1. Community Pharmacy Considerations for HIV & HCV Therapy
Larry Pineda, PharmD, PhC, BCPS, AAHIVP
Visiting Assistant Professor
UNM College of Pharmacy

2. Conflicts of Interest Disclosure
No conflicts of interest

3. Learning Objectives – Pharmacist
List the DHHS recommended HIV antiretroviral regimens
Describe current HCV direct-acting antivirals
Discuss the importance of adherence counseling for HIV antiretrovirals and HCV direct-acting antivirals
Recognize common prescription and nonprescription drug interactions with HIV antiretrovirals and HCV direct-acting antivirals

4. Learning Objectives – Pharm Tech
Identify common HIV antiretrovirals and HCV direct-acting antivirals
State the minimum number of antiretroviral drugs in an appropriate HIV antiretroviral regimen
Understand the importance of adherence counseling for HIV antiretrovirals and HCV direct-acting antivirals
Describe the impact of drug-drug interactions with HIV and HCV medications 

5. HIV therapy considerations

6. HIV Antiretroviral Therapy
Inhibit viral replication
HIV life cycle
Antiretroviral drugs target key steps in replication
Figure:

7. HIV Antiretroviral Therapy
Entry inhibitors
Attachment
Selzentry (maraviroc)
Fusion
Fuzeon (enfuvirtide)
Reverse transcriptase inhibitors
Nucleoside
Truvada (tenofovir disoproxil (TDF)/emtricitabine)
Descovy (tenofovir alafenomide (TAF)/emtricitabine)
Epzicom (abacavir/lamivudine)
Non-nucleoside
Sustiva (efavirenz)
Edurant (rilpivirine)

8. HIV Antiretroviral Therapy
Integrase strand transfer inhibitors
Isentress (raltegravir)
Vitekta (elvitegravir)
Always with cobicistat (booster)
Tivicay (dolutegravir)
Protease inhibitors
Prezista (darunavir)
Reyataz (atazanavir)
Norvir (ritonavir)

9. DHHS Recommended Agents
Updated July 2016
Available at:
5 recommended HAART regimens:
4 integrase-based regimens
1 protease inhibitor-based regimen

10. Integrase-Based Regimens
Single tablet
Triumeq (dolutegravir/abacavir/lamivudine)
Genvoya (elvitegravir/cobicistat/TAF/emtricitabine) or
Stribild (elvitegravir/cobicistat/TDF/emtricitabine)
Two tablet
Dolutegravir + TDF/emtricitabine or TAF/emtricitabine
Raltegravir* + TDF/emtricitabine or TAF/emtricitabine
*Twice daily dosing

11. Protease Inhibitor-Based Regimen
Darunavir/ritonavir + TDF/emtricitabine or TAF/emtricitabine
Atazanavir based regimens moved to alternative
Non-nucleoside reverse transcriptase inhibitor based regimens on alternative list
Entry inhibitors typically reserved for patients with resistance to recommended agents

12. What is the minimum number of antiretroviral agents that should be included in an ideal HIV treatment regimen?

13. HAART Highly Active Anti-Retroviral Therapy
3 active antiretroviral drugs
2 nucleoside reverse transcriptase inhibitors
Plus 3rd active agent:
Integrase strand transfer inhibitor
Non-nucleoside reverse transcriptase inhibitor
Protease inhibitor with pharmacokinetic enhancer (cobicistat, ritonavir)
Goal: undetectable HIV viral load
Adherence critical for success

14. What is the percentage of adherence to HAART needed for optimal virologic supression?

15. Virologic Impact of Adherence
Adherence to a regimen is essential to optimize therapeutic outcomes and is important in terms of evolution of resistance
In order to achieve optimal suppression (or virologic response) it requires the patient to have almost perfect adherence
Microelectronic monitoring system
Patterson DL et al. Ann Intern Med. 2000;133:21-30

