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Antiretroviral Agents-April 2021.ppt

This document discusses various antiviral agents used to target different viruses. It provides details on the mechanism of action, classes, and specific drugs used to treat HIV. The main classes of antiretroviral agents for HIV include entry inhibitors, nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), integrase inhibitors, and protease inhibitors. Common NRTIs discussed are emtricitabine, tenofovir, lamivudine, and zidovudine. Efavirenz and nevirapine are highlighted as preferred NNRTIs. The document also reviews dosing, formulations, metabolism and toxicity profiles of

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ANTIRETROVIRAL AGENTS Dr. Sarah Nanzigu,
Viruses targeted by current antiviral therapy Cytomegalovirus (CMV) Herpes simplex virus (HSV) Human immunodeficiency virus (HIV) Influenza: A, B, HIN Respiratory syncytial virus (RSV) Some VHF (Lassa Fever, CCHF)
Viral Replication and Possible Sites of Drug Action Steps in Viral Replication Viral attachment Cell entry Transcription Translation Viral assembly Viruses are obligate, – Can only replicate after accessing host genome
Antivirals: Mechanism of Action Inhibit viral attachment Inhibit viral replication – May prevent viral uncoating/ release of genetic material for replication – May compete with DNA building blocks (nucleosides) – May target unique enzymes (Reverse Transcriptase) Prevent genetic copying of virus Prevent viral protein production Several Antiviral agents compete DNA building blocks
Antivirals: Analogues of DNA Nucleosides Purine Analo Antiviral Activity Adenosines Didanosine HIV Pyrimidine Analo Antiviral Activity Cytosines Lamivudine HIV Zalcitabine HIV Thymine Zidovudine (AZT) HIV Stavudine (d4T) HIV
Structural Similarities Thymidine Zidovidine
Understanding HIV and Possible Drug targets DRUGS USED AGAINST HIV
Mechanism of Action of ARVs NNRTI NRTI Protease Inhibitor Illustration by David Klemm Entry Inhibitors: Fusion Inhibitor & Chemokine Receptor Antagonist Integrase Inhibitor
Antiretroviral Classes  Entry Inhibitors: Fusion Inhibitors  Entry Inhibitors: Chemokine Receptor Antagonists  NRTIs (Nucleoside OR Nucleotide Reverse Transcriptase Inhibitors, aka “Nukes”)  NNRTIs (Non-Nucleoside Reverse Transcriptase Inhibitors, aka “Non-Nukes”)  Integrase Inhibitors  PIs (Protease Inhibitors)
Generic Name Year of FDA Approval Nucleoside Reverse Transcriptase Inhibitors (NRTI) Emtricitabine (FTC) 2003 Enteric coated didanosine (ddI EC) 2000 Abacavir sulfate (ABC) 1998 Lamivudine (3TC) 1995 Stavudine (d4T) 1994 Zalcitabine dideoxycytidine (ddC) No longer marketed 1992 Didanosine (ddI) 1991 Zidovudine (AZT) 1987 Nucleotide Reverse Transcriptase Inhibitors (NtRTI) Tenofovir disoproxil fumarate ((TDF) 2001 Non-nucleoside Reverse Transcriptase Inhibitors Rilpivirine 2011 Etravirine 2008 Efavirenz (EFV) 1998 Delavirdine (DLV) 1997 Nevirapine Immediate release (NVP) 1996 Nevirapine extended release 2011 Protease Inhibitors (PI Rilpivirine if VL<100,000 Amprenavir (APV) (no longer marketed) 1999 Tipranavir (TPV) 2005 Indinavir (IDV) 1996 Saquinavir mesylate (SQV) 1995 Lopinavir + Ritonavir (LPV/RTV) 2000 Fosamprenavir Calcium(FOS-APV) 2003 Ritonavir (RTV) 1996 Darunavir 2006 Atazanavir sulphate (ATV) 2003 Atazanavir + Ritonavir Nelfinavir mesylate (NFV) 1997 HIV Entry Inhibitors Enfuvirtide (T-20) 2003 Maraviroc 2007 Integrase Inhibitors Raltegravir 2007 Elvitegravir Dolutegravir 2013 Others Cobicistat (Booster)
What do I do with all these drugs? Student: Which of these drugs should I master? Clinician: Which of these drugs should I prescribe?
