HIV Antiretroviral (ART) Medications Lowervirologicefficacy,notsuggestedforVL200 * "Beingstudies(Phase3withCAB)aslong?actinginjectable* Efavirenz(EFV " Sustiva

HIV Antiretroviral (ART) Medications Class Generic Brand Preparations Combo Pill Dosing Side Effects

Drug Interactions

Comments

Nucleoside / N

ucleotide Re

verse Tran

scrip

tase Inhibitors -‐ N

RTI

Nucleoside / Nucleotide Reverse Transcriptase Inhibitors MOA: Analogues of nucleo(t)side which replace a base during reverse transcription of viral RNA to DNA à chain termination Resistance: -‐ Needs only one resistant base pare mutation to acquire resistance -‐ If using two analogues, and both were same analogue, resistant would waste drugs à use 2 NRTIs that are different analogues. Long half lives. Renal Dosing: Try to avoid NRTIs all together, it’d be best Class Interaction: Ribavirin (hepatotoxicity)

Abacavir Guanosine analogue ABC Ziagen

300 mg tab ViiV

Kivexa 1 QD Triumeq 1 QD

Trizivir 1 BID

300 mg po BID 600 mg po QD

can safely use in CKD

Common: • Headache • N/D • Malaise

Serious: • Hypersensitivity reaction (HR) in 8%

↓[Methadone]

ü Black Box: Only Rx for HLA-‐B*5701 negatives à Testing predicts HR in Caucasians. Rechallenge in HR patients C/I à life threatening

ü Sings of HR: fever, rash, tired, upset stomach, vomit, belly pain, flu-‐like sx, sore throat, cough. Occurs < 6 wks after start (mean 11 days). Stop drug right away & see MD.

ü Meta-‐analysis à no signal for increased MI à but if higher MI risk, ABC not best choice

ü Can cause hepatitis and lactic acidosis esp in women and obese

Lamivudine Cytidine analogue 3TC Heptovir

3TC

150, 300 mg tab GSK

Kivexa 1 QD Triumeq 1 QD

Trizivir 1 BID

Combivir 1 BID


Renal

Well Tolerated • Headache begging • N/D/Abd pain transient • Insomnia uncommon • Pancreatitis more peds

Emtricitabine [X] à both Cytosine analogues (no point in using both)

ü Some people have headache in first few days, stick with it and use Tylenol and Advil if needed

Tenofovir Adenosine analogue

Only Nucleotide Reverse Transcriptase

Inhibitor (NtRTI)

TDF TAF

Viread TDF

150, 200, 250, 300 mg tab

40 mg/g powder Gilead

Truvada TDF 1 QD Descovy TAF 1 QD Stribild TDF 1 QD Genvoya TAF 1 QD Complera TDF 1 QD Odefsey TAF 1 QD Atripla TDF 1 QD

300 mg po QD Renal

avoid TDF in CKD

Mostly Well Tolerated • N/V/D/Gas • Renal impairmentTDF • Reduced bone density TDF

↓[atazanavir] ↑[didanosine -‐ ddi] Clinically not used with TDF anyways any longer

ü TDF = tenofovir disoproxil fumarate (pro-‐drug), efficacy of TDF = TAF ü TAF = tenofovir alafenamide fumarate (targeted pro-‐drug), less bone &

renal issues (TAF safe till CrCl 30 mL/min, TDF safe till CrCl 70 mL/min) ü Preferred over ABC due to activity in cases Hep B virus co-‐infection and

not needing HLA testing ü Favorable lipid profile

Emtricitabine Cytidine analogue FTC Emtriva

200 mg cap Gilead

200 mg po QD cap 240 mg po QD sol’n

Renal

Well Tolerated • Headachecommon, dizziness • N/D • Rash, skin pig’n

Lamuvidine [X] à both Cytosine analogues (no point in using both)

ü Black Box: severe exacerbation of hep B on stopping drug in pts w Hep B ü Only part of combos w Tenofovir in Canada ü Rarely pts may experience bad diarrhea. Headache most common s/e.

Zidovudine Thymidine analogue

AZT Retrovir

100, 250 mg cap 10 mg/mL syrup 10 mg/mL inject

ViiV

Trizivir 1 BID

Combivir 1 BID 300 mg po BID

Also I.V. form

Not Well Tolerated • Headache 62% • N 50% / V 17% / Anorexia 20% • Insomnia • Nail pigmentation • Hematologic tox

stavudine [X] also a thymidine analogue

ü Black Box: hematologic toxicity, myopathy, anemia, granulocytopenia, thrombocytopenia

ü Used in 1980s as one of the earliest HIV drugs, when people were dying from AIDS.

