Pharm II Week 8 (Antiretroviral Agents)

HIV Replication CYCLE

HIV = Retrovirus

•Cellular integration in CD4 cells

•Uses reverse transcriptase to transcribe viral RNA into dsDNA

Most antivirals aim to reduce/prevent replication

Pathophysiology: HIV Infection

Typical CD4 count vs AIDS

•Typical CD4 count: 500-1200 cells/mm3

•Acquired immunodeficiency syndrome (AIDS): CD4 <200 cells/mm3

Antiretroviral therapy (ART) - drug classes

•Nucleoside/ nucleotide reverse transcriptase inhibitor (NRTIs)

•Non-nucleoside reverse transcriptase inhibitor (NNRTIs)

•Integrase inhibitor (INSTIs)

•Protease inhibitor (PIs)

•Entry Inhibitors

Treating HIV (Generally speaking)

know this very well

Treating HIV (Generally speaking)

Pre-exposure prophylaxis (PrEP)

2 NRTIs

Truvada (TDF/FTC)

Tenofovir disoproxil Fumarate/ Emtricitabine

Or

Descovy (TAF/FTC)**

Tenofovir Alafenamide/ Emtricitabine

Descovy (TAF/FTC)** Tenofovir Alafenamide/ Emtricitabine

NOT used in what pts??

**DESCOVY (TAF/FTC) for PrEP is not for use in people assigned female at birth who are at risk of getting HIV from vaginal sex, because its effectiveness has not been studied.

Treatment of HIV (know this well)

INSTI + 2 NRTIs (2 NRTIs is backbone of HIV treatment)

Biktarvy: Bictegravir INSTI + Tenofovir alafenamide (TAF) NRTI + Emtricitabine (FTC) NRTI

Triumeq: Dolutegravir (DTG) = INSTI, Abacavir (ABC) = NRTI, Lamivudine (3TC) = NRTI

**Before using abacavir test for HLA-B*5701

Tivicay + Descovy/Truvada

• Dolutegravir (DTG) = INSTI

• Emtricitabine (FTC) NRTI + TAF/TDF = 2 NRTIs

Dovato: Dolutegravir (DTG) = INSTI, Lamivudine (3TC) = NRTI. This one is weird bc its only 1 INSTI + 1 NRTI.

Post-exposure prophylaxis (PEP)

INSTI + 2 NRTIs PEP within 72-hour rule

Biktarvy (BIK/TAF/FTC)

Bictegravir/Tenofovir alafenamide/

Emtricitabine 

Or

Dolutegravir (DTG) + Truvada (TDF/FTC)

Tenofovir disoproxil Fumarate/

Emtricitabine

length of post-exposure prophylaxis (PEP)

x28 days

Nucleoside/ nucleotide reverse transcriptase inhibitors (NRTIs)

drugs

•Tenofovir disoproxil fumarate/TDF (Viread)

•Tenofovir alafenamide/TAF (Vemlidy)

•Emtricitabine/FTC (Emtriva)

•Abacavir/ABC (Ziagen)

•Lamivudine/3TC (Epivir)

NRTIs MOA

MOA: Competes for binding to cause incorrect DNA strands = leading to termination

•Blocking reverse transcriptase (converts RNA --> DNA)

•NRTIs work by competing w/ natural nucleosides (dTTP, dCTP, dGTP, and dATP) and incorporate into viral DNA

•Causes chain termination --> prevents replication of virus.

NRTIs ADRs (know all of these well)

Mitochondrial toxicity

•Lactic acidosis with hepatic steatosis

•Pancreatitis

•Peripheral neuropathy

•Lipoatrophy (peripheral fat wasting)

•Neuromuscular weakness

NRTIs: Tenofovir disoproxil fumarate (TDF)

ADRs

•Decreased bone mineral density (BMD)

•Nephrotoxicity

•Fanconi syndrome (when the kidneys leak substances)

•CrCL < 50

NRTIs: Tenofovir alafenamide (TAF)

ADRs

Less bone and renal concerns - why/how: bc a prodrug!

CrCL < 15

NRTIs: Emtricitabine (FTC)

ADRs

CrCL < 50

Tenofovir disoproxil fumarate (TDF), Tenofovir alafenamide (TAF), Emtricitabine (FTC)

Hepatic dose adjustment?

Activity against HBV?

Hepatic dose adjustment? NO

Activity against HBV? YES!!

Truvada and Descovy are commonly used in?

PrEP, PEP, and HVI treatment

NRTIs: Lamivudine (3TC) ADRs

CrCL < 50

Lamivudine (3TC) Hepatic dose adjustment? Activity against HBV?

Hepatic dose adjustment? NO

Activity against HBV? Moderate

Abacavir (ABC)

ADRs/comments

Increased risk of myocardial infarction and

platelet aggregation (DAD Study Group, 2008; Fletcher et al. 2024)

Hypersensitivity reaction (Blackbox warning)

•HLA-B*5701 allele (Requires Genetic Testing!!)

