1. Infectious Disease and Internal Medicine Update for the Pharmacist- Focus on HIV
Dustin Wilson, PharmD, BCPS
Assistant Professor of Pharmacy Practice
Campbell University College of Pharmacy & Health Sciences
Clinical Faculty Pharmacist
Duke University Hospital
Co-Director Internal Medicine/Infectious Diseases/Academics Residency
Campbell University CPHS/Duke University Hospital

2. Disclosures
I have no relevant financial relationships with the manufacturers of any commercial products and/or providers of commercial services discussed in this CME activity

3. Objectives
Briefly review the epidemiology and pathophysiology of HIV infection
Discuss updates to the most recent adult and adolescent HIV treatment guidelines
Describe recently approved antiretroviral agents used to treat HIV infection in adults

4. Outline HIV epidemiology and pathophysiology – 10 min
Treatment guidelines updates – 10 min
Recently approved antiretroviral agents – 20 min
Wrap-up and questions – 10 min

5. Audience Poll
Pharmacist
Technician
Other
Inpatient
Outpatient
Other

6. Quiz
The number of new HIV infections per year in the US has _______ over the past decade?
Increased
Remained the same
Decreased

7. Epidemiology – United States

8. Epidemiology – United States

9. Epidemiology – United States
***2012 – ~1.2 million
More than 20% of these people are unaware of their infection
~1,148,200 adults and adolescents living with HIV infection at the end of 2009
1 in 5 are unaware of their infection
33% are prescribed ART
25% are virally suppressed
More than 13% of these people (1 in 8) are unaware of their infection
~1.2 million adults and adolescents living with HIV infection at the end of 2012
1 in 8 are unaware of their infection
36% are prescribed ART
30% are virally suppressed
2012 – ~1.2 million

10. Epidemiology – North Carolina
Epidemiologic profile from the NC dept of health and human services
Number of new HIV cases
2014 ~1351

11. Epidemiology – North Carolina

12. Epidemiology – North Carolina
Persons living with HIV/Aids in North Carolina

13. Pathophysiology
HIV attaches to and penetrates host T cells via CD4+ molecules and chemokine receptors (see Fig. 1: Breast Disorders: Breast examination.). After attachment, HIV RNA and enzymes are released into the host cell. Viral replication requires that reverse transcriptase (an RNA-dependent DNA polymerase) copy HIV RNA, producing proviral DNA; this copying mechanism is prone to errors, resulting in frequent mutations. These mutations facilitate the generation of HIV that can resist control by the host's immune system and by antiretroviral drugs. Proviral DNA enters the host cell's nucleus and is integrated into the host DNA in a process that involves HIV integrase. With each cell division, the integrated proviral DNA is duplicated along with the host DNA. Proviral HIV DNA is transcribed to viral RNA and translated to HIV proteins, including the envelope glycoproteins 40 and 120. The HIV proteins are assembled into HIV virions at the inner cell membrane and budded from the cell surface; each host cell may produce thousands of virions. After budding, protease, another HIV enzyme, cleaves viral proteins, converting the immature virion into a mature, infectious form.
Fusion of HIV with a target cell
The gp120 molecule of HIV first interacts with the CD4 antigen of the target cell.
Heparan sulfate proteoglycan stabilizes the interaction of the gp120 with CD4 antigen
This interaction induces a conformational change in the gp120 exposing sites that interact with the chemokine receptor (CCR5 or CXCR4)
This further stablizes the interaction and the virus fusion protein (gp41) is uncovered and also undergoes a conformational change
Gp41 inserts into the membrane of the host cell to initiate the fusion of the two bilayers  
EMBO reports 4, S1, S10–S14 (2003)

14. Updated Treatment Guidelines
Updated July 2016
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 Accessed September 10, 2016.

15. Quiz
Which of the following patients diagnosed with HIV infection should be started on antiretroviral therapy? Select all that apply.
35 year old male with oral thrush and CD4 count of 198
28 year old pregnant female with CD4 count of 400
31 year old male with CD4 count of 700
42 year old female with Pneumocystis jirovecii pneumonia and CD4 count of 100

16. What has changed over the past year?
Jan 2016
Start and Temprano studies
Both studies demonstrated about a 50% reduction in morbidity and mortality among HIVinfected individuals with CD4 counts >500 cells/mm3 randomized to receive ART immediately versus delaying initiation of ART (described in more detail below)
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 Accessed September 10, 2016.

