disease Risk
When selecting a regimen, a number of patient and regimen specific characteristic should be considered
The goal is to provide a potent, safe, tolerable, and easy to adhere to regimen for the patient in order to achieve sustained virologic control
CVD is one of several specific comorbidities listed among those to consider
“In patients with high cardiac risk, consider avoiding abacavir containing regimens”
Associated with increased cardiovascular risk in some…but not all studies
US DHHS. Guidelines for Use of Antiretroviral Agents in HIV-1−Infected Adults and Adolescents Accessed March, 2018.

35. Summary
Currently there are six targets for antiretroviral therapy agents within the HIV life cycle
These agents differ in terms of efficacy, tolerability, safety, durability and their potential for drug-drug interactions
All of these factors must be considered when selecting antiretroviral therapy for patients living with HIV

36. Antiretroviral Medications: What you need to know
Jason J. Schafer, PharmD, MPH, BCPS, AAHIVP
Associate Professor, Department of Pharmacy Practice
Jefferson College of Pharmacy, Thomas Jefferson University

37. ACTHIV 2018: A State-of-the-Science Conference for Frontline Health Professionals
ACTIVITY CODE TD342