1. HIV Medication Update Neha Sheth Pandit, PharmD, AAHIVP, BCPS
University of Maryland School of Pharmacy
Associate Professor, HIV/Infectious Diseases
September 2018

2. Dr. Neha Sheth Pandit, Pharm.D., AAHIVP, BCPS has nothing to disclose.
Disclosure
Dr. Neha Sheth Pandit, Pharm.D., AAHIVP, BCPS has nothing to disclose.

3. Objectives Identify previous and current guidelines for HIV treatment
Describe clinical uses of recently marketed anti-retrovirals
Describe the potential influence new anti-retrovirals will have on HIV management

4. Epidemiology
Since the beginning of the epidemic 77.3 million people have been infected
In 2017, 36.9 million people were living with HIV worldwide
In 2015, 1.1 million people were living with HIV in the US
In 2016, 30,430 people were living with HIV in Maryland
In 2015, 12,473 people were living with HIV in Baltimore City
In 2001 there were 3.4 million new infections
In 2016 there were 1.8 million new infections worldwide
In 2015 there were 38,500 new infections in the US
In 2016, there were 1,118 new infections in the Maryland
In 2015, there were 353 new infections in Baltimore City

5. Changes in HIV Treatment Guidelines
What to initially treat HIV with
Additional antiretroviral (ARV) medications
Regimen Simplification

6. When to treat HIV 1991: First Approved HIV medication
1998: Symptomatic, CD4< 500, VL >10,000
2001: Symptomatic, CD4< 350, VL >30,000
2002: Symptomatic, CD4< 350, VL >55,000
2004: Symptomatic, CD4< 350, VL >100,000
2007: Symptomatic, CD4< 350
2012: All HIV infected patients
When to treat HIV
reference
Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. Available at 6 6

7. When to Initiate ART?
Clinical Category
Recommendation
All HIV-infected individuals
Therapy is Recommended
Pregnancy
AIDS-defining illness
HIV-associated dementia/malignancies/nephropathy
CD4 < 200 cells/mm3
Acute HIV infection
Hepatitis co-infection
Higher urgency to start
If patient is not willing to commit to lifelong therapy
May Defer Therapy
reference
Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. Available at

8. HIV Continuum of Care 2015

9. 2007: 1st Integrase Inhibitor
1987: 1st NRTI Approved
1987: Zidovudine
1991: Didanosine
1992: Zalcitabine
1994: Stavudine
1995: Lamivudine, Saquinavir
1996: Nevirapine, Ritonavir, Indinavir
1997: Delavirdine, Nelfinavir, Saquinavir
1998: Abacavir, Efavirenz
1999: Amprenavir
2000: Lopinavir/ritonavir
2001: Tenofovir
2003: Enfuviritide, Atazanavir, Emtricitabine, Fosamprenavir
2005: Tipranavir
2006: Darunavir
2007: Raltegravir, Maraviroc, Etravirine
2011: Rilpivirine
2012: Elvitegravir
2013: Dolutegravir
2015: Tenofovir alafenamide
2018: Ibalizumab, Bictegravir, Doravirine
1995: 1st PI
1996: 1st NNRTI
2003: 1st Fusion Inhibitor
reference
2007: 1st Integrase Inhibitor
2012: 1st Pre-exposure Prophylaxis 9 9

10. Antiretroviral (ARV) Drug Classes
Nucleoside/nucleotide reverse transcriptase inhibitor (NRTIs)
Tenofovir disoproxil fumarate, Viread®, TDF
Tenofovir alafenamide, Vemlidy®, TAF
Emtricitabine, Emtriva®, FTC
Lamivudine, Epivir®, 3TC
Abacavir, Ziagen®, ABC
Zidovudine, Retrovir®, AZT
Didanosine, Videx EC®, ddI
Stavudine, Zerit®, d4T
Non-nucleoside reverse transcriptase inhibitor (NNRTIs)
Efavirenz, Sustiva®, EFV
Rilpivirine, Edurant®, RPV
Nevirapine, Viramune®, NVP
Etravirine, Intelence®, ETV
Doravirine, Pifeltro™, DOR
CCR5 Antagonists
Maraviroc, Selzentry®, MVC
Fusion inhibitors
Enfuvirtide, Fuzeon®, EFV
Protease inhibitors (PI)
Ritonavir, Norvir®, RTV
Atazanavir, Reyataz®, ATV
Atazanavir/cobicistat, Evotaz™, ATV/c
Darunavir, Prezista®, DRV
Darunavir/cobicistat, Prezcobix®, DRV/c
Lopinavir/ritonavir, Kaletra®, LPV/r
Fosamprenavir, Lexiva®, FPV
Nelfinavir, Viracept®, NFV
Indinavir, Crixivan®, IND
Saquinavir, Invirase®, SQV
Tipranavir, Aptivus®, TPV
Integrase Inhibitors (INSTIs)
Raltegravir, Isentress®, RAL
Elvitegravir, Vitekta®, EVG
Dolutegravir, Tivicay®, DTG
Bictegravir, in Biktarvy®, BIC
Pharmacokinetic Enhancers
Cobicistat, Tybost®, COBI AW
Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. Available at

