hiv antiretroviral review and pharmacist impactrecognize clinically significant drug-drug...

HIV Antiretroviral Review and Pharmacist Impact

LT David Moore, PharmD

United States Public Health Service

PGY-1 Pharmacy Resident

Alaska Native Medical Center – Alaska Native Tribal Health Consortium

Disclosures

I do not have (nor does any immediate family member have) a vested interest in or affiliation with any corporate organization offering

financial support or grant monies for this continuing education activity, or any affiliation with an organization whose philosophy could

potentially bias my presentation

Objectives

1. Review current guideline recommendations for HIV pharmacotherapy and prophylaxis

2. Recognize clinically significant drug-drug interactions involving HIV antiretrovirals

3. Discuss the role of pharmacists in intervention strategies to improve clinical outcomes for HIV patients

Pre-assessment

Question 1:

HIV guidelines recommend initiation with at least 3 agents representing at least two mechanisms in ARV-naïve patients.

a. True

b. False

Pre-assessment

Question 2:

AK is a 28 yo M currently taking omeprazole 20mg daily, sertraline 50mg daily, cetirizine 10mg daily and dolutegravir-rilpivirine 50mg-25mg once daily. After reviewing the medication list you:

a. Recommend substituting the ARV regimen due to an interaction with omeprazole

b. Recommend substituting omeprazole due to an interaction with the ARV regimen

c. Recommend increasing the omeprazole dose to compensate for an interaction with the ARV regimen

d. Recommend revision of the HIV ARV regimen – it is currently incomplete and there are no clinically significant drug interactions

Pre-assessment

Question 3:

Progression of HIV infection can increase the risk of which of the following? Select all that apply:

a. Opportunistic infections

b. Diabetes Mellitus

c. MI & Stroke

d. Acquired Immunodeficiency Syndrome (AIDS)

HIV: Epidemiology

HIV Update (DHHS: Alaska Section of Epidemiology – 2018)

• December 31, 2018: 699 persons with HIV

• 54% with history of AIDS

• 75% male

• 39% white, 29% AN/AI, 14% black, 8% other

• 58 cases were reported in 2018 (38% were new diagnoses)

• 94% were reported as receiving medical care

• 89% were considered virally suppressed (<200 copies/mL)

48%

27%

9%

8%

7%

1%

Transmission Category

MSM

Heterosexual

IVDU

Other

MSM/IVDU

Perinatal

HIV: Pathogenesis

• Human Immunodeficiency Virus is a retrovirus that uses host cellular machinery for replication

• CD4+ T cell involvement – underlying mechanism for immunodeficiency

• Modern ARV therapy targets multiple steps of the HIV lifecycle

Gandhi M, Gandhi RT. Single-pill combination regimens for the treatment of HIV-1 infection. N Engl J Med. 2014; 371:248-259

HIV: Pathogenesis

• The virus may not be detectable until seroconversion – potentially months following primary infection

• Immunosuppression will eventually manifest clinically several years later

• Acquired Immunodeficiency Syndrome will eventually result with more severe symptoms

• AIDS-defining illness or CD4+ <200 cells/mm

Naif HM. Pathogenesis of HIV Infection. Infect Dis Rep. 2013;5(Suppl 1):e6. Published 2013 Jun 6. doi:10.4081/idr.2013.s1.e6 U.S. Department of Health and Human Services: AIDS info. Understanding HIV/AIDS: HIV Overview. Available at: https://aidsinfo.nih.gov/understanding-hiv-aids/fact-sheets/19/45/hiv-aids--the-basics. Updated July 3, 2019.

https://aidsinfo.nih.gov/understanding-hiv-aids/fact-sheets/19/45/hiv-aids--the-basics













Clinical Guidelines

AIDSinfo: https://aidsinfo.nih.gov/ • Guideline summaries • Drug information summaries • Patient education resources • Clinical trial database

https://aidsinfo.nih.gov/

Clinical Guidelines: HIV Prophylaxis (PrEP)

• Daily oral prophylaxis with Emtricitabine/Tenofovir disoproxil fumarate (Truvada®)

• Sexually active adult men and women considered at substantially high risk of HIV acquisition

• Adults who inject illicit substances

• Tenofovir disoproxil fumarate may be used alone in adults injecting illicit substances

(requires high adherence)

• Emtricitabine/Tenofovir Alafenamide (Descovy®) was recently approved in October of 2019 for use as PrEP after a study showed non-inferiority to Truvada® at 48 and 96 weeks

