(4/27) Smith Lecture: Pharmacology of Antiretrovirals I HIV Information/Terminology

- Resistance Testing: There are a couple methods for evaluating the viruses resistance o GART: Genotypic Antiretroviral Resistance Testing o Phenotype-resistance testing: check the ‘fold-change,’ by monitoring growth in a medium o Trofile Test: A resistance test specific to entry inhibitors. Must be done prior to Maraviroc

- HLAB-5701: PGen tests are available for testing for the presence of this allele, required prior to ABC dosing - IRIS: Immune reconstitution inflammatory syndrome – when the immune system is very weakened/depleted Integrase Inhibitors (-gravir) NRTI NRTI Combos STR

Bictegravir BIC Tenofovir alaf. TAF Epzicom ABC/3TC Biktarvy BIC/TAF/FTC Dolutegravir DTG(Tivicay) Tenofovir diso TDF Descovy TAF/FTC Genvoya TAF/FTC/EVG/c Elvitegravir EVG Lamivudine 3TC(Epvir) Truvada TDF/FTC Odefsey TAF/FTC/RPV Raltegravir RAL(Isentress HD) Emtricitabine FTC(Emtriva) Boosting Agents Triumeq ABC/3TC/DTG

Entry Inhibitors Abacavir ABC(Ziagen) Ritonavir RTV(Norvir) Juluca RPV/DTG Maraviroc MVC(Selzentry) Cobicistat COBI(Tybost) (C)

General Comments

- All integrase inhibitors are indicated for initial therapy in newly diagnosed patients. - Reverse Transcriptase Inhibitors [NRTI: TAD, TDF, 3TC, FTC, ABC] [NNRTI: EFV, RPV]

o NRTI: Mimic nucleosides, incorporated into DNA by RT, resulting in prevention of transcription o NNRTI: Activity outside the catalytic domain, they attach to RT elsewhere

- STR: Single-tablet regimens are indicated for the initial treatment of HIV infection o The two most favored initial therapies (not considering contraX) are Biktarvy and Genvoya

- Genvoya (TAF/FTC/EVG/c) vs Stribild (TDF/FTC/EVG/c) o The only difference is TAF in Genvoya and TDF in stribild. The goal is to switch individuals from

Stribild to Genvoya thanks to the improved safety results found for TAF. - Odefsey (TAF/FTC/RPV) vs Complera (TDF/FTC/RPV) (RPV = Rilpivirine, a NNRTI)

o Again, the only difference is TDF and TAF. Move to switch individuals from Complera to Odefsey - Isentress (RAL 400mg) vs Isentress HD (RAL 600mg)

o Isentress HD is now favored, because it can be taken 2 tabs QDaily, rather than I PO BID - If concurrent HBV: Should be using two agents active against HBV - Exposure to the HIV Virus: Integration into the DNA takes a maximum of 72 hours. Therefore, if exposed to

infected (or suspected to be infected) body fluids, go to the emergency room within 72 hours and start on HIV meds to avoid development of an infection (Post-exposure Prophylaxis – PeP)

Initial Combination Therapy: In a ARV-Naïve Patient [Standard] à INSTI-based regimens: All combinations are equally efficacious. Selecting STR with TAF, not TDF, is best.

o Biktarvy (BIC/TAF/FTC) CrCl ³ 30mL/min I PO QD Medium o Genvoya (EVG/c/TAF/FTC) CrCl ³ 30mL/min I PO QD Medium o Triumeq (DTG/ABC/3TC) Must be HLAB*507(-) I PO QD Large o Stribild (EVG/c/TDF/FTC) CrCl ³ 70mL/min I PO QD Huge o Tivicay (DTG) + [Truvada (TDF/FTC) -OR—Descovy (TAF/FTC)] QD/BID

- The role of the integrase inhibitors is to prevent the permanent integration of viral DNA into the host DNA.