11. Combination Products Combivir® Trizivir® Epzicom® Truvada® Descovy®
Zidovudine 300 mg + Lamivudine 150 mg po bid
Trizivir®
Zidovudine 300 mg + Lamivudine 150 mg + Abacavir 300 mg po bid
Epzicom®
Lamivudine 300 mg + Abacavir 600 mg po daily
Truvada®
TDF + Emtricitabine 200 mg po daily
Descovy®
TAF + Emtricitabine 200 mg po daily
Cimduo
TDF + Lamivudine 300 mg po daily AW
Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. Available at

12. Combination Products Single Tablet Regimens (STRs)
Atripla®
TDF + Emtricitabine 200 mg + Efavirenz 600 mg po daily
Symfi
TDF + Lamivudine 300 mg + Efavirenz 600 mg po daily
Symfi Lo
TDF + Lamivudine 300 mg + Efavirenz 400 mg po daily
Complera®
TDF + Emtricitabine 200 mg + Rilpivirine 25 mg po daily
Odefsey®
TAF + Emtricitabine 200 mg + Rilpivirine 25 mg po daily
Delstrigo™
TDF + Lamivudine 300 mg + Doravirine 100 mg po daily AW
Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. Available at

13. Combination Products Single Tablet Regimens (STRs)
Triumeq®
Abacavir + Lamivudine + Dolutegravir po daily
Stribild®
TDF + Emtricitabine 200 mg + Elvitegravir 150 mg + Cobicistat 150 mg po daily
Genvoya®
TAF + Emtricitabine 200 mg + Elvitegravir 150 mg + Cobicistat 150 mg po daily
Biktarvy®
TAF + Emtricitabine 200 mg + Bictegravir 50 mg po daily
Symtuza™
TAF + Emtricitabine 200 mg + Darunavir 800 mg + Cobicistat 150 mg po daily
Juluca®
Dolutegravir 50 mg + Rilpivirine 25 mg po daily
Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. Available at

14. Pathophysiology
REFERENCE

15. At least 3 active ARV agents
What ART to initiate?
2 NRTIs + 1 INSTI
2 NRTIs + 1 NNRTI
2 NRTIs + 1 PI
At least 3 active ARV agents
REFRENCE
Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. Available at

16. Which ART to initiate? Column A Column B NNRTI PI Integrase 2-NRTI
Preferred
Bictegravir
Dolutegravir
Elvitegravir/c
Raltegravir
Tenofovir/
Emtricitabine or
Abacavir/
Lamivudine
Alternative
Efavirenz Darunavir/r or c
Rilpivirine Atazanavir/r or c

17. Bictegravir, BIC 144 Week Study in ART Naïve patients
Adverse Drug Reactions
BIC = 0 discontinuations
DTG = 4
Pancreatitis/steatorrhoea
nausea/rash
Depression
thrombocytopenia
Week 48
BIC/FTC/TAF (n=316)
92.4%
difference −0·6%, 95·002% CI −4·8 to 3·6
p=0·78
BIC/3TC/ABC (n=315)
93%
Gallant J, et al. Lancet 2017;390(10107): doi: /S (17)

18. Bictegravir, BIC 48 Week Study in patient on DTG/3TC/ABC
Virologically suppressed for ≥ 3 months
Adverse Drug Reactions
BIC = 2% discontinuations
Headache, vomiting, CVA, Abnormal dreams, suicidal ideation
DTG = 1%
Headache, pruritis
Week 48
BIC/FTC/TAF (n=282)
93.6%
Difference: 0·7%, 95·002% CI: −1 to 2.8
p=0·59
BIC/3TC/ABC (n=281)
95%
Molina JM, et al. Switch to Bictegravir/F/TAF/ from DTG and ABC/3TC. CROI 2018 Abstract # 22.