Abacavir (ABC)

Renal Dose adjustment?

Hepatic dose adjustment?

Activity against HBV?

Hepatic dose adjustment? YES

Activity against HBV? No

Need to test for _______ in patients starting Abacavir

HLA-B* 5701 allele

(requires genetic testing)

NRTI Summary SLIDE

Non-nucleoside reverse transcriptase inhibitor (NNRTIs)

agents

•Efavirenz/EFV (Sustiva)

•Rilpivirine/RPV (Edurant)

•Doravirine/DOR (Pifeltro)

•Etravirine/ETR (Intelence)

•Nevirapine/NVP (Viramune)

•Delavirdine/DLV (Rescriptor)

Non-nucleoside reverse transcriptase inhibitor (NNRTIs)

MOA

Allosterically blocking the reverse transcriptase, which converts RNA into DNA; causing termination

MOA: Allosteric inhibitor binds to an enzyme at a site other than the active site, causing change in the confirmation of the enzyme

Non-nucleoside reverse transcriptase inhibitor (NNRTIs)

Common ADRs

•Increased LFTs

•Rash (including Stevens-Johnson Syndrome)

•NO renal dosage adjustments

•Affects the LIVER! (Use caution in hepatic impairment)

Non-nucleoside reverse transcriptase inhibitor (NNRTIs)

CI

Severe hepatic dysfunction (Child-Pugh class B or C)

NNRTIs: Efavirenz (EFV)

ADRS

Neuropsychiatric symptoms (may resolve in 2-4 weeks)

•Abnormal dreams, dizziness, morning confusion, depression, suicidality

QTc prolongation

NNRTIs: Efavirenz (EFV) Administration

Take on empty stomach at bedtime to decrease CNS effects

Use with caution in the 1st trimester of pregnancy; birth defects seen in primate studies

NNRTIs: Rilpivirine (RPV) ADRs

Do not co-administer Rilpivirine w:

•Proton pump inhibitors

•Certain anticonvulsants

•Phenytoin, phenobarbital, oxcarbazepine

•Rifabutin, rifampin, rifapentine

•St. John’s Wort

Depression is observed in cases

NNRTIs: Rilpivirine (RPV) Administration

Must be administered with a MEAL (> 400 cal)!

Requires an acidic environment for appropriate absorption (Do not give w PPI)

CANNOT be started in patients with VL <100,000 copies/mL and CD4 >200 cells/mm3

NNRTIs: Doravirine (DOR) ADRs

Well tolerated

Treatment-emergent DOR resistance mutations may confer resistance to certain NNRTIs

NNRTIs: Efavirenz (EFV) tx study

•Acute psychosis as a side effect of efavirenz therapy (seen in > 40%)

•High-fat meals can increase lvl +60% concentrations

•Dizziness, abnormal dreams, headache, depression, suicidality, insomnia, somnolence

Integrase strand transfer inhibitors (INSTis)

agents

•Dolutegravir/DTG (Tivicay)

•Raltegravir/RAL (Isentress)

•Elvitegravir/EVG (coformulated as Genvoya/Stribild)

•Bictegravir/BIC (coformulated as Biktarvy)

Cabotegravir/ CAB (coformulated as Cabenuva)

Integrase strand transfer inhibitors (INSTis) MOA

Prevent HIV integrase from incorporating proviral DNA into human host cells, which inhibits the HIV-catalyzed strand transfer step. This step is essential in the viral lifecycle and has no human homolog, making it a specific and effective HIV drug target

Integrase strand transfer inhibitors (INSTis)

ADRs

•Well tolerated (N/V/D)

•Weight gain

Weight gain-related issues w/ INSTI: all showing some metric of increased weight gain/ BMI in pts taking INSTI

Biggest issue w INSTIs??

Class drug interaction with polycation supplements (Chelation) + Weight Gain

Integrase Inhibitors: Class Drug Interaction (FYI SLIDE)

Chelation concerns!! INSTIs have 2 binding sites for metals that can be chelated by polycation

INSTis: Raltegravir (RAL) ADRs

Increases in creatine kinase, myopathy, and rhabdomyolysis have been reported

INSTis: Dolutegravir (DTG) ADRs

Preferred INSTI for Pregnancy/ People trying to conceive

Contraindicated with dofetilide (can cause T de point)

Neural Tube Defect (NTD) considerations... study results DO NOT show an increased risk of NTDs in exposed infants

INSTis: Bictegravir (BIC) ADRs

Large majority of HIV patients are on BIKTARVY

Well tolerated

Recently approved for use in pregnancy!