16. Virologic Impact of Adherence
Adherence was estimated using pharmacy refill data in 886 treatment-naive individuals in British Columbia followed prospectively for a median of 19 months after starting ART. Of the 502 individuals at the % adherence rate, 84% achieved plasma viral loads <500 copies/mL, whereas only 64% of the 64 people at the 90% to <95% adherence rate achieved this level of suppression (p = 0.001). Thus, while adherence measurement with MEMS caps and pharmacy refill data may not be strictly comparable, this study also found that near-perfect levels of adherence are required for reliable viral suppression.
Low-Beer S, Yip B, O'Shaughnessy MV, Hogg RS, Montaner JS. Adherence to triple therapy and viral load response. J Acquir Immune Defic Syndr 2000; 23:360-1.
Low-Beer S et al. J Acquir Immune Defic Syndr. 2000; 23:360-1

17. Adherence Considerations
Do not assume prescriber has provided education
Monitor refill history
Offer adherence devices
Pill box
Blister packaging
Reminders (alarms, logs, apps, visual med calendar)
Recognize “outdated” regimens
Screen for polypharmacy
Avoid treatment gaps

18. Antiretroviral Considerations
Do not dispense partial regimens
Question regimens with < 3 agents
Truvada for preexposure prophylaxis (PrEP) and nuc-sparing regimens are exception
Recognize “outdated” regimens
Quality of life
Assist with prior authorizations
Facsimile response monitoring
Drug interactions
Alert fatigue

19. Drug Interactions New agents have less drug interactions
Are not void of interactions
Keep in mind OTC/supplements/herbals
Bookmark key resources
Don’t assume provider has checked

20. Integrase Inhibitors Low drug interactions Polyvalent cations
Ca++, Fe++, Mg++, Zn++, Al+++
Chelate integrase inhibitors
Does not include food products
Maalox, Tums, multivitamins
Administer 2 hours before or 6 hours after taking products containing polyvalent cations

21. St. John’s Wort Induction of UGT1A1 and CYP3A4
Decreased dolutegravir exposure
Decreased elvitegravir/cobicistat concentrations
Potentially decreased raltegravir exposure
Decreased darunavir concentrations

22. Herbals Induce CYP3A4 Inhibit CYP3A4 Garlic supplements Ginkgo biloba
Can induce CYP3A4 and/or P-gp
Inconsistent data on allicin containing formulations
Does not apply to dietary exposure
Dolutegravir, ritonavir and cobicistat
Ginkgo biloba
Inhibit CYP3A4
Grapefruit, goldenseal, ginseng
Grapefruit juice can inhibit cytochrome P450 3A4 (CYP3A4)

23. Pharmaceutical Boosters
Ritonavir and cobicistat
Inhibit CYP3A4, others vary
Anticoagulants
Warfarin (R enantiomer)
Monitor INR
Apixaban, dabigatran, rivaroxaban, ticagrelor
Avoid concomitant use
Anticonvulsants
Carbamazepine, phenobarbital, phenytoin
Decreases dolutegravir – UGT1A1, CYP3A4 induction
Alternative – levetiracetam (Keppra)
Warfarin is a mixture of enantiomers which are metabolised by different cytochromes. R-warfarin is primarily metabolised by CYP1A2 and 3A4. S-warfarin (more potent) is metabolised by CYP2C9. Cobicistat could potentially increase warfarin concentrations by inhibition of CYP3A4. Monitor INR during coadministration and for the first weeks after stopping cobicistat.
Ritonavir induces CYP2B6, CYP2C9 instead of inhibit

24. Corticosteroids Interaction with both ritonavir and cobicistat
Cushing’s syndrome, adrenal suppression
Intranasal
Fluticasone (Flonase)*
Triamcinolone (Nasacort)*
Budesonide (Rhinocort)*
Inhaled
Fluticasone/salmeterol (Advair)
Budesonide/formoterol (Symbicort)
Alternative
Beclomethasone (QVAR, QNASL)
*available over the counter

25. Serotonin Reuptake Inhibitor (SSRI)
Paroxetine, fluoxetine, citalopram
Metabolized by CYP2D6
Ritonavir inhibits metabolism
Increased SSRI exposure
Sertraline
Metabolized by CYP2B6
Ritonavir induces metabolism
Decreased SSRI exposure