Class Drugs Entry Inhibitors: Fusion Inhibitor: Enfuvirtide, Chemokinine Receptor Antagonist (CCR5): Maraviroc Nucleoside/tide Reverse Transcriptase Inhibitors (NRTIs) Abacavir, Zidovûdine, Emtricitabine, Lamivudine, Stavudine, Didanosine, NtRTI:Tenoforvir, Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) Efavirenz, Niverapine, Delavirdine, Etravrine, Lilprivine Integrase Inhibitors (ISTIs) Raltegravir, Elvitegravir, Dolutegravir Protease Inhibitors (PIs) Ritonavir, Lopinavir, Saquinavir, Indinavir, Amprenavir, Fosampranavir, Nelfinavir, Darunavir Abbreviations MVC = maraviroc ENF = enfuvirtide (T-20) ABC= Abacavir AZT= Zidovudine 3TC = Lamivudine FTC = Emtricitabine d4T = Stavudine ddC = Zalcitabine ddI = Didanosine TDF = Tenofovir EFV = Efavirenz NVP = Nevirapine ETR = Etravirine DLV= Delavirdine RAL = Raltegravir EVG = Elvitegravir DTG = Dolutegravir RTV = Ritonavir LPV = Lopinavir APV = Amprenavir ATV = Atazanavir DRV = Darunavir FPV = Fosamprenavir IDV = Indinavir LPV/r = lopinavir/ritonavir NFV = nelfinavir /r = ritonavir, low dose SQV = saquinavir
Population Preferred first-line regimen Alternative first-line Regimen Special circumstances Adults and adolescen ts TDF + 3TC (or FTC) + DTG TDF + 3TC + EFV 400 mg TDF + 3TC (or FTC) + EFV 600 mg AZT + 3TC + EFV 600 mg TDF + 3TC (or FTC) + PI/r TDF + 3TC (or FTC) + RAL TAF + 3TC (or FTC) + DTG ABC + 3TC + DTG Children ABC + 3TC + DTG ABC + 3TC + LPV/r ABC + 3TC + RAL TAF + 3TC (or FTC) + DTG ABC + 3TC + EFV (or NVP) AZT + 3TC + EFV (or NVP) AZT + 3TC + LPV/r (or RAL) Neonates AZT + 3TC + RAL AZT + 3TC + NVP AZT + 3TC + LPV/r
What should I know
REVERSE TRANSCRIPTASE INHIBITORS NNRTI – Efavirenz (EFV) – Niverapine (NVP) – Delavirdine – Etravirine – Rilpivirine NRTI – Zidovudine (AZT) – Lamivudine (3TC) – Abacavir – Emtricitabine (FTC) – Didanosine – Stavudine ( OL) d4T NtRTI – Tenofovir (TDF) Highlighted for first line ISTI Dolutegravir Raltegravir Elvitegravir
NRTI Combinations FDC Drugs Standard Dose* Dosage forms Combivir Lamivudine/ Zidovudine 1 Tablet bid * 150/300mg tabs Trizivir Abacavir/Lamivudine/Zidovudine 1 Tablet bid* 300/150/300mg tabs Truvada Tenofovir/Emtricitabine 1 Tablet qd* 300/200mg tabs Epzicom Abacavir/Lamivudine 1 Tablet qd* 600/300mg tabs Atripla Tenofovir/Emtricitabine/Efavirenz 1 Tablet qd* 300/200/600 mg tabs *dose reduce for renal dysfunction
Newer FDCs  Tenofovir/Lamivudine/Dolutegravir  Tenofovir/Emtricitabine/Rilpivirine  Tenofovir/Emtricitabine/Cobicistat/Elvitegravir
NRTIs Mechanism of Action  Nucleoside analogs (like AZT which is a thymidine analogue)  Analog of thymidine, cytosine, adenine, or guanine  Triphosphorylated inside lymphocytes to active compound  Incorporate into the growing HIV viral DNA strand by reverse transcriptase  Nucleotide analog  Currently only tenofovir (TDF)  Does NOT need to be tri-phosphorylated only di-phosphorylated to active compound After incorporation of the NRTI, viral DNA synthesis will be terminated.