17. The Evidence
Initiation of Antiretroviral Therapy in Early Asymptomatic HIV Infection. NEJM 2015;373(9):

18. The Evidence Study population
HIV-positive adult subjects who had a CD4 count > 500 and had not been initiated on ART
Interventions
Immediate-initiation ART vs deferred-initiation ART
Deferred initiated:
CD4 < 350
AIDS-related event
Primary endpoint
Serious AIDS-related events and serious non-AIDS-related events
Started recruiting patients in 2009
Initiation of Antiretroviral Therapy in Early Asymptomatic HIV Infection. NEJM 2015;373(9):

19. The Evidence Follow up 3 years Results Enrolled 4685 subjects
Immediate – 2326; Deferred – 2359
Primary endpoint
42 in the immediate group vs 96 in the deferred group
(95% CI ; p<0.001)
Interim analysis stopped study – the question had been answered.
Initiation of Antiretroviral Therapy in Early Asymptomatic HIV Infection. NEJM 2015;373(9):

20. The Evidence No. of participants: 2,413
A Trial of Early Antiretrovirals and Isoniazid Preventive Therapy in Africa. NEJM 2015;373(9):

21. The Evidence Study population
HIV-positive adult subjects who had a CD4 count < 800 and had not been initiated on ART
Interventions
2-by-2 factorial
Deferred ART
Deferred ART + isoniazid preventive therapy
Early ART
Early ART + isoniazid preventive therapy
Primary endpoint
Death from any cause, AIDS-defining disease, non-AIDS-defining cancer, non-AIDS-defining invasive bacterial disease
Started recruiting patients in 2008
A Trial of Early Antiretrovirals and Isoniazid Preventive Therapy in Africa. NEJM 2015;373(9):

22. The Evidence Follow up 30 months Results Enrolled 2076 subjects
849 (41%) had baseline CD4 counts > 500
Primary endpoint (patients with CD4 > 500)
23 in the early group vs 38 in the deferred group
(95% CI )
A Trial of Early Antiretrovirals and Isoniazid Preventive Therapy in Africa. NEJM 2015;373(9):

23. Quiz
Which class(es) of ART in combination with dual NRTI therapy is/are represented as Recommended regimens per guidelines for treatment naïve patients?
NNRTIs
PIs
Integrase inhibitors
A & B
B & C

24. What has changed over the past year?
Jan 2016 and July 2016
In this context, DRV/r may have an important role given the low rate of transmitted PI resistance, its high genetic barrier to resistance, and low rate of treatment-emergent resistance during many years of clinical experience
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 Accessed September 10, 2016.

25. Treatment Overview

26. Available Treatment Options
NRTIs
Zidovudine (Retrovir)
Didanosine (Videx EC)
Stavudine (Zerit)
Lamivudine (Epivir)
Abacavir (Ziagen)
Tenofovir disoproxil fumarate
(Viread) (TDF)
Emtricitabine (Emtriva)
Tenofovir alafenamide*** (TAF)
NNRTIs
Efavirenz (Sustiva)
Nevirapine (Viramune)
Delavirdine (Rescriptor)
Etravirine (Intelence)
Rilpivirine (Edurant)
PIs
Saquinavir (Invirase)
Ritonavir (Norvir)
Indinavir (Crixivan)
Nelfinavir (Viracept)
Fosamprenavir (Lexiva)
Lopinavir+ritonavir (Kaletra)
Atazanavir (Reyataz)
Tipranavir (Aptivus)
Darunavir (Prezista)
More than 25 approved agents in 6 different classes
***Only available as combo formulation
***Only available as combo formulations
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 Accessed September 10, 2016.

27. Available Treatment Options
Fusion inhibitor
Enfuvirtide (Fuzeon)
CCR5 antagonist
Maraviroc (Selzentry)
Integrase inhibitor
Raltegravir (Isentress)
Elvitegravir (Vitekta)
Dolutegravir (Tivicay)
Pharmacokinetic enhancers
Ritonavir (Norvir)
Cobicistat (Tybost)
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 Accessed September 10, 2016.