*This study did not include cisgender women

• These are the only agents with FDA approval – substitutions are not recommended

• Insufficient data on efficacy and safety in adolescents

Clinical Guidelines: HIV Prophylaxis (PEP)

• Regimen should contain 3 or more agents for occupational exposures

• Initiate within 72 hours

• Complete 4 week duration

Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV. Department of Health and Human Services. Available at http://aidsinfo.nih.gov/contentfiles/lvguidelines/AdultandAdolescentGL.pdf. Accessed December 29, 2019.

http://aidsinfo.nih.gov/contentfiles/lvguidelines/AdultandAdolescentGL.pdf

Clinical Guidelines: HIV Prophylaxis (nPEP)

• Initiation is determined by case-based risk of transmission if care is sought < 72 hours of exposure

• Recommend a 28-day duration of a 3-drug regimen

• Regimens with INSTI component are preferred

• PrEP should be considered depending on individual risk or receipt of nPEP within the last year



Clinical Guidelines: HIV Treatment (adults) • Immediate initiation of ARV therapy

• Initial treatment: 2 nucleoside reverse transcriptase inhibitors (NRTIs) in combination with:

• integrase strand transfer inhibitor (INSTI)

• non-nucleoside reverse transcriptase inhibitor (NNRTI)

• boosted protease inhibitor (PI)

• *Recent update: Initial treatment option - dolutegravir/lamivudine (Dovato®)



Clinical Guidelines: HIV Treatment (adults)

• Certain clinical situations may justify the use of alternative regimens with less data

Clinical Guidelines: HIV Treatment (pregnancy)

• Dolutegravir is recommended as a preferred agent irrespective of trimester

• Dolutegravir is shown to have higher rates of viral suppression and faster decline – risk of neural tube defects is minimal after 6 weeks gestation

• Co-administration of folic acid 400mcg daily is recommended in those potentially conceiving due to the increased risk of neural tube defects

Panel on Treatment of Pregnant Women with HIV Infection and Prevention of Perinatal Transmission. Recommendations for the Use of Antiretroviral Drugs in Pregnant Women with HIV Infection and Interventions to Reduce Perinatal HIV Transmission in the United States. Available at http://aidsinfo.nih.gov/contentfiles/lvguidelines/PerinatalGL.pdf. Accessed December 29, 2019.

http://aidsinfo.nih.gov/contentfiles/lvguidelines/PerinatalGL.pdf

Clinical Guidelines: HIV Treatment (pregnancy)

• Alternative regimens that otherwise pose unwanted toxicities may be considered due to advantages required during pregnancy




Clinical Guidelines: HIV Treatment (neonates)

• Newborns exposed perinatally should be treated immediately after birth



Clinical Guidelines: HIV Treatment (pediatrics)

• Recommend immediate initiation (1-2weeks) for those <12 months, otherwise assess plan for adherence prior to initiation

• Therapy should be individualized based on regimen and patient characteristics

Panel on Antiretroviral Therapy and Medical Management of Children Living with HIV. Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection. Available at http://aidsinfo.nih.gov/contentfiles/lvguidelines/pediatricguidelines.pdf. Accessed December 29, 2019.

http://aidsinfo.nih.gov/contentfiles/lvguidelines/pediatricguidelines.pdf

Clinical Guidelines: HIV Treatment (pediatrics) • Alternative regimens have shown efficacy but clinical use is limited and some may entail difficult

administration

Panel on Antiretroviral Therapy and Medical Management of Children Living with HIV. Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection. Available at http://aidsinfo.nih.gov/contentfiles/lvguidelines/pediatricguidelines.pdf. Accessed December 29, 2019.