26. Drug Interaction Resource
Not all inclusive…resource
Also available as an app: hivichart

27. Hcv therapy considerations

28. Abbreviations SVR: sustained virologic response IFN: interferon
RBV: ribavirin
Peg: pegylated
BOC: boceprevir
TPV: telaprevir
SMV: simeprevir
SOF: sofosbuvir
PrOD: paritaprevir/ritonavir + ombitasvir + dasabuvir
PrO: paritaprevir/ritonavir + ombitasvir
DCV: daclatasvir
EBR/GZR: elbasvir/grazoprevir
LDV/SOF: ledipasvir/sofosbuvir
SOF/VEL: sofosbuvir/ velpatasvir
Reference

29. HCV Treatment Historically complex therapy
Gastroenterology, hepatology, infectious diseases
Severe side effects, injectable
Low cure rates
Advent of new direct acting all oral medications has simplified management
Less side effects
Shorter duration
Higher cure rates
Goal of treatment is SVR
New agents highly effective SVR rates >90%

30. Evolution of HCV Treatment
2014
2016
LDV/SOF
DCV+ SOF
EBR/ GZR
SOF/ VEL
BOC and TPV
2013
PrOD
SOF
SMV
>90
>90
>90
>90
>90
100
89+
80+
PegIFN
2011 80
RBV
2001
Standard
IFN
70+
1998 60 55
SVR (%)
1991 42 39 40 34
Focus on how many are approved recently
Treatment for HCV has evolved dramatically. On the y-axis, you see here the % of patients expected to achieve cure-defined as sustained virologic response, or SVR. On the x-axis are the various HCV therapies. For nearly two decades the standard of care was an interferon based regimen for 6-12 months, combined with ribavirin resulting in, at best, 50% of patients achieving cure with a year’s worth of treatment.
In 2011, the first generation of direct-acting antivirals were approved- boceprevir and telaprevir. Although these agents markedly improved SVR rates, in addition to the toxicities and laboratory abnormalities of interferon, these early agents were also plagued by substantial side effects and a high pill burden.
By 2014, we entered a new era of therapy hallmarked by the ability to treat with an all-oral regiment, sparing the need for interferon, with few side effects and, more importantly high cure rates with abbreviated courses of treatment. In the last year, in addition to simeprevir, sofosbuvir, ledipasvir-sofosbuvir combination tablet, and paritaprevir boosted with ritonavir, ombitasvir, and dasabuvir, daclatasvir was approved in combination with sofosbuvir and most recently, in Jan 2015, the combination of elbasvir/grazoprevir was approved in the US. 20 16 6
PegIFN/
RBV/
BOC or TPV
6-12 mos
IFN
12 mos
IFN/RBV
6 mos
IFN/RBV
12 mos
PegIFN
12 mos
PegIFN
RBV 12 mos
PegIFN/
RBV/
SMV
24-48 wks
PegIFN/
RBV/
SOF
12-24 wks
LDV/ SOF
8-12 wks
PrOD + RBV
12-24 wks
SOF + DCV
12 wks
IFN
6 mos
EBR/ GZR
12-16 wks
SOF/ VEL
12 wks
Slide courtesy Paulina Deming, PharmD, PhC

31. Key Differences in HCV Therapy
PegIFN Based Therapy
Direct Acting Antivirals
Injections
Significant laboratory abnormalities
Pancytopenias
Ribavirin  hemolytic anemia
Substantial side effect profile
Limited use in advanced liver disease
Limited drug interaction potential
Low SVR
All oral
Limited laboratory abnormalities
Ribavirin  hemolytic anemia
Low side effect profile
Variable drug interaction potential
Variable use in advanced liver disease
High SVR
Emerging concerns for HCV resistance

32. HCV Treatment Highlights
Guided by HCV genotype
G1a most common in US
Finite duration of treatment
Typically ~12 weeks
Adherence vital for treatment success
Retreatment
Lower SVR rates
Longer duration, + ribavirin
Cost of treatment high