28. Available Treatment Options
Combination products
Combivir®
Lamivudine + zidovudine
Truvada™
Emtricitabine + tenofovir (TDF)
Epzicom®
Abacavir + lamivudine
Trizivir™
Abacavir + lamivudine + zidovudine
Atripla™
Efavirenz + tenofovir (TDF) + emtricitabine
Combination products
Complera™
Rilpivirine + tenofovir (TDF) + emtricitabine
Stribild™
Elvitegravir + cobicistat + tenofovir (TDF) + emtricitabine
Triumeq™
Dolutegravir + abacavir + lamivudine
Evotaz
Atazanavir + cobicistat
Prezcobix
Darunavir + cobicistat
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 Accessed September 10, 2016.

29. Available Treatment Options
Combination products
Genvoya®
Elvitegravir + cobicistat + tenofovir (TAF) + emtricitabine
Descovy
Tenofovir (TAF) + emtricitabine
Odefsey
Rilpivirine + tenofovir (TAF) + emtricitabine
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 Accessed September 10, 2016.

30. Tenofovir alafenamide (TAF)

31. Pathophysiology
HIV attaches to and penetrates host T cells via CD4+ molecules and chemokine receptors (see Fig. 1: Breast Disorders: Breast examination.). After attachment, HIV RNA and enzymes are released into the host cell. Viral replication requires that reverse transcriptase (an RNA-dependent DNA polymerase) copy HIV RNA, producing proviral DNA; this copying mechanism is prone to errors, resulting in frequent mutations. These mutations facilitate the generation of HIV that can resist control by the host's immune system and by antiretroviral drugs. Proviral DNA enters the host cell's nucleus and is integrated into the host DNA in a process that involves HIV integrase. With each cell division, the integrated proviral DNA is duplicated along with the host DNA. Proviral HIV DNA is transcribed to viral RNA and translated to HIV proteins, including the envelope glycoproteins 40 and 120. The HIV proteins are assembled into HIV virions at the inner cell membrane and budded from the cell surface; each host cell may produce thousands of virions. After budding, protease, another HIV enzyme, cleaves viral proteins, converting the immature virion into a mature, infectious form.
Fusion of HIV with a target cell
The gp120 molecule of HIV first interacts with the CD4 antigen of the target cell.
Heparan sulfate proteoglycan stabilizes the interaction of the gp120 with CD4 antigen
This interaction induces a conformational change in the gp120 exposing sites that interact with the chemokine receptor (CCR5 or CXCR4)
This further stablizes the interaction and the virus fusion protein (gp41) is uncovered and also undergoes a conformational change
Gp41 inserts into the membrane of the host cell to initiate the fusion of the two bilayers  
EMBO reports 4, S1, S10–S14 (2003)

32. Tenofovir alafenamide
Prodrug of tenofovir
Increased intracellular concentrations
Doses are < 1/10 of tenofovir (TDF)
Only available in combination products currently:
Elvitegravir/cobicistat/tenofovir alafenamide/emtricitabine (Genvoya)
Tenofovir alafenamide/emtricitabine (Descovy)
Rilpivirine/cobicistat/tenofovir alafenamide/emtricitabine (Odefsey)
disoproxil fumarate
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 Accessed September 10, 2016.

33. Elvitegravir/Cobicistat/Tenofovir alafenamide/Emtricitabine (Genvoya®)
FDA approved in November 2015
Indicated as a complete regimen for the treatment of HIV-1 infection in adults and pediatric patients 12 years of age and older:
Who are treatment naïve
Replace current ART regimen
Added as a Recommended regimen in the treatment guidelines for treatment naïve patients
Virologically suppressed <50, on a stable regimen for 6 months, and no mutations

34. Elvitegravir/Cobicistat/Tenofovir alafenamide/Emtricitabine (Genvoya®)
Available as a tablet
150 mg elvitegravir/150 mg cobicistat/200 mg emtricitabine/10 mg tenofovir alafenamide
Adult dosing
One tablet taken once daily with food
Dosage adjustments
Should not be initiated in patients with a CrCl < 30 ml/min
Not recommended in patients with severe hepatic impairment
Pharmacokinetic enhancer

35. Elvitegravir/Cobicistat/Tenofovir alafenamide/Emtricitabine (Genvoya®)
Drug Interactions
Many! Big chart in prescribing information
Elvitegravir  metabolized by CYP3A and is a CYP2C9 inducer
Cobicistat  metabolized by CYP3A and CYP2D6 and is a CYP3A and CYP2D6 inhibitor
Contraindicated
Alfuzosin
Rifampin
St. John’s wort
Simvastatin/lovastatin
Separate from antacids by 2 hours
Limit the use of NSAIDs

36. Elvitegravir/Cobicistat/Tenofovir alafenamide/Emtricitabine (Genvoya®)
Adverse reactions
Nausea (10%), diarrhea (7%), headache (6%), fatigue (5%)
Renal insufficiency (<3%)
Increase in Scr
Cobicistat inhibition of tubular secretion of creatinine
Watch for increase > 0.4 mg/dL in SCr
Decrease in BMD
Tubulopathy
No fanconi syndrome
Monitor PO4 in CKD
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 Accessed September 10, 2016.