ü Place for therapy: IV form and syrup still used in MTCT in pregnancy and delivery and infants with HIV

Didanosine Adenosine analogue ddi Videx

EC

125, 200, 250, 400 mg EC cap

2, 4 g oral sol’n bottles Bristol-Myers

None

400 mg po QD

> 60kg

take ½ hr before or 2 hr after meal

Not Well Tolerated • Lipoatrophy very common • D/N/Abd pain • Rash • Headache, Fever • Hyperuricemia • Peripheral neuropathy

↑[conc] of: • Allopurinol (avoid)

↓[conc/abs] of: • Methadone • Rifampin, FLQ • Itra/ketoconazole

Black Box: fatal pancreatitis esp w d4T +/-‐ hydroxyurea If 25-‐60 kg then 250 mg QD DDinx w Ethanol, lamivudine, pentamidine à ↑pancreatitis

ü Lipodistrophy: ↑ metabolic issues (TG, LDL, sugars) & fat wasting in cheeks, hips, arms, legs, but fat gain tissue in abdo area MOA: all the NRTIs look like nucleosides, can also target mitochondrial polymerase. DNA replicate in mitochondria à polymerase in mitochondria inhibited (more lactic acid, more cell apaptosis, if mitochondrial in nerve cell led to neuropathy, if in fat cell lipodistrophy)

Stavudine Thymidine analogue d4T Zerit

15,20,30,40 mg cap

1 mg/mL oral Bristol-Myers

None 40 mg po q12h > 60 kg

• Lipoatrophy very common • Headache • N/V/D • Peripheral neuropathy

Dapson, INH Ribavirin Zidovudine

Black Box: fatal pancreatitis esp w d4T, fatal lactic acidosis

Fusion Inhibitor Enfuvirtide ENF Fuzeon 90 mg vial Genentech

None 90 mg SC BID • Inj site reaction • Bacterial pneumonia • Hypersensitivity

ü Was historically used in era between 1st and 2nd generation PIs ü Unstable drug, dose needs to be prepared before administering each

dose

Class Generic Brand Preparations Combo Pill Dosing Side Effects Drug Interactions Comments Non

-‐nucleoside RT

Inhibitors -‐ NNRT

I NNRTI ___vir___ MOA: NNRTIs bind allosterically in a pocket located near the catalytic site in the palm domain of the p66 subunit site of the Reverse Transcriptase (RT) enzyme Resistance: Single point attachments, easy for mutant to make attachment not happen, easy resistance “low generic barrier to resistance” K103N Mutation

Rilpivirine RPV Edurant 25 mg tab

Janssen

Complera TDF 1 QD Odefsey TAF 1 QD

25 mg po QD w food ++

• Rash 3% • Headache 3% • Insomnia • Depression 8% • Hyperlipidemia • Hepatotoxicity

↓[Edurant] with: Inducers of 3A Drugs inc pH

ü Among smallest HIV tablets ü Best absorbed with a good meal (350 cal) ü PPI contraindicated, H-‐2 blockers need dose reduction. ü Favorable lipid profile ü Lower virologic efficacy, not suggested for VL < 100,000 & CD4 > 200 ü Being studies (Phase 3 with CAB) as long-‐acting injectable

Efavirenz EFV Sustiva 600 mg tab

50, 200 mg cap Bristol-Myers

Atripla TDF 1 QD

600 mg po QD

avoid fatty meals on empty stomach

(inc abs’n leading to s/e)

CNS S/E 52%

• Dizziness, vivid dreams • Insomnia, somnolence • Impaired concentration • Hyperlipidemia

• Rash 26% (can treat through it mostly)

↑[Cocain]

↓[conc] of: • Benzos (-‐olam are issues, -‐pams are ok)

• most opioids • methadone (monitor response, don’t dose adjust in beginning)

ü let MD know if history of psych illness à should avoid this med ü Vivid dreams bothersome to some, enjoyable to some other ü CNS s/e worst after 1st or 2nd dose, get better in 2-‐4 weeks ü if you’re on methadone, you may need higher doses of it ü May cause false +ve cannabinoid test ü Avoid if hx of HIV-‐associated dementia (HAD) ü Not favourable in pregnancy (neural tube defects in animal studies, not

as significant in humans)