NRTI- Class PK Generally low protein binding Most have low volume of distribution Bioavailability varies, highest with 3TC, lowest wih TDF Short T1/2 except Emtricitabine and Tenofovir Largely Renal elimination and phase II metabolism No CYP metabolism
PK of some NRTI NRTI Generic Name Bioavailability (%) VD (L/kg) Protein Binding Metabolism / Elimination Half-Life, h Abacavir 83 0.86 50% Phase II Metabolism by Alcohol dehydrogenase and glucuronyl transferase 1.5 Didanosine 30-40 1.08 <5% Renal 30-50% Hepatic up o 50% 1.5 Emtricitabine 93 Unknown <4% Glomerular Filtration and Tubular Secretion 10 Lamivudine Adults- 93% Children 68% 1.3 <36% 70% Renal Elimination 5.6% to trans-sulfoxide metabolite 5-7 Tenofovir 25 1.2-1.3 7% Active tubular secretion and Glomerular filtration 17 Zidovudine Up to 70% 1.6 25%-38% Hepatic glucuronidation 1
NRTI Class Toxicities Lactic Acidosis – Elevated lactate, low pH/bicarbonate, N/V, shortness of breath, if untreated can lead to death – Results from damage to mitochondria in cells Hepatomegaly with Steatosis – Enlarged liver – Results from build up of fat droplets inside liver cells
Emtricitabine Nucleoside analog of cytidine Dose: Adult 200mg, pediatric 6mg/kg od; usually 3TC+TDF Oral bioavailability, up to 93%. AUC approx 10 h*µg/ml; Cmax is 1.8 +_0.7 µg/ml , Cmin 0.09 +_ 0.07 µg/ml T1/2 estimated at 10 hours; Longer Intracellular T1/2 Undergoes glomerular filtration and active tubular secretion, and limited hepatic oxidation/conjugation Avoided if creatine clearance <50mL/min
NtRTI- Tenofovir Tenofovir-diphosphate: analogue of the natural 2′- deoxyadenosine-triphosphate 300mg oral dose, Oral bioavailability of 25% Peak concentration 326 ng/ml; AUC 3324 ng*hr/ml Undergoes active tubular secretion mainly with OAT-1 and OAT-3 organic anion transporters T1/2=17hrs; ionised triphosphate form is trapped intracellularly prolonging T1/2 to 150 hours main toxicity is damage of proximal renal tubule due to accumulation following uptake by transporters
NRTIs Drug Standard Dose* Dosage forms Common Side Effects Metabolism/ Elimination Zidovudine (ZDV/AZT) Retrovir 300mg bid* 300mg tab, 100mg cap, iv, oral soln Fatigue, malaise, HA myalgia, anemia, GI Mainly Phase II Renal Lamivudine (3TC) Epivir 150mg bid* or 300mg od 150, 300mg tab, solution Well tolerated Renal Emtricitabine (FTC) Emtriva 200mg od 200mg cap Well tolerated Renal Didanosine (ddI) Videx 400mg EC qd ( 60kg) 250mg EC qd <60kg)* 125,200,250, 400mg cap, pwdr for soln Pancreatitis, peripheral neuropathy, LA/HS Renal Lactic acidosis can occur with any NRTIs; * reduce dose for renal dysfunction Stavudine (d4T) Zerit No longer in first line 40mg bid ( 60kg) 30mg bid (<60kg) 15,20,30,40 mg cap,oral soln Peri neuropathy, Pancreatitis, LA/HS, Lipoatrophy, facial wasting Renal Abacavir (ABC) Ziagen 300mg bid, 600mg qd 300mg tabs, oral soln Severe Hypersensitivity Due to HLA-B*5701 Highest in India and least in SSA Hepatic by alcohol dehydrogenase and glucuronyl transferase Tenofovir (TDF) Viread 300mg qd* 300mg tabs Renal toxicity, bone resorption Renal
NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS (NNRTIs)  NNRTI bind to reverse transcriptase to an allosteric site, causing structural alterations that prevents addition of new nucleosides to the growing DNA chain  NNRTIs do not require phosphorylation to be active RT
NNRTIs Drug Standard Dose Dosage forms Common AEs Metabolism CYP450 (enough for undergraduates) Delavirdine (DLV) Rescriptor 400 mg tid 100mg tab, 200mg cap Rash Potent CYP3A inhibitor; 3A4 substrate Nevirapine (NVP) Viramune 200 mg qd x 14 d then 200 mg bid 200mg tabs, Oral susp Rash (SJ), hepatotoxicity, CNS toxicity CYP3A inducer, auto inducer; 3A4, 2B6 substrate Efavirenz* (EFV) Sustiva 600 mg qhs 50, 100, 200mg cap, 600mg tab Abnormal dreams, drowsiness or insomnia, rash (SJ), hyperlipidemia Substrate and inducer; CYP3A, 2B6, 3A5, UGT, Pgp Rilpivirine dizziness, abnormal dreams, depression CYP3A4, 2C19, 1A2, Weak inducer CYP3A4, 2B6 and 2C19 May inhibit CYP2B6, 1A2