HIV and Comorbidities

Cardiovascular Disease: (MI & Stroke)

• Recent studies have shown increased MI and stroke risk due to low CD4+ count and high HIV viremia

• Elevated levels of inflammatory markers as well as immune activation markers have been associated with increased risk of coronary atherosclerosis and plaque progression

• HIV infection is also related to metabolic changes that contribute to CVD

• ARV therapy including certain PIs and NRTIs may also contribute to increased ASCVD risk


Cardiovascular Disease (Heart Failure)

• Studies also show increased risk of systolic and diastolic HF (1.5 to 2 times greater) in HIV-infected individuals likewise, due to low CD4+ and high viral load

• HIV-infection contributes to multiple mechanisms that may result in heart failure: • Vascular stiffness (ARV use)

• Inflammation

• Immune and autonomic dysregulation

• Metabolic dysfunction


Cardiovascular Disease

• Grand, et al. conducted a meta-analysis on cardiovascular risk in those infected with HIV

• This study found the pooled prevalence of moderate to high cardiovascular risk was 20.41% (95% CI: 16.77-24.31)

• The most prevalent individual risk factors were: • Dyslipidemia (39.5%)

• Smoking (33%)

• Hypertension (19.8%)

• Diabetes (7.24%)

• DAD (Data Collection on Adverse Events of Anti-HIV Drugs) – investigated the association of PIs and NRTIs with MI risk in over 23,000 HIV-infected patients

• Relative rate of MI/year: PI 1.16 (95% CI: 1.1 – 1.23) NRTI 1.05 (95% CI: 0.98 – 1.13)

• Adjustment for serum lipid levels maintained a 10% difference in the relative rate/year

• There was no association detected between CD4+ nadir and peak HIV-1 RNA level



ASCVD Risk in HIV:

ACC/AHA has published a modified risk assessment algorithm



ASCVD Risk in HIV:

• Incorporates risk-enhancing factors

• Based on 1.5-2 x increased risk of ASCVD associated with high viral load, low CD4+ or delayed initiation of therapy



ASCVD Risk in HIV:

• Statin therapy: • Pravastatin and pitavastatin – minimal CYP450 involvement

• Observational cohorts show statins (except simvastatin and lovastatin) can be safely used

• Randomized studies have suggested that both pitavastatin and rosuvastatin may also effectively reduce certain immune and inflammatory markers as well as improvement of vascular inflammation

• REPRIEVE – ongoing randomized trial investigating CV benefit of statin therapy in low-moderate risk patients


Diabetes Mellitus

• HIV has been associated with increased insulin-resistance • Increased inflammatory cytokines stimulated by lipodystrophy (increased CRP and leptin levels in metabolic syndrome)

• Potential association through growth hormone dyscrasias

• Hernandez et al. assessed prevalence of diabetes mellitus using data from a national survey system: Medical Monitoring Project

• Reported prevalence amongst HIV-infected individuals as 3.8% higher than non-infected

• DM associated independently with: age, obesity, duration of HIV, and mean CD4+

• Samad et al. analyzed data from 1065 HIV-infected patients followed over 13 years for incidence and risk factors associated with diabetes

• Reported incidence 1.39 times higher than non-infected individuals in the same area

• Incidence was associated with longer durations of ARV therapy and more severe progression of HIV infection (increased viral load and decreased CD4)


Diabetes Mellitus

• HIV-ARV therapy may contribute to hyperglycemia • Particular protease inhibitors have been shown to contribute to lipodystrophy, dyslipidemia and insulin

resistance

• Mediated by interference and inhibition of GLUT-4 and PPAR receptors

• Brown et al. studied diabetes prevalence in the context of ARV therapy over a 4-year follow-up period:

• Prevalence ratios compared with non-infected:

• HIV-infected individuals 2.21 (95% CI: 1.12-4.38)

• HIV-infected individuals on ARV 4.64 (95% CI: 3.03-7.10)

• ARV therapy included:

• PI: lopinavir, indinavir, nelfinavir, saquinavir, amprenavir, ritonavir

• NNRTI: efavirenz, nevirapine, delavirdine mesylate


Immunizations (CDC 2019)

• Influenza

• Hepatitis B

• Human Papillomavirus (< 26yr.)

• Meningococcal

• Pneumococcal

• Tetanus, diphtheria and pertussis

*Encourage meeting with a provider for travel-specific indications

Administration: Drug-Drug Interactions

Absorption

• Acid-altering medications:

H2RAs/PPIs/antacids may decrease absorption of drugs requiring gastric acidity (rilpivirine, atazanavir, tipranavir)

This interaction may be avoided by separate administration times by several hours

*PPIs are contraindicated and substitution is recommended

• Polyvalent cations:

Decrease intestinal absorption via cationic chelation (INSTIs)

• P-gp efflux transporter:

Substrates are normally pumped back into intestinal lumen (INSTIs, PIs, NRTIs)