Nevirapine NVP Viramune 200 mg IR tab 400 mg SR tab

Boehringer

None 200 mg QD X 14

days then 200 mg po BID

• Rash 37% • Hepatic failure • Fever • Nausea

CYP3A4 substrate inducers/inhibitors of 3A4 will interact

ü Black Box: severer rash & hepatotoxicity ü higher CD4 associated w hypersensitivity à can treat through rash, but if

w fever and inc LFTs sign of hyperactivity ü Lead-‐in phase to reduce rash, occurs in 1st 6 wks, more in women… also

drug is auto inducer (will reduce its own level) ü XR version (400 mg QD) more common

Etravirine ETR Intelence 100, 200 mg tab

Janssen

None 200 mg po BID or 400 mg po QD

• Rash 9% • Dyslipidemia • Nausea • Rhabdomyolysis uncommon

CYP3A4, 2C9, 2C19 substrate inducers/inhibitors

will interact

ü Tabs are large; dissolve very readily in water (can help with swallowing). Also chucky and swallowing not easy of whole tab.

ü Sever rash reported

Delavirdine DLV Rescriptor 300 mg tab

ViiV

None 400 mg po TID • Rash 18% • N/V/D • Headache


ü Completely not used at, cumbersome dosing

INST

I

Integrase Inhibitors ___tegravir Resistance: Low genetic barrier to R Class Interaction: 2 hrs before 6 hrs after cations

Raltegravir RAL Isentress 400 mg tab

Merck

None


new study QDMRK w or w/o food

Well Tolerated • Rash, hypersensitivity • N/D, Headache • Insomnia • ↑ LFTs, ↑ CK, rhabdo

No CYP3A4 inx -‐ Rifampin may

reduce [ralteg] à 800 mg BID of RAL -‐ Al & Mg antacids

ü 1st to market INSTI à Being studied: 1200 mg po QD (given as 2X 600mg) ü More favourable lipid profile ü Aluminum or Magnesium antacids reduce abs’n RAL (use Ca antacid) ü Lower genetic barrier to resistance than PIs or DTG à can spare DTG,

start with RAL first & if resistance happened, change to DTG

Dolutegravir DTG Tivicay 50 mg tab

ViiV

Triumeq 50 mg po QD 50 mg po BID*

Well Tolerated • Insomnia • Headache • ↑ SCr small

No CYP3A4 inx -‐ Metformin (inc 2 fold [metformin]) -‐ C/I Dolfodelide

ü No food requirements J ü Inhibits renal tubular secretion of creatinine, SCr “falsely” increases ü Higher barrier to resistance than EVG or RAL ü Diarrhea uncommon ü BID dosing for heavily tx experienced, INSTI resistant, or given w rifampin

Elvitegravir EVG Vitekta 85, 150 mg tab

Gilead

Stribild Genvoya

85-‐150 mg po QD boosted

w small food

Well Tolerated • Hyperlipidemia • D/N • Headache


ü Better absorption w food/snack ü More favourable lipid profile ü Must be given with PI, RTV or another ARV

Cabotegravir CAB TBD

? 200 mg/mL inj

30 mg tab ViiV

TBD 400 mg CAB + 600 mg RPV IM q4w

(TBD) TBD TBD ü As of Sept 2016 in phase 3 trials à LATTE-‐2 & FLAIR Phase 3 studies

ü 1st long acting injectable ART, nuc sparing regimen under study with RPV

Class Generic Brand Preparations Combo Pill Dosing Side Effects Drug Interactions Comments Protease In

hibitors -‐ PI

Protease Inhibitor _____avir Class S/E: Hyperlipidemia MOA: PI bind to active site in center of molecular complex of protease, locks in at multiple points and won’t allow the protease to cleave à high genetic barrier to mutation

Ritonavir PK booster RTV Norvir

100 mg tab/cap 80 mg/mL oral

Abbott

Kaletra 100-‐400 po/day

• Bitter aftertaste • Numbness around mouth at HIV doses

• N/V/D • ↑ LFTs, ↑ TG

Inducer of: • 1A2, 2B6, 2C9

Inhibitor of: • 3A4 strong 2C8, 2C9

ü Black Box: many drug interactions: 3A4, 2D6 à life threatening ü Extremely strong inhibition 3A4 & PGP ü HIV active at higher doses but toxicity & inx (not used for HIV treatment) ü 100 mg per dose to boost (e.g. if using with BID drug, give 100 mg BID) ü Fluorinated steroids (even inhaled) can lead to cushing’s syndrome

Darunavir DRV Prezista

Prezista: 600, 800 mg tab

Prezcobix: 800 mg + 150 mg COB tab

Janssen

Prezcobix w cobicistat 1 QD

600 mg po BID or 800 mg po QD

w food

+ RTV 100 mg BID

• Rash 10% • Headache • N/D • ↑ amylase • Hepatotoxic • Kidney stones?