33. Cost of HCV Treatment

34. HCV Drug Targets Ribavirin Boceprevir (BOC) Telaprevir (TVR)
Core E1 E2 P7
NS2
NS3 4A
NS4B
NS5A
NS5B
5’UTR
3’UTR
NS3 Protease Inhibitors
NS5A Replication Complex Inhibitors
NS5B Polymerase
(Nucleotide) Inhibitors
NS5B Polymerase
(Non-nucleotide) Inhibitors
Ribavirin
Boceprevir (BOC)
Telaprevir (TVR)
Simeprevir (SMV)
Paritaprevir (PTV)
Grazoprevir (GRZ)
Daclatasvir (DCV)
Ledipasvir (LDV)
Ombitasvir (OMV)
Elbasvir (EBR)
Velpatasvir (VEL)
Sofosbuvir (SOF)
Dasabuvir (DSV)
Pulled from market
This diagram shows the proteins encoded by HCV genome, and where DAAs target their activity against the virus
Slide courtesy Monique, Dodd, PharmD, MLS(ASCP)

35. HCV Direct Acting Antivirals (DAAs)
Target
NS3/4A: Protease Inhibitors
(-previr)
NS5A: Replication Complex Inhibitors
(-asvir)
NS5B: Polymerase Inhibitors
(-buvir)
DAA
Boceprevir*
Telaprevir*
Simeprevir
Paritaprevir
Grazoprevir
Ledipasvir
Ombitasvir
Daclatasvir
Elbasvir
Velpatasvir
Nucleotide: Sofosbuvir
Non-nucleoside: Dasabuvir
Currently available DAAs fall into 1 of 3 categories
* Pulled from market

36. Treatment Resources
Joint guidelines of the American Association for the Study of Liver Diseases (AASLD) and Infectious Diseases Society of America (IDSA)
Updated frequently – check online for most current version of guidelines
Available at:
Hepatitis C Online (Univ. of Washington)
HCV medication information, calculators, guidance
HCV course (modules)

37. Pharmacy Considerations
High cost – specialty pharmacy
High copays, patient assistance networks
Avoid treatment gaps
Time it takes to order medication
Counseling:
Adverse effects
Adherence
Despite short, finite duration
Drug interactions

38. Side Effect Profile of DAAs
Most commonly reported side effects:
Headache
Fatigue
Nausea
Most common laboratory abnormalities:
ALT elevations with PrOD and ethinyl-estradiol use; ALT elevations with EBR/GZR
Anemia with concomitant use of ribavirin
Ribavirin causes hemolytic anemia
Overall well tolerated

39. What is the percentage of adherence to HCV DAAs needed for optimal outcome?

40. HCV Therapy Adherence
No published literature on DAA adherence correlation to SVR
Optimal adherence yet to be determined
Recommend 100% adherent to DAAs
Adherence assessment and counseling at all healthcare encounters

41. Drug Interaction Concerns for DAAs
Overall have low potential for drug-drug interactions
Amiodarone with sofosbuvir and other DAA
Serious symptomatic bradycardia
Potential for other drugs to lower DAA concentrations
Strong CYP3A inducers (e.g. carbamazepine, oxcarbazepine, phenobarbital, phenytoin)
Strong intestinal P-glycoprotein inducers (e.g. rifampin)
St. John’s wort (avoid all herbals/supplements)
Statins
Interactions vary by DAA and statin

42. Acid Suppressive Therapy
Ledipasvir and velpatasvir solubility decreases with increases in pH
Requires acidity for absorption – greatest concern with velpatasvir
Antacids
Separate administration by 4 hours
H2RAs
Administered simultaneously with or 12 hours apart
PPIs
Can be administered simultaneously if medically necessary

43. Drug Interaction Resource
Liverpool – England so some spelling is different (less is more sometimes when searching for meds) acyclovir for example, spelled aciclovir
Also available as an app: hepichart

44. Patient Case
DD is a 48 year old HIV+ male with HCV coinfection. His provider has prescribed Harvoni (ledipasvir/sofosbuvir) x 12 weeks.
Medications: famotidine prn heartburn, Tums prn heartburn, dolutegravir, emtricitabine/TDF, acyclovir
No known drug allergies

45. What relevant drug interactions would you notify prescriber about?

46. Questions/considerations?