Administration: Drug-Drug Interactions Metabolism

• CYP450: *3A4 – most common pathway Substrates: INSTIs, PIs, NNRTIs, CCR5 antagonist Inhibitors: PIs, Etravirine, Elvitegravir Inducers: PIs, NNRTIs

• UGT1A1: Primary enzymatic pathway for INSTIs PIs may inhibit/induce

Pharmacokinetic Boosters

Ritonavir and Cobicistat: Strong inhibitors of CYP3A4 Utilize metabolic interaction to boost exposure of 3A4 substrates (PIs)

Administration: Food Medication Take WITH food Take WITHOUT food

NRTIs

Stavudine X

Tenofovir Disoproxil Fumarate X

NNRTIs

Efavirenz X

Etravirine, Rilpivirine X

INSTIs

Dolutegravir, Elvitegravir X

PIs/boosters

Atazanavir, Darunavir, Ritonavir, Saquinavir, Tipranavir, Cobicistat

X

Fixed Dose Regimens

Atripla X

Truvada, Stribild, Genvoya X

Medication Adherence

• Medication intolerance and poor adherence are the most common reasons for treatment failure and emergence of resistance

• Sethi et al. • Cohort of 310 patients and found an association with 70-89% regimen adherence and the

development of clinically significant HIV drug resistance

• Nonadherence has also been associated with increased AIDS-related morbidity, mortality and hospitalization

• Hogg et al. • Population-based analysis of 1,282 patients for all-cause mortality found adherence rates of

<75% to be significantly associated with mortality (almost 3 times more likely).

RR=2.97 (95% CI: 1.33-6.62; p=0.008)

Medication Adherence

• Counsel patients on the importance of daily adherence to prevent the development of drug-resitant HIV

• Assist patients with strategies to increase adherence: • Utilize pill boxes/routine synchronization

• Provide extra vials/containers depending on need

• AIDSinfo App – consumer & healthcare professional versions

• Encourage enrollment in refill adherence programs

Pharmacist Impact

• Understand the contribution of HIV infection to the risk and severity of comorbidities

• Incorporate understanding of individual ARV agent risks and effects on comorbidities into review of patient medication lists

• Review clinical relevance of important drug interactions and recommend reasonable solutions

• Ensure adequate awareness and access to necessary resources for medication adherence

• Be an educator and coordinator to ensure sufficient immunization coverage

Post-assessment

Question 1:

HIV guidelines recommend initiation with at least 3 agents representing at least two mechanisms in ARV-naïve patients.

a. True

b. False

Post-assessment

Question 2:

AK is a 28 yo M currently taking omeprazole 20mg daily, sertraline 50mg daily, cetirizine 10mg daily and dolutegravir-rilpivirine 50mg-25mg once daily. After reviewing the medication list you:

a. Recommend substituting the ARV regimen due to an interaction with omeprazole

b. Recommend substituting omeprazole due to an interaction with the ARV regimen

c. Recommend increasing the omeprazole dose to compensate for an interaction with the ARV regimen

d. Recommend revision of the HIV ARV regimen – it is currently incomplete and there are no clinically significant drug interactions

Post-assessment

Question 3:

Progression of HIV infection can increase the risk of which of the following? Select all that apply:

a. Opportunistic infections

b. Diabetes Mellitus

c. MI & Stroke

d. Acquired Immunodeficiency Syndrome (AIDS)

References

1. Naif HM. Pathogenesis of HIV Infection. Infect Dis Rep. 2013;5(Suppl 1):e6. Published 2013 Jun 6. doi:10.4081/idr.2013.s1.e6

2. Gandhi M, Gandhi RT. Single-pill combination regimens for the treatment of HIV-1 infection. N Engl J Med. 2014; 371:248-259

3. U.S. Department of Health and Human Services: AIDS info. Understanding HIV/AIDS: HIV Overview. Available at: https://aidsinfo.nih.gov/understanding-hiv-aids/fact-sheets/19/45/hiv-aids--the-basics. Updated July 3, 2019.

4. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV. Department of Health and Human Services. Available at http://aidsinfo.nih.gov/contentfiles/lvguidelines/AdultandAdolescentGL.pdf. Accessed December 29, 2019.

5. Panel on Treatment of Pregnant Women with HIV Infection and Prevention of Perinatal Transmission. Recommendations for the Use of Antiretroviral Drugs in Pregnant Women with HIV Infection and Interventions to Reduce Perinatal HIV Transmission in the United States. Available at http://aidsinfo.nih.gov/contentfiles/lvguidelines/PerinatalGL.pdf. Accessed December 29, 2019.