19. Bictegravir, in Biktarvy, BIC
50 mg po daily w/ or w/out food
With TAF + FTC (Descovy)
Adverse Reactions
Similar to DTG
Diarrhea, nausea, headache
Increase in SCr by week 4 (by 0.1) (similar to DTG group)
Increase in T. bili (1-2.5 x ULN)
No discontinuations seen NP

20. Doravirine (DOR) 96 Week Study in ART Naïve patients
Adverse Drug Reactions
DOR = 2% discontinuations
EFV = 6% discontinuations
DOR had better psychiatric outcomes compared to EFV
Week 48
DOR/3TC/TDF (n=364)
84.3%
Difference: 3.5%, 95% CI: −2 to 9
EFV/FTC/TDF (n=364)
80.8%
Orkin C, et al. CID 2018; Aug 31. doi: /cid/ciy540.

21. Doravirine (DOR) 96 Week Study in ART Naïve patients
Either given TDF/FTC or ABC/3TC
Adverse Drug Reactions
DOR = 1% discontinuations
DRV/r = 2% discontinuations
Week 48
DOR (n=385)
84%
Difference: 3.9%, 95% CI: −1.6 to 9.4
DRV/r (n=384)
80%
Molina JM, et al. Lancet HIV 2018; 5(5):e211-e220. doi: /S (18)

22. Doravirine, Pifeltro™, DOR
Dose: 100 mg po daily w/ or w/out food
CYP3A4 substrate
Increase to 100 mg BID if given with rifabutin
Adverse Reactions:
Headache, fatigue, abnormal dreams, nausea
Peak plasma levels 2hr
Half-life: 15 hours
Co-formulated with Lamivudine and TDF NP

23. Regimen Simplification/De-esclation
Changing an effective regimen to a ‘simpler’ regimen
Ensure patient is adequately suppressed
Within Class:
Efavirenz to Rilpivirine
TDF to TAF
Raltegravir to Elvitegravir/Dolutegravir/Bictegravir
RTV boosted PI to coformulated COBI boosted PI
Less pill burden

24. HIV Switch/Simplification Strategies
Switching regimens when patients maintain a VL < 50 copies/ml and no documented mutations or previous failures
Stable for 6 months
Juluca 1 tablet po daily
Genvoya 1 tablet po daily
Stribild 1 tablet po daily
Odefsey 1 tablet po daily
Complera 1 tablet po daily
Stable for 3 months
Biktarvy 1 tablet po daily

25. Why Dolutegravir? Long plasma half-life = 15.3 hours
High barrier to resistance
Low incidence of severe toxicities
Minimal drug-drug interactions

26. Dolutegravir/Lamivudine (DTG/3TC)
GEMINI 1 and 2 Trials
Included:
ART naïve patients
HIV RNA ≤ 500,000 copies/ml
Intervention:
DTG/3TC or DTG+ TDF/FTC once daily x 48 weeks
New data results are being presented to FDA for prescribing information change
GEMINI-1
GEMINI-2
Pooled
Snapshot responders
DTG+3TC
320/356 (90%)
335/360 (93%)
655/716 (91%)
DTG+TDF/FTC
332/358 (93%)
337/359 (94%)
669/717 (93%)
Adjusted Difference (95% CI)
-2.6 (-6.7, 1.5)
-0.7 (-4.3, 2.9)
-1.7 (-4.4, 1.1)

27. Ibalizumab

28. Ibalizumab Mechanism of Action:
humanized‐monoclonal antibody
HIV post‐attachment inhibitor
HIV gp120 binds to domain 1 of CD4 receptors. Conformational changes in the receptor occur leading to…
Ibalizumab binds to domain 2 causing conformational changes preventing/changing binding of gp120 and co‐receptors
Co‐receptor binding (CCR5 or CXCR4). Conformational changes occur leading to…
Fusion of HIV to the CD4 membrane and subsequently viral entry and replication.

29. Ibalizumab Dose: Half‐life elimination: 3.1‐3.3 days
Loading Dose: 2000 mg x 1 dose IV followed by
Maintenance Dose: 800 mg every 2 weeks IV
Missed dose: If missed maintenance dose by ≥3 days,
re‐give loading dose and resume 2 week schedule
Half‐life elimination: 3.1‐3.3 days

30. Ibalizumab Efficacy: 40 subjects:
mean baseline VL was 100,287 copies/ml
median CD4 of 73 cells/mm3
Resistance seen:
93% to NRTIs; 93% to NNRTIs; 88% to PIs; 68% to INSTIs
Exhausted ARV classes
53% ≥ 3; 35% ≥ 4; 15% all
43% required fostemsavir as part of treatment (17/40 patients)
Safety: mild‐moderate: headache, rash, dizziness, diarrhea, nausea
9 discontinuations: 4 deaths (liver failure; KS; AIDS; lymphoma); 3 consent withdrawals; 1 lost to follow‐up
No anti‐ibalizumab antibodies or infusion related reactions (IRRs)
Lewis S, Fessel J, Emu B, et al. Long‐acting ibalizumab in patients with multi‐drug resistant HIV‐1: a 24 week study. Poster presented at CROI: Feb 13‐16,
2017; Seattle, WA. Poster 449LB.
Emu B, Fessel J, Schrader S, et al. 48 week safety and efficacy on treatment analysis of ibalizumab in patients with multi‐drug resistant HIV‐1. IDWeek; Oct
4‐8, 2017; San Diego, CA.