- Diet: With or without food (EVG needs food). Make sure to separate with antacids

- Biktarvy (BIC/TAF/FTC) I PO QDaily *(Renal-adjustment) T1/2 = 17h o Latest approved STR, used as an initial regimen with no resistance. o Avoid in: CrCl < 30mL/min, Severe hepatic impairment o Diet: May be taken with or without food. With INSTI, it is important to separate administration of

antacids with polyvalent cations (Al3+, Mg2+, Ca2+) for at least 2 hours after taking Biktarvy o AE: Well-tolerated. TAFàHA. Otherwise – NVD o DDI: BIC is a -Substrate of 3A4 and UGT1A1 à strong inducers/inhibitors are contraX

-Inhibitor of OCT2 and MATE1 à Dofetilide is a substrate ~ contraX dof.

- Genvoya (EVG/c/TAF/FTC) I PO QDaily o Also known as Stribild 2.0 o Avoid in: CrCl < 30mL/min o Diet: Must be taken with food. With INSTI, it is important to separate administration of antacids with

polyvalent cations (Al3+, Mg2+, Ca2+) for 2h before or 6h after taking Genvoya o AE: GI Upset, Headache o DDI: Cobicistat is a Strong 3A4 inhibitor - Any meds reliant on 3A4 metabolism may need to be adjusted

§ EVG is a 3A4 and UGT1A1/3 Substrate - Triumeq (DTG/ABC/3TC) I PO QDaily

o A popular STR with no resistance. Although, it is the Largest tablet, OUCH! o Avoid in: HLA-B*5701(+) – Must HLA test, due to presence of ABC. o Diet: May be taken with or without food. With INSTI, it is important to separate administration of

antacids with polyvalent cations (Al3+, Mg2+, Ca2+) for 2h before or 6h after taking Triumeq o AE: HSR, if it occurs, it should occur within the first 6 weeks. Flu-like Sx.

§ Otherwise: Insomnia, fatigue, HA o DDI: DTG is a -Substrate of 3A4 and UGT1A1 à strong inducers/inhibitors are contraX

-Inhibitor of OCT2 and MATE1 à Dofetilide is a substrate ~ contraX dof. - Tivicay (DTG) + [Descovy (TAF/FTC) -or- Truvada (TDF/FTC)] I PO of each QDaily

o Hmm, less popular because having to take multiple pills. o Diet: May be taken with or without food. With INSTI, it is important to separate administration of

antacids with polyvalent cations (Al3+, Mg2+, Ca2+) for 2h before or 6h after taking the combo therapy o AE: Insomnia and HA

§ If experiencing new onset or worsening of renal impairment or decreased bone mineral density, switch from Truvada to Descovy (TDF à TAF)

- Stribild (EVG/c/TDF/FTC) I PO QDaily o This drug contains a booster, cobicistat, a frequent friend of EVG. Otherwise, 3A4 chews up EVG. o Avoid in: CrCl < 70mL/min (need good kidneys!) o Diet: Must be taken with food.. With INSTI, it is important to separate administration of antacids with

polyvalent cations (Al3+, Mg2+, Ca2+) for 2h before or 6h after taking Stribild o AE: GI Upset, Headache

§ TDF: New or worsening renal impairment. Decrease in bone mineral density o DDI: Cobicistat is a Strong 3A4 inhibitor - Any meds reliant on 3A4 metabolism may need to be adjusted

§ EVG is a 3A4 and UGT1A1/3 Substrate o Resistance consideration: EVG shares cross-resistance with RAL. If resistant to RALà resistant to EVG

- Isentress/Isentress HD (RAL) add to Truvada or Descovy (Descovy > Truvada) o AE: Side effects from Isentress alone are minimal, though combination with Truvada or Descovy may

yield HA, N, and decreased renal function/Fanconi (Truvada), decreased BMD (Truvada) § Rhabdo

o DDI: Statins. Upon initiation, should push off statin therapy for a few weeks. This is because Isentress may cause Rhabdo, and we want to be able to know who to blame for it.