37. Tenofovir alafenamide/Emtricitabine (Descovy®)
FDA approved in April 2016
Indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults and pediatric patients 12 years of age and older
Added as one of the Recommended dual NRTI regimens in the treatment guidelines for treatment naïve patients
Dolutegravir/Raltegravir/Darunavir + ritonavir  tenofovir alafenamide/emtricitabine

38. Tenofovir alafenamide/Emtricitabine (Descovy®)
Available as a tablet
200 mg emtricitabine/25 mg tenofovir alafenamide
Adult dosing
One tablet taken once daily with or without food
Dosage adjustments
Should not be initiated in patients with a CrCl < 30 ml/min
Not recommended in patients with severe hepatic impairment
Pharmacokinetic enhancer

39. Tenofovir alafenamide/Emtricitabine (Descovy®)
Drug Interactions
Contraindicated (strong inducers)
Rifampin
St. John’s wort
Phenytoin
Limit the use of NSAIDs
Adverse Reactions
Refer to slide 35

40. Take Home Points
Incidence of new HIV infections in the US is decreasing!
Early ART regardless of CD4 count is beneficial
Tenofovir alafenamide (TAF)
Decreased adverse effects on renal markers and BMD compared to tenofovir (TDF)
Increased lipids

41. Take Home Points
Elvitegravir/Cobicistat/Tenofovir alafenamide/Emtricitabine (Genvoya®)
Cost ~$3,100/month
Should not be initiated in patients with a CrCl < 30 ml/min
Elvitegravir/Cobicistat/Emtricitabine/Tenofovir (Stribild®)
Cost ~ $3,250/month
Should not be initiated in patients with a CrCl < 70 ml/min
Discontinue therapy in patients with a CrCl < 50 ml/min

42. Take Home Points Tenofovir alafenamide/Emtricitabine (Descovy®)
Cost ~$1,760/month
Should not be initiated in patients with a CrCl < 30 ml/min
Being evaluated for PrEP
Tenofovir (TDF)/Emtricitabine (Truvada)
Cost ~$1,760/month
Renal dose adjustments starting at CrCl < 50 ml/min
Approved for PrEP

43. Basic Statistics. http://www. cdc. gov/hiv/basics/statistics. html
Basic Statistics. Accessed September 10, 2016 New HIV Infections in the United States. Accessed September 10, 2016 HIV and AIDS in the United States of America (USA). Accessed September 10, 2016 HIV in the United States: At a Glance. Accessed September 10, 2016 HIV Incidence Estimate in North Carolina. Accessed September 10, 2016 North Carolina HIV/STD Surveillance Unit. (2015) North Carolina HIV/STD Epidemiologic Profile. North Carolina Department of Health and Human Services, Raleigh, North Carolina. Accessed September 10, 2016 North Carolina Epidemiologic Profile for HIV/STD Prevention and Care Planning. Accessed September 10, 2016 Weiss R. HIV and AIDS in relation to other pandemics. EMBO reports 2003;4:S10-S14.

44. Panel on Antiretroviral Guidelines for Adults and Adolescents
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 Accessed September 10, Initiation of Antiretroviral Therapy in Early Asymptomatic HIV Infection. NEJM 2015;373(9): A Trial of Early Antiretrovirals and Isoniazid Preventive Therapy in Africa. NEJM 2015;373(9): Genvoya [package insert]. Gilead Sciences, Inc., Foster City, CA; September Descovy [package insert]. Gilead Sciences, Inc., Foster City, CA; April 2016.

45. Infectious Disease and Internal Medicine Update for the Pharmacist- Focus on HIV
Dustin Wilson, PharmD, BCPS
Assistant Professor of Pharmacy Practice
Campbell University College of Pharmacy & Health Sciences
Clinical Faculty Pharmacist
Duke University Hospital
Co-Director Internal Medicine/Infectious Diseases/Academics Residency
Campbell University CPHS/Duke University Hospital