INSTis: Elvitegravir (EVG) + Cobicistat

ADRs

MUST be given with a “booster”

(combined w Cobicistat; a potent CYP 3A4 inhibitor)

Needs to be given w Food

INSTis: Cabotegravir (CAB) vs CAB/RPV

"Future of HIV"

CAB Singular component - PrEP

CAB/RPV = HIV treatment

Cabotegravir (CAB) and Cabotegravir/ Rilpivirine (CAB/RPV)

ADRs

IM infection is given every 2 months

Used in patients w controlled HIV

ADR: painful IM injection

General questions during eligibility check for CAB and CAB/RPV

•Hep B history

•Pregnancy/ trying to conceive?

•History of depression? May incr

•HIV resistance history? Get injection regularly

•Travel plans - will have to switch agents

•Appointment adherence

HIV and missing a dose

Missing HIV medication doses can cause drug levels to fall too low --> allows virus to replicate & develop resistance

Once resistance develops to one med, HIV can become resistant to other drugs in the same class, limiting future tx options and forcing patients to use alternative or later-line regimens.

List of Protease inhibitors (PIs)

•Darunavir/DRV (Prezista)

•Atazanavir/ATV (Reyataz)

•Lopinavir/ritonavir-LPV/r (Kaletra)

•Tipranavir/TPV (Aptivus)

•Indinavir/IDV (Crixivan)

•Saquinavir/SQV (Invirase)

•Fosamprenavir/FPV (Lexiva)

•Nelfinavir/NFV (Viracept)

List of “Boosters” (Pharmacokinetic Enhancers)

•Cobicistat (Tybost)

•Ritonavir (Norvir)

PROTEASE INHIBITORS (Pis) + BOOSTER

MOA

•Prevent viral replication by selectively binding to viral proteases (e.g. HIV-1 protease) and blocking proteolytic cleavage of protein precursors that are necessary for the production

PROTEASE INHIBITORS (Pis) + BOOSTER

Common ADRs

•Lipodystrophy (via buffalo hump)

•Increased transaminases (affect LFTs)

•Gastrointestinal intolerance (Diarrhea is VERY COMMON)

Metabolic abnormalities

•Hyperlipidemia

•Insulin resistance

PROTEASE INHIBITORS (Pis) + BOOSTER

Contraindications

Severe hepatic dysfunction (Child-Pugh class C)

See list in later slides (DDI)

General comments - PROTEASE INHIBITORS (Pis)

•Protease Inhibitor and Boosters – STRONG 3A4 Inhibitor

•High genetic barrier to resistance

•Use with caution in hepatic impairment

•Must take w food

Pis: Darunavir (DRV)

ADRs

Rash observed (10%); sulfa moiety

Pis: Atazanavir (ATV)

ADRs/comments

•Reversible indirect hyperbilirubinemia (35-47% patients)

•Requires an acidic environment for appropriate absorption (space out administration when given w PPIs, H2 blockers, Antacids)

Pis: Lopinavir (LPV)

comments

Always taken w Ritonavir

PROTEASE INHIBITORS (Pis) + BOOSTER

what are the boosters

Cobicistat (COBI/c)

Ritonavir (r)

Cobicistat (COBI/c) and Ritonavir (r) are both? (think DDI)

Extremely strong CYP 450 inhibitors!

Cobicistat (COBI/c) - ADRs/Comments

•No HIV activity

•Not recommended when CrCL < 70 mL/min

•Approved for use only with darunavir and atazanavir

Ritonavir (r) - ADRs/Comments

•Minimal HIV activity

Summary Slide 1

Summary Slide 2

Which HIV ARV also has anti-hepatitis B activity?

A.Abacavir

B.Tenofovir alafenamide

C.Efavirenz

D.Rilpivirine

B. Tenofovir alafenamide

Which of the following NRTIs requires dose adjustments in patients with hepatic impairment?

A.Tenofovir alafenamide

B.Lamivudine

C.Abacavir

D.Emtricitabine

C. Abacavir

Which of the following NNRTIs must be taken on an empty stomach?

A.Efavirenz

B.Rilpivirine

C.Doravirine

A. Efavirenz

Which of the following NNRTIs is contraindicated with omeprazole?

A.Efavirenz

B.Rilpivirine

C.Doravirine

B. Rilpivirine

Opportunistic Infections in HIV(in 1 slide)

If CD4 is >200, usually don’t treat!!!

<200 always use bactrim

<50 = use bactrim AND azithromycin

what pathogens for:

CD4 < 200

CD4 < 100

CD4 < 50

200 - Pneumocystis pneumonia (PCP)

100 - Toxoplasma gondii Encephalitis (TE)

50 - Mycobacterium avium complex (MAC)

Bactrim alternatives are?

Azithromycin alternative?

Bactrim alternatives = dapsone or atovaquone

Azithromycin alternative = Rifabutin

bactrim and azithro adrs

Bactrim:

- SJS

- Rash

- Sulfa allergy/hypersensitivity

- Hyperkalemia

Azithromycin:

- Allergy/rash

- QTc prolongation → risk of arrhythmias

Dapsone requires

G6PD testing

If they have it = increased risk hemolytic anemia.