6. Panel on Antiretroviral Therapy and Medical Management of Children Living with HIV. Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection. Available at http://aidsinfo.nih.gov/contentfiles/lvguidelines/pediatricguidelines.pdf. Accessed December 29, 2019.

7. Strubble K, Murray J, Cheng B, et al. Antiretroviral therapies for treatment-experienced patients: current status and research challenges AIDS: May 20th, 2005 - Volume 19 - Issue 8 - p 747–756.

















References

8. Feinstein MJ, Hsue PY, Benjamin LA, et al. Characteristics, Prevention, and Management of Cardiovascular Disease in People Living With HIV. Circulation. 2019;140:e98–e124. DOI: 10.1161/CIR.0000000000000695.

9. Grand M, Bia D, Diaz A. Cardiovascular Risk Assessment in People Living With HIV: A Systematic Review and Meta-Analysis from Real-Life Data. Curr HIV Res. 2019 Dec 11.

10.DAD Study Group, Friis-Moller N, Reiss P, Sabin CA, Weber R, Monforte Ad, El-Sadr W, Thiébaut R, De Wit S, Kirk O, Fontas E, Law MG, Phillips A, Lundgren JD. Class of antiretroviral drugs and the risk of myocardial infarction. N Engl J Med. 2007;356:1723–1735.

11.Noubissi EC, Katte J-C, Sobngwi E. Diabetes and HIV. Current Diabetes Reports (2018) 18:125

12.Hernandez-Romieu AC, Garg S, Rosenberg ES, Thompson-Paul AM, Skarbinski J. Is diabetes prevalence higher among HIV-infected individuals compared with the general population? Evidence from MMP and NHANES 2009-2010. BMJ Open Diabetes Res Care. 2017;5(1):e000304. Published 2017 Jan 5. doi:10.1136/bmjdrc-2016-000304

13.Samad F, Harris M, Puskas CM, Ye M, Chia J, Chacko S, et al. Incidence of diabetes mellitus and factors associated with its development in HIV-positive patients over the age of 50. BMJ Open Diabetes Res Care. 2017;5(1):e000457.

14.Brown TT, Cole SR, Li X, Kingsley LA, Palella FJ, Riddler SA, et al. Antiretroviral therapy and the prevalence and incidence of diabetes mellitus in the multicenter AIDS cohort study. Arch Intern Med. 2005;165(10):1179–84.

15.Ajay K. Sethi, David D. Celentano, Stephen J. Gange, Richard D. Moore, Joel E. Gallant, Association between Adherence to Antiretroviral Therapy and Human Immunodeficiency Virus Drug Resistance, Clinical Infectious Diseases, Volume 37, Issue 8, 15 October 2003, Pages 1112–1118, https://doi.org/10.1086/378301

16.Hogg RS, Heath K, Bangsberg D, Yip B, Press N, O'Shaughnessy MV, Montaner JS. Intermittent use of triple-combination therapy is predictive of mortality at baseline and after 1 year of follow-up. AIDS. 2002 May;16(7):1051-8

https://www.ncbi.nlm.nih.gov/pubmed/31830884



https://doi.org/10.1086/378301

Drug Interactions: NRTI

Antiviral NRTI Effect Recommendation

Adefovir TAF/TDF TDF concentrations may increase AVOID coadministration

Valgan-/Ganciclovir TAF/TDF Antiviral or tenofovir concentration may increase

Monitor for toxicity

Zidovudine Zidovudine concentration increase Monitor for toxicity

Ledipasvir/ Sofosbuvir

TDF Increased tenofovir concentrations AVOID coadministration, substitute with TAF

Ribavirin Zidovudine Zidovudine concentration increase Monitor for toxicity

Sofosbuvir/ Velpatasvir

TDF Increased tenofovir concentrations Monitor for toxicity – substitute with TAF

Sofosbuvir/ Velpatasvir/ Voxilaprevir

TDF Increased tenofovir concentrations Monitor for toxicity – substitute with TAF

Drug Interactions: NRTI

Protease Inhibitor NRTI Effect Recommendation

Atazanavir

TDF Atazanavir concentrations decrease; Tenofovir concentrations increase

Recommend atazanavir 300mg (plus ritonavir 100mg or cobicistat 150mg) with TDF 300mg