31. Ibalizumab

32. Fostemsavir Prodrug of temsavir (BMS-626529)
Binds to the HIV gp120 protein, preventing HIV and CD4 T-lymphocyte attachment
272 patients resistant to ≥2 classes of ART
Fostemsavir 600 mg BID x 8 day +failing regimen, then
Optimized background therapy
10% had no fully active ART in OBR
Day 8: 0.79 vs 0.17 log viral reduction (fostemsavir vs. placebo)
Will likely apply for FDA approval in 2019
Pialoux G et al. Phase 3 study of fostemsavir in heavily treatmentexperienced HIV-1-infected participants: BRIGHTE week 24 subgroup analysis in randomized cohort subjects. 22nd International ADIS Conference (AIDS 2018), 23–27 July 2018, Amsterdam. Poster abstract THPEB045.

33. HIV Pipeline Medications
Integrase Inhibitor
Cabotegravir oral and LA
Cabotegravir/Rilpivirine LA
Fusion Inhibitor
Albuvirtide
Monoclonal Antibodies
PRO 140
UB-421

34. Cabotegravir/Rilpvirine
Induction x 20 weeks
Oral CAB +ABC/3TC
At week 16 RPV was added
Discontinued when entering Maintenance period
In VL < 50 copies/ml, then eligible for Maintenance
Maintenance x 96 weeks
Virologic Suppression
IM CAB +RPV q 4 weeks (n=115)
87%
IM CAB + RPV q 8 weeks (n=115)
94%
Oral CAB + ABC/3TC (n=56)
84%
Margolis DA, et al. Long-acting intramuscular cabotegravir and rilpivirine in adults with Hiv-1 infection (LATTE-2): 96-week results of a randomized, open-label, phase 2b, non-inferiority trial. Lancet 2017;390:

35. Patient Example
54 y/o AAF with HIV, substance abuse, dyslipidemia, GERD
Patient has been on:
Etravirine and Trizivir x 4 years and controlled
Prior exposure:
Efavirenz, Atazanavir, Lopinavir/r, and Darunavir
Mutation: M184V (resistance to lamuvudine/emtricitabine)
Could this patient benefit from regimen simplification?

36. Patient Example: Key Points
Patient is currently stable and has been on the same regimen for years
Currently on a BID regimen
No exposure to INSTI

37. Objectives Identify previous and current guidelines for HIV treatment
All HIV infected patients should be offered HIV treatment
Changes in initial combination regimens recommended
Discussion of regimen simplification

38. Objectives
Describe clinical uses of recently marketed anti-retrovirals
Ibalizumab
Treatment simplification

39. Objectives
Describe the potential influence new anti-retrovirals will have on HIV management
Long-acting medications
New Entry Inhibitors
Multi-drug resistance

40. References
UNAIDS Global HIV & AIDS Statistics – 2018 fact Sheet:
CDC HIV in the United States: At a Glance:
MDH: HIV in Maryland, 2014: August 2016:
MDH: World AIDS Day 2013:
Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. Available at
CDC Understanding the HIV Care Continuum:
FDA What’s New at the FDA in HIV/AIDS:
Gallant J, et al. Lancet 2017;390(10107):
Molina JM, et al. CROI 2018 Abstract # 22.
Orkin C, et al. CID 2018; Aug 31.
Molina JM, et al. Lancet HIV 2018; 5(5):e211-e220.
Cahn P, et al. AIDS TUAB0106LB
Lewis S, et al. CROI Poster 449LB.
Emu B, et al. IDWeek 2017.
Pialoux G et al. AIDS Abstract THPEB045.
Margolis DA, et al. Long-acting intramuscular cabotegravir and rilpivirine in adults with Hiv-1 infection (LATTE-2): 96-week results of a randomized, open-label, phase 2b, non-inferiority trial. Lancet 2017;390:

41. HIV Medication Update Neha Sheth Pandit, PharmD, AAHIVP, BCPS
University of Maryland School of Pharmacy
Associate Professor, HIV/Infectious Diseases
September 2018

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