Failure of contraceptives

ü Currently highest prescribed PI: 2nd Gen PI ü Works in those who are R to other PIs ü Cobicistat will cause tubular creatinine reabsorption à SCr “pseudo” rise

of 10-‐30 mmol/L from pts normal baseline ü Needs RTV boosting ü 800 QD + 100 mg RTV for naïve, [600 mg + 100 RTV] BID for experienced ü Contains Sulfa moiety

Atazanavir ATV Reyataz

Reyataz: 150, 200,

300mg tab

Evotaz: 300 mg + 150 mg COB tab

Bristol-Myers

Evotaz w cobicistat

300 mg po QD boosted w RTV 100 mg 400 mg po QD

unboosted w food

• Kidney stone 10 fold inc • Increased billi 60% (cosmetic, not harmful)

• D/N/Abd pain • Headache 6% • Rash 20%


ü 2X150 mg (300 mg) + RTV 100 mg daily (TDF increases excretion of ATZ) ü 2X200 mg (400 mg) unboosted with Kivexa (needs RTV boost w others) ü Nuc sparing: w Raltegravir (boost each other) à ATZ 300 mg + RAL 400

mg BID (each) ü Increased QTc, PR, more torsads ü Jaundice as result of increased direct bilirubin à not harmful, pt may

decide to switch for cosmetic reason

Lopinavir / RTV

LPV Kaletra 200 mg + 50 mg

RTV tab Abbott

Kaletra 4 QD 400 mg po BID 800 mg po QD

• Diarrhea 24% • N • ↑ LFTs, billi, Lipids, MI

Many ↑ [benzos] Fentanyl Phenytoin

ü Deathly interaction with fentanyl . ü Funky interaction with phenytoin à RTV inhibitor, LPV inducer of CYP.

Unpredictable pheny level (unpredictable) ü +++ diarrhea, worse with q24h ü May need higher doses if tx experienced

Tipranavir TPV Aptivus 250 mg cap

100 mg/mL oral Boehringer

None 500 mg po BID • D/N/Abd pain • Rash >10% esp women • ↑ Lipids

Many à Inducer AND

inhibitor of CYP

ü Black Box: hepatitis, fatal hepatic failure, intracranial hemorrhage ü Contains Sulfa moiety ü Not clinically used due to cerebral bleeds and many drug interactions

Indinavir IDV Crixivan 200,400 mg cap

Merck

800 mg po q12h w RTV 100 mg

• Kidney stone hydration • ↑MI, LFTs, billi 15% • N/V/D/Metallic taste • Ingrown nail, dry skin

ü Lots of resistance to it! ü Need > 2 glasses water per dose! Otherwise kidney disease. ü Had to be on empty stomach ü Historically unboosted as q8h w restrict adherence needed à but

boosting removed all this requirement

Nelfinavir NFV Viracept 250, 625 mg tab

Roche

1250 mg po BID w lots of food

• Diarrhea 24% • N • Rash

ü Takes 5 tablets to make a dose! Not used routinely anymore. ü Place in therapy: Paediatric population

CC

R-5

CCR-‐5 Co Receptor Antagonists

Maraviroc MVC Celsentri 150, 300 mg tab

ViiV

None

150-‐600 mg po BID

Dose depends on DDinx

• cough 13 • Rash 10% , Abdo pain • Dizziness, myalgia • Ortho hypo, syncope • Upper resp infection


ü Black Box: hepatotoxicity, inc MI? ü Used later in tx only for CCR-‐5-‐tropic HIV virus, cannot use for CXCR-‐4-‐

tropic virus which is seen more and more in advance dx

Tool Created by: Afshin Azami, PharmD, RPh, ACPR(c) ~ Chief Editor: Linda Robinson, BSc.Phm, RPh, AAHIVP (HIV Pharmacotherapy Specialist) ~ Windsor Regional Hospitals (WRH) ~ Sept 2016 References: 1) AIDSinfo Guidelines 2016 2) Stanford Guide to HIV/AIDS Therapy 2015-‐16 3) Lexi-‐Comp Drug Monographs for each respective drug 4) “Antiretroviral Therapy for HIV Infection” Johnson et al. IAS-‐USA Vol. 23 Iss 5: 161-‐167 (Jan 2016)