Tipranavir/ritonavir TAF TAF concentration decrease AVOID coadministration

Other NRTI Effect Recommendation

Methadone Zidovudine Zidovudine concentration increase Monitor for toxicities

Carbamazepine TAF TAF concentration decrease AVOID coadministration

Rifamycins TAF TAF concentration decrease AVOID coadministration

Atovaquone Zidovudine Zidovudine concentration increase Monitor for toxicities

Drug Interactions: NNRTI

Acid reducers NNRTI Effect Recommendation

Antacid

Rilpivirine

Rilpivirine concentration decrease

Separate antacid administration to 2 hours before or 4 hours after rilpivirine

H2-RA Separate H2-RA administration to 12 hours before or 4 hours after rilpivirine

PPI Contraindicated


α-adrenergic antagonists

NNRTI Effect Recommendation

Alfuzosin, Doxazosin, Silodosin

Efavirenz, Etravirine, Nevirapine

α-adrenergic antagonists concentration decrease

AVOID coadministration, therapy substitution is recommended

Tamsulosin Tamsulosin concentration decrease

Monitor therapeutic effectiveness for 2-4 weeks; Dose increase to 0.8mg is recommended if no therapeutic response


Macrolides NNRTI Effect Recommendation

Clarithromycin

Doravirine, Rilpivirine

NNRTI concentration increase

Recommend considering alternative agent (*azithromycin – no significant interactions)

Etravirine Etravirine concentration increase; Clarithromycin concentration decrease

Efavirenz, Nevirapine

Clarithromycin concentration decrease

Erythromycin


NNRTI concentration increase

Etravirine, Efavirenz, Nevirapine

NNRTI concentration increase; Erythromycin concentration decrease


Anticoagulants NNRTI Effect Recommendation

Apixaban Efavirenz, Etravirine, Nevirapine

Anticoagulant concentration decrease

AVOID coadministration, recommend substitution Rivaroxaban

Warfarin Recommend continuation with warfarin – adjust per INR as needed

Antiplatelets NNRTI Effect Recommendation

Clopidogrel Efavirenz, Etravirine, Nevirapine

Clopidogrel concentration decrease AVOID coadministration,

recommend substitution Ticagrelor Ticagrelor concentration decrease


Anticonvulsant NNRTI Effect Recommendation

Carbamazepine, Phenobarbital, Phenytoin


NNRTI concentration decrease Contraindicated

Efavirenz, Nevirapine,Etravirine

NNRTI concentration decrease AVOID coadministration, recommend substitution

Oxcarbazepine Doravirine, Rilpivirine

NNRTI concentration decrease

Contraindicated

Efavirenz, Nevirapine, Etravirine

NNRTI concentration decrease AVOID coadministration, recommend substitution

Eslicarbazepine (All NNRTIs) NNRTI concentration decrease AVOID coadministration, recommend substitution


Antidepressants NNRTI Effect Recommendation

Bupropion, Es-/citalopram, Nefazodone, Ttrazadone, Sertraline


Antidepressant concentration may be reduced

Efficacy of antidepressant regimen should be closely monitored and titrated with continued coadministration

Antipsychotics NNRTI Effect Recommendation

Aripiprazole, Brexipiprazole, Lurasidone, Olanzapine, Quetiapine


Antipsychotic concentration may be reduced

Efficacy of antipsychotic regimen should be closely monitored and titrated with continued coadministration

Cariprazine, Pimavanserin


Antipsychotic concentration decrease AVOID coadministration, recommend substitution


Antifungals NNRTI Effect Recommendation

Fluconazole Nevirapine Nevirapine concentration increase AVOID coadministration, recommend substitution

Itraconazole Efavirenz, Nevirapine

Itraconazole concentration decrease AVOID coadministration – unless potential benefits outweigh risk

Posaconazole Efavirenz Posaconazole concentration decrease AVOID coadministration – unless potential benefits outweigh risk

Voriconazole Efavirenz Voriconazole concentration significantly decreased

Contraindicated (standard dosing) *May adjust to voriconazole 400 mg BID with efavirenz 300 mg daily