§ RAL is a UGT1A1 substrate Initial Combination Therapy: Special Clinical Situations

- Integrase Inhibitors (INSTI)-based regimens are first-line. If they are not an option, then the preferred alternative is protease inhibitors combined with NRTI

- Boosted PI + 2 NRTIs [In general, boosted DRVPrezista is preferred over boosted ATVReyataz] o DRV/c -or -DRV/r + Descovy/Truvada Level of evidence A, Ir,IIc o ATV/c -or- ATV/r + Descovy/Truvada Level of evidence B, I o DRV/c -or- DRV/r + Epzicom Level of evidence B, II [MUST HLA-B*5701 test!]

- The HIV Protease enzyme is responsible for maturing the transcribed virus. Protease inhibitors (PIs) prevent this maturation, thus preventing assembly of new viral components and ability to bud off from cell

- Reason to Boost: Without it, we only get ~8 hours above the MIC – true for all protease inhibitors. With the booster, they now can last over 200 hours. As a result, protease inhibitor regimens are considered to be ‘forgiving,’ because you will still have active drug therapy if you are a little late taking your dose.

- Take WITH FOOD: Protease inhibitors need to be taken with food

Initial Combination Therapy: Special Clinical Situations – PI - Continued - PI AE: Significant NVD, Rash, Paresthesia

o Reyataz (ATV): Indirect hyperbilirubinemia – yellowing of eyes. This is simply cosmetic jaundice, tell them to drink more water.

- Best Evidence: Prezista (darunavir, DVR) + Norvir (ritonavir, RTV) + Descovy (TAF/FTC) Complications associated with Anti-Retroviral Therapy (ART)

- Body Shape Changes o Fat Wasting (Facial or limb wasting) o Fat Accumulation (Buffalo humps, gynecomastia, abnormal viscera)

§ HIV Lipodystrophy – Fat Redistribution Syndrome. Patients may develop a goiter or buffalo hump as the fat accumulates intraviscerally.

§ à Exercise, Liposuction (buffalo hump). If desired, DART is an option although discouraged - Metabolic Changes

o Abnormal Lipids: TGÝ, LDLÝ, HDLß This is less of a problem with the newer agents § à ‘diet, exercise, and low dose atorvastatin’. Follow lipid guidelines, including If indicated,

statins are preferred albeit DDI considerations with the protease inhibitors (PIs) § ‘atorvastatin, rosuvastatin, or pravastatin are safer’

o Insulin Resistance: ART may precipitate insulin resistance and even DM § à Diet, Exercise, and Metformin (max 1000mg/daily – fear of lactic acidosis – monitor) § DTG significantly increases [metformin] due to OCT2 and MATE1 inhibition

o Bone Disease: BMD associated with Tenofovir, precipitating osteoporosis and and/or osteopenia o Mitochondrial Toxicity: Very rare, but are associated with NRTI use. Complications include neuropathy,

acidosis, pancreatitis, and hepatitis. o Avascular Necrosis (AVN): A very painful joint disorder prevalent in older populations

§ à Joint Replacement is the best option. Otherwise, most patients do end up on narcotics and receiving roid injections

(4/30) Smith Lecture: Pharmacology of Antiretrovirals II Entry Inhibitors

- Ibalizumab (Trogarzo) A new injectable [Target: D2] o Place in Therapy: Indicated for treatment-experienced adults with

MDR currently failing therapy o MoA: Binds to D2 of CD4 thereby preventing viral CD4 binding.

However, it does not prohibit MHC binding, and therefore does not produce immunosuppression. This is a good thing. J

o Dosing: Requires a loading dose (2000mg IV) and adherent maintenance dosing (800mg q2w) § If ³ 3 days late for maintenance injection, must restart with loading dose

o AE: NVD, Rash, Dizziness o DDI: None

- Maraviroc (Selzentry) A new tablet [Target: CCR5] o MoA: Binds to the CCR5 coreceptor thereby preventing viral coreceptor binding. However, some HIV

viruses with resistance mechanisms may alternatively use the CXCR4 coreceptor. Thus tropism testing is required upon initiation

o Dosing: Specific dose depends on drug-interactions. The standard dose is 300mg PO BID § Concurrent 3A4 Inhibitors à 150mg BID (PIs, Itraconazole, Clarithromycin) § Concurrent 3A4 Inducers à 600mg BID (Efavirenz, Rifampin, Carbamazepine, PB, Phenytoin)

o AE: Hepatotoxicity is rare, but will initially present as a rash. See a rash? Check LFT. Otherwise, dizziness, postural hypotension, blah blah