Tool Created by: Afshin Azami, PharmD, RPh, ACPR(c) ~ Chief Editor: Linda Robinson, BSc.Phm, RPh, AAHIVP (HIV Pharmacotherapy Specialist) ~ Windsor Regional Hospitals (WRH) ~ Sept 2016 References: 1) AIDSinfo Guidelines 2016 2) Stanford Guide to HIV/AIDS Therapy 2015-‐16 3) Lexi-‐Comp Drug Monographs for each respective drug 4) “Antiretroviral Therapy for HIV Infection” Johnson et al. IAS-‐USA Vol. 23 Iss 5: 161-‐167 (Jan 2016)

HIV Combination Antiretroviral Regimens 1

Tab

let

- O

nc

e D

aily

Brand Names

NRTI Backbones Add-‐on Antiretroviral AIDSinfo Evidence Considerations

Drug Plan Coverage

(as of Sept 2016) 1st NRTI 2nd NRTI 3rd NRTI N-‐NRTI Integrase Inhibitor PK Booster

Truvada Emtricitabine 200 mg

Tenofovir TDF 300 mg

paired w INSTI: Dolutegravir A1 Raltegravir A1 or a boosted PI: Darunavir A1 Atazanavir B2

ü only combo also effective against Hep B ü Better viral suppression than Kivexa when VL >

100,000 c/mL ü TDF à Can use until 70 mL/min ü TAF à Can use until 30 mL/min ü TAF has smaller rates of renal insufficiency and

bone mineral density reduction than TDF ü If on a booster, use 10 mg TAF instead of 25 mg

ODB (gen) ✓ Private ✓

Descovy Emtricitabine 200 mg

Tenofovir TAF 10, 25 mg

Max ✓

Private ✓

Stribild Emtricitabine 200 mg


Elvitegravir 150 mg

Cobicistat 150 mg

Evidence A1

ü w small food ü TDF à Can use until 70 mL/min ü TAF à Can use until 30 mL/min ü Genvoya one of only combos to use till 30 mL/min ü Cobi inhibits renal tubular secretion of creatinine ü Cobi has many drug inx via CYP3A4 inhibition

Max ✓ ODB ✓

Private ✓

Genvoya Emtricitabine 200 mg

Tenofovir TAF 10 mg

Elvitegravir 150 mg

Cobicistat 150 mg

Evidence A1

Max ✓ Private ✓

Complera Emtricitabine 200 mg


Rilpivirine 25 mg

Evidence B1 ü w larger meals (~ 350 kcal) for abs’n of RPV ü Use if HIV RNA < 100,000 & CD4 > 200 ü RPV Drug inx: Acid suppressing (PPI C/I) ü RPV fewer CNS s/e compared to Efavirenz ü RPV fewer rash and dyslipidemia than Efavirenz ü RPV more prone to drug resistance ü TDF à Can use until 70 mL/min ü TAF à Can use until 30 mL/min

Max ✓ ODB ✓

Private ✓

Odefsey Emtricitabine 200 mg

Tenofovir TAF 25 mg

Rilpivirine 25 mg

Evidence B2

Atripla Emtricitabine 200 mg


Efavirenz 600 mg

Evidence B1 ü Avoid efavirenz if woman at risk of pregnancy à teratogen in 1st 6-‐8 wks

ODB ✓ Private ✓

Kivexa Lamivudine 300 mg

Abacavir 600 mg

when paired w:

Darunavir B2 Atazanavir C3 Efanvirenz C1 Raltegravir C2

ü No food requirement J ü Abacavir not ideal for those with CV risk factors ü HLA needs to be –ve before giving abacavir ü Comments also applies to Triumeq


Triumeq Lamivudine 300 mg

Abacavir 600 mg

Dolutegravir

50 mg Evidence A1

ü W or w/o food. Ca 2 hrs before or 6 hrs after. ü HLA-‐B*5701 has to be –ve before giving abacavir ü No major CYP drug interactions J ü Dolutegravir higher barrier to resistance

ODB ✓ Private ✓

1 BI

D

Combivir Lamivudine 150 mg

Zidovudine 300 mg

ü No food requirement J ODB (gen) ✓

Private ✓

Trizivir Lamivudine 150 mg

Abacavir 300 mg

Zidovudine 300 mg

ü No food requirement J ü Not recommended as 1st tx à inferior virologic

efficacy, even if w TDF


Documents

HIV Antiretroviral (ART) Medications Lower*virologic*efficacy,notsuggestedforVL200 * "Being*studies*(Phase*3*with*CAB)as*long?actinginjectable* Efavirenz(EFV " Sustiva

HIV Antiretroviral (ART) Medications Lowervirologicefficacy,notsuggestedforVL200 * "Beingstudies(Phase3withCAB)aslong?actinginjectable* Efavirenz(EFV " Sustiva