Antivirals (Hep C) NNRTI Effect Recommendation

Daclatasvir Efavirenz, Etravirine, Nevirapine

Daclatasvir concentration increase Recommend dosing daclatasvir 90 mg once daily

Dasabuvir + Paritaprevir/ Ombitasvir/ritonavir

Etravirine, Nevirapine

DAAs concentration decrease AVOID coadministration, recommend substitution

Rilpivirine Rilpivirine concentration is significantly increased

AVOID coadministration, recommend substitution

Efavirenz No available data Contraindicated

Elbasvir/Grasoprevir Etravirine, Nevirapine

DAAs concentration decrease


Efavirenz DAAs concentration decrease Contraindicated


Antivirals (Hep C) NNRTI Effect Recommendation

Glecaprevir/ Pibrentasvir


DAAs concentration decrease


Sofosbuvir/ Velpatasvir +/- Voxilaprevir

Other NNRTI Effect Recommendation

Dexamethasone Rilpivirine Rilpivirine concentration significantly decreased

Contraindicated

St. John’s Wort (All NNRTIs) NNRTI concentration decrease Contraindicated

Oral contraceptive

Efavirenz Etonogestrel, levonorgestrel, norelgestromin concentration decrease


Atorvastatin, Simvastatin, Lovastatin, Pravastatin


Statin concentration decrease Recommend dose adjustment to lipid response – not exceeding maximum dosing

Drug Interactions: PI

Acid reducers PI Effect Recommendation

Antacid

Atazanavir, Tipranavir

PI concentration decrease

Separate antacid administration to 2 hours before or 1-2 hours after

H2-RA Atazanavir Atazanavir concentration decrease *Requires boosting Administer 2 before or 10 hours after Single dose should not exceed famotidine 20 mg equivalent

PPI Atazanavir, Tipranavir

PI concentration decrease




PI Effect Recommendation

Alfuzosin

(All PIs) α-adrenergic antagonists concentration increase

Contraindicated

Silodosin

Tamsulosin AVOID coadministration – unless potential benefits outweigh risk

Doxazosin Recommend initiation at lowest dose and titrating per clinical response and adverse effects. Consider dose reduction Terazosin


Rifamycins PI Effect Recommendation

Bedaquiline

(All PIs)

Bedaquilline concentration increase AVOID coadministration – unless potential benefits outweigh risk

Rifapentine PI concentration decreased

Rifampin PI concentration significantly decreased Contraindicated

Rifabutin Rifabutin concentration increase Recommend decreasing dose to rifabutin 150 mg daily


Anticoagulants PI Effect Recommendation

Apixaban

(boosted PIs)

Anticoagulant concentration increased

*May decrease apixaban dose by 50% (from 5-10mg dosing) AVOID coadministration, recommend substitution if 2.5mg

Rivaroxaban

Warfarin Warfarin effect decreased

Recommend continuation with warfarin – adjust per INR as needed

Antiplatelets PI Effect Recommendation

Clopidogrel, Ticagrelor, Vorapaxar

(All PIs)

Antiplatelet concentration increased; Clopidogrel concentration decreased


Prasugrel Prasugrel concentration decreased Insufficient data


Antidepressants PI Effect Recommendation

Bupropion, Buspirone, Nefazodone, Ttrazadone, TCAs, SSRIs

(All PIs)

Antidepressant concentrations are altered and may be either increased or reduced

Recommend initiating the lowest possible dose and titrating slowly based on clinical response

Antipsychotics PI Effect Recommendation

Lurasidone, Pimozide

(All PIs)

Antipsychotic concentration may be increased

Contraindicated

Ziprasidone, Pimavanserin

Lopinavir Antipsychotic concentration may be increased (increased QTc prolongation)


Other antipsychotics

(All PIs) Antipsychotic concentration may be increased

Recommend initiating the lowest possible dose and titrating slowly based on clinical response


Antifungals PI Effect Recommendation

Fluconazole, Itraconazole

(All PIs) PI concentration increased Recommend administering doses of fluconazole <200 mg daily and itraconazole <200 mg daily

Isavuconazole, Posaconazole

(All PIs)

Antifungal concentration increased Recommend continuing dosing but monitoring for related adverse events

Voriconazole (boosted PIs) Voriconazole concentration decreased AVOID coadministration – unless potential benefits outweigh risk

Anticonvulsant PI Effect Recommendation


PI *boosted with cobicistat

PI concentration decreased Contraindicated

Atazanavir Atazanavir concentration decreased



Antivirals (Hep C) PI Effect Recommendation

Daclatasvir Atazanavir Daclatasvir concentration increase Recommend decreasing dosing to daclatasvir 30 mg once daily