- Enfuvirtide (Fuzeon) A new injectable [Target: ?] o MoA: Inhibits the final step of viral penetration into the cell o Dosing: Vials with powders for reconstitution, add saline. 90mg (1mL) SubQ BID

§ Injection sites: abdomen, upper thighs, and upper arms. Rotate. § Reconstitution: Takes like 30 minutes to stir, huuuuge molecule. Roll the vial, have fun!

o AE: ~100% of patients experience injection site reactions. Injection sites will become welts, which is a good indicator for adherence.

o Inhibits the last step – penetration of the virus into the cell o Efficacy: Works incredibly well as a monotherapy

Tropism Testing

- Background - Coreceptors of HIV Entry: Viral HIV binds to either CCR5 or CXCR4 of the CD4 cell when making contact. In general, HIV viruses lacking resistance mechanisms, such as those often found in treatment-naïve patients, prefer the CCR5 coreceptor. Over time, resistance may develop whereupon the virus switches its preference to the CXCR4

- Blood Test: Get a sample and send to California – hear back in a month. (A month!? – have a plan B!) Change of Plans – Over the course of a patient’s therapy, diverse situations may occur resulting in a change of therapy

- To manage or prevent drug toxicity: Metabolic, bone, renal - To simplify the regimen: Decrease pill burden - To address food restrictions - To address drug interactions: Perhaps they get an illness or transplant requiring contraXd meds

o Fluticasone Nasal Spray (Flonase) interaX with PI à Fluticasone-induced Cushing’s syndrome o H2RA and PPI: Some myths to dispel, H2RA and PPI are not contraX with INSTI. There are cation

limitations whereby binding of these ions will prevent drug absorption - To plan for pregnancy - To reduce cost - To address new HBV coinfection - Resistance: During unchecked replication, billions of innate mistakes occur that precipitate polymorphisms

conferring resistance. o Shit happens: Naturally acquired a resistant virus, occurred due to non-adherence, absorption of INSTIs

impaired by cations, DDI, Baseline GART wasn’t completed, given inappropriate regimens o Best way to prevent development of resistance: Adherence – But adherence is multifactorial. Trouble

with psych, insurance coverage, pharmacy, and privacy all play a role § The longer a patient is left on a failing regimen the more mutations they will develop

o GART: A genotyping method that checks the relevant parts of the viral genome. Such as CCR5 Trofile § This is resistance testing, which we can compare to known polymorphisms to interpret § Phenotype Testing: A sendout that takes a while to receive results on – analyzes the effect of the

mutation § Stanford FTW: A team from Stanford has paired polymorphisms to known resistance

mechanisms and the implications they have on therapy – https://hivdb.standford.edu/ o ART Hx: Knowing a patient’s medication history is important for predicting the patient’s mutations

Undetectable Viral Load? Hellloooo Juluca (Dolutegravir 50mg/Rilpivirine 25mg) - Indication: FDA-Approved for switch therapy in individuals suppressed on current ARV regimen for ³ 6 months

with no history of treatment failure. Patient must have undetectable viral load and no known resistance o Not Recommended: Viral Load > 100k, Co-infected with HBV o SWORD Clinical Trial: Following switch therapy, essentially everyone remains undetectable viral load

- Dosing: I PO QDaily with food PrEP: Pre-Exposure Prophylaxis The ongoing use of HIV ARV meds by an HIV-negative person to reduce their risk of getting HIV

- Indication: Must be taken every day, starting the course before possible exposure o Individuals with substantial risk for acquiring HIV – copious sexcapades, IVDA, partner with HIV o Drug of Choice: There is only 1 FDA-approved drug combination: Truvada

- Proven by clinical trials: Effectiveness improves with adherence. Hmm…. PEP: Post-Exposure Prophylaxis

- Indication: To be started at the latest, 72h after exposure.