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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.
Clinical Guidelines
AIDSinfo: https://aidsinfo.nih.gov/ • Guideline summaries • Drug information summaries • Patient education resources • Clinical trial database
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.
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
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.
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®)
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.
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.
Clinical Guidelines: HIV Treatment (pregnancy)
• Alternative regimens that otherwise pose unwanted toxicities may be considered due to advantages required during pregnancy
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.
Clinical Guidelines: HIV Treatment (neonates)
• Newborns exposed perinatally should be treated immediately after birth
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.
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.
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
HIV and Comorbidities
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
HIV and Comorbidities
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
HIV and Comorbidities
Cardiovascular Disease
ASCVD Risk in HIV:
ACC/AHA has published a modified risk assessment algorithm
HIV and Comorbidities
Cardiovascular Disease
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
HIV and Comorbidities
Cardiovascular Disease
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
HIV and Comorbidities
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)
HIV and Comorbidities
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
HIV and Comorbidities
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
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
Drug Interactions: NNRTI
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
Drug Interactions: NNRTI
Drug Interactions: NNRTI
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
Doravirine, Rilpivirine
NNRTI concentration increase
Etravirine, Efavirenz, Nevirapine
NNRTI concentration increase; Erythromycin concentration decrease
Drug Interactions: NNRTI
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
Drug Interactions: NNRTI
Anticonvulsant NNRTI Effect Recommendation
Carbamazepine, Phenobarbital, Phenytoin
Doravirine, Rilpivirine
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
Drug Interactions: NNRTI
Antidepressants NNRTI Effect Recommendation
Bupropion, Es-/citalopram, Nefazodone, Ttrazadone, Sertraline
Efavirenz, Etravirine, Nevirapine
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
Efavirenz, Etravirine, Nevirapine
Antipsychotic concentration may be reduced
Efficacy of antipsychotic regimen should be closely monitored and titrated with continued coadministration
Cariprazine, Pimavanserin
Efavirenz, Etravirine, Nevirapine
Antipsychotic concentration decrease AVOID coadministration, recommend substitution
Drug Interactions: NNRTI
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
Drug Interactions: NNRTI
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
AVOID coadministration, recommend substitution
Efavirenz DAAs concentration decrease Contraindicated
Drug Interactions: NNRTI
Antivirals (Hep C) NNRTI Effect Recommendation
Glecaprevir/ Pibrentasvir
Efavirenz, Etravirine, Nevirapine
DAAs concentration decrease
AVOID coadministration, recommend substitution
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
AVOID coadministration, recommend substitution
Atorvastatin, Simvastatin, Lovastatin, Pravastatin
Efavirenz, Etravirine, Nevirapine
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
AVOID coadministration, recommend substitution
Drug Interactions: PI
α-adrenergic antagonists
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
Drug Interactions: PI
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
Drug Interactions: PI
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
AVOID coadministration, recommend substitution
Prasugrel Prasugrel concentration decreased Insufficient data
Drug Interactions: PI
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)
AVOID coadministration, recommend substitution
Other antipsychotics
(All PIs) Antipsychotic concentration may be increased
Recommend initiating the lowest possible dose and titrating slowly based on clinical response
Drug Interactions: PI
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
Carbamazepine, Phenobarbital, Phenytoin
PI *boosted with cobicistat
PI concentration decreased Contraindicated
Atazanavir Atazanavir concentration decreased
AVOID coadministration, recommend substitution
Drug Interactions: PI
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
AVOID coadministration, recommend substitution
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
Drug Interactions: INSTI
α-adrenergic antagonists
INSTI Effect Recommendation
Alfuzosin, Silodosin
Elvitegravir
α-adrenergic antagonists concentration increase
Contraindicated
Tamsulosin Tamsulosin concentration increase
AVOID coadministration, recommend substitution
Drug Interactions: INSTI
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
AVOID coadministration, recommend substitution
Drug Interactions: INSTI
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
Drug Interactions: INSTI
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
AVOID coadministration, recommend substitution
Antiplatelets INSTI Effect Recommendation
Clopidogrel Elvitegravir Clopidogrel concentration decreased
AVOID coadministration, recommend substitution
Ticagrelor Ticagrelor concentration increased
Vorapaxar Vorapaxar concentration increased
Drug Interactions: INSTI
Anticonvulsant INSTI Effect Recommendation
Carbamazepine, Phenobarbital, Phenytoin
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
Drug Interactions: INSTI
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
Drug Interactions: INSTI
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
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