Dasabuvir + Paritaprevir/ Ombitasvir/ritonavir

Darunavir, Lopinavir, Tiprenavir

Darunavir concentration increase; DAA concentration decrease


Elbasvir/Grazoprevir (All PIs) DAA concentration increase Contraindicated

Glecaprevir/Pibrentasvir Atazanavir DAA concentration increase

Contraindicated Other PIs

Sofosbuvir/ Velpatasvir/ Voxilaprevir

(All PIs) *except darunavir

DAAs concentration decrease AVOID coadministration, recommend substitution

Drug Interactions: INSTI

Acid reducers INSTI Effect Recommendation

Antacid (Al/Mg/Ca) Bictegravir

Bictegravir concentration decreased (Al/Mg): Separate antacid administration 2 hour before or 6 hours after (Ca): Ensure both are taken with food

Dolutegravir Dolutegravir concentration decreased

Separate dolutegravir administration 2 hour before or 6 hours after antacid

Elvitegravir Elvitegravir concentration decreased Separate administration by > 2 houra

Raltegravir Raltegravir concentration decreased

AVOID coadministration, recommend substitution *may administer raltegravir 400 mg BID maximum with calcium-based antacid



INSTI Effect Recommendation

Alfuzosin, Silodosin

Elvitegravir

α-adrenergic antagonists concentration increase

Contraindicated

Tamsulosin Tamsulosin concentration increase



Rifamycins INSTI Effect Recommendation

Rifabutin Bictegravir, Elvitegravir

INSTI concentration decreased AVOID coadministration, recommend substitution

Rifampin Bictegravir, Elvitegravir

INSTI concentration significantly decreased

Contraindicated

Dolutegravir Dolutegravir concentration decreased Recommend increasing dose to dolutegravir 50mg BID (*if no suspected INSTI-mutation)

Raltegravir Raltegravir concentration decreased Recommend increasing dose to raltegravir 800mg BID

Rifapentine (All INSTIs) INSTI concentration significantly decreased



Macrolides INSTI Effect Recommendation

Clarithromycin Elvitegravir/ cobicistat

Cobicistat and clarithromycin concentration increased

Recommend decrease in clarithromycin dose by ~50% AVOID coadministration, recommend substitution if CrCl<50mL/min


Anticoagulants INSTI Effect Recommendation

Apixaban Elvitegravir

Anticoagulant concentration decrease

*May decrease apixaban dose by 50% (from 5-10mg dosing) AVOID coadministration, recommend substitution if 2.5mg

Rivaroxaban


Antiplatelets INSTI Effect Recommendation

Clopidogrel Elvitegravir Clopidogrel concentration decreased


Ticagrelor Ticagrelor concentration increased

Vorapaxar Vorapaxar concentration increased


Anticonvulsant INSTI Effect Recommendation


Bictegravir, Raltegravir, Dolutegravir

INSTI concentration decreased AVOID coadministration, recommend substitution (*may recommend increasing dose to dolutegravir 50mg if INSTI-naïve)

Elvitegravir Contraindicated

Oxcarbazepine Bictegravir, Dolutegravir

NNRTI concentration decreased AVOID coadministration, recommend substitution

Eslicarbazepine (All INSTIs) INSTI concentration decreased AVOID coadministration, recommend substitution


Antipsychotics INSTI Effect Recommendation

Cariprazine Elvitegravir Antipsychotic concentration increased

Recommend decreasing cariprazine to 1.5mg daily and titrating per response

Lurasidone, Pimozide

Antipsychotic concentration increased

Contraindicated

Aripiprazole, Brexipiprazole

Antipsychotic concentration increased

Recommend decreasing dose to 25% of usual and titrating per response

Quetiapine Antipsychotic concentration increased

Recommend decreasing dose to 1/6 usual or lowest possible and titrating per response


Antifungals INSTI Effect Recommendation

Itraconazole

Elvitegravir Itraconazole and INSTI concentration decrease

Administration with high doses (>200 mg) should not be coadministered

Voriconazole

Voriconazole and INSTI concentration increased

AVOID coadministration – unless potential benefits outweigh risk

HIV Antiretroviral Review and Pharmacist Impact

LT David Moore, PharmD

United States Public Health Service

PGY-1 Pharmacy Resident

Alaska Native Medical Center – Alaska Native Tribal Health Consortium

hiv antiretroviral review and pharmacist impactrecognize clinically significant drug-drug...

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