NNRTIs-Class Chracteristics No activity on HIV2 Generally High protein binding Long T1/2 CYP450 Metabolism, minimal additional phase II rxn CYP450 Modification, including autoinduction CNS toxicity: sleep disturbances, depression, hallucinations Cross resistance: K103,
Efavirenz Adult dose is 600mg OD; Oral bioavailability is 45% Time to steady state 6-10 days Cmax is12.9 ± 3.7μmol/l, Cmin) 5.6 ± 3.2μmol/l Oral clearance of 0.18 ± 0.072L/h/kg Linear PK; AUC increases proportionally with increasing dose T1/2 is 52-76hrs for single dose; drops to 40-55H due to AI Metabolised primarily by CYP2B6, also CYP3A4/5 and UGT Substrate of ABCB1 Primary and major metabolite is 8-hydroxyefavirenz, and 7- hydroxyefavirenz is the minor metabolite Efv induces several (3A4, 2B6, UGT2B7, ABCB1) Resistance and cross resistance with other NNRTIs
Etravirine 200mg bd Shares many properties with efavirenz – Highly protein binding (>99.8%) – Metablised mainly by CYP3A4, – Mainly Induces CYP3A4, Inhibits CYP2C9, Lower rates of rash and CNS adverse events Has inherent molecular flexibility permitting some affinity to RT despite NNRTI resistance mutations
Comparison of PK Profiles 0 5 10 15 20 25 30 Mean EFV (95%CI) conc in µmol/l 0 1 2 3 4 6 8 16 24 Time of blood draw PKDay 1 PKDay 14 Zidovudine Emtricitabine Abacavir Efavirenz
Fifteen health volunteers received a single dose of Truvada (Tenofovir +Emtricitabine) (300mgTDF + 200 FTC) Concentrations of Tenofovir (TDF or TFV) and Emtricitabine (FTC) were measured over 14 days in blood plasma (Graph A), Cervical-viginal fluid (Graph B), and in seminal fluid (Graph C). TDF and FTC concentrations were higher in cervicovaginal fluid (graph B), and seminal fluid (C) than in plasma (graph A) Note that the graphs are not drawn to the same scale (Y-axis scales differ) Comparison of Truvada in Plasama, Cervical-viginal and seminal fluids
Integrase Inhibitors Raltegravir (Isentress™) Dosed 400mg BID (1 tab BID) No modification of CYP450 enzymes or Pgp Metabolized by UGT1A1 – Only affected by drugs that inhibit/ induce UGTs ( Rif) Mutation in any of the AA causes resistance:
Ugandan MOH ART recommendations Patient category Recommended ART regimens Alternative ART regimens Adults and adolescents ≥30Kg, including pregnant and breastfeeding women TDF+3TC+DTG ABC+3TC+DTG (if TDF is contraindicated) TDF +3TC+ EFV400 (if DTG is contraindicated) ABC +3TC+ EFV400 (if DTG is contraindicated) TDF +3TC+ATV/r (if DTG and EFV, are contraindicated) ABC + +3TC+ATV/r (if DTG and EFV, are contraindicated) Children ≥ 20Kg - <30Kg ABC+3TC+DTG (AZT or TAF) +3TC+DTG (if ABC is contraindicated (ABC or AZT or TAF)+3TC+LPV/r (if DTG is contraindicated) (ABC or AZT or TAF)+3TC+EFV (if DTG is contraindicated) Children< 20Kg ABC+3TC+DTG AZT+3TC+DTG (if ABC is contraindicated) (ABC or AZT or RAL) +3TC+LPV/r (if DTG is contraindicated) Tripple NRTI (ABC or AZT ) +3TC + RAL
Data in favor of Integrase Strand Transfer Inhibitors Research shows that when compared to the current NNRTI-based regimens, ISTIs Have a high virological efficacy, Low resistance rate given their high genetic barrier to resistance Excellent safety and tolerability profile that can salvage prior treatment failures to be included in the “first line regiments”. Minimal drug-drug interactions as opposed to NNRTIs
PROTEASE INHIBITORS (PIs) Mechanism of Action  Protease enzyme cleaves HIV precursor proteins (gag/pol polyproteins) into active proteins that are needed to assemble a new, mature HIV virus.  PIs bind to protease preventing the cleavage and inhibiting the assembly of new HIV viruses PI HIV-1 Protease X HIV
Protease Inhibitors Standard Dose Dosage Forms Metabolism CYP450 Common AEs** Saquinavir (Invirase) (1) 1000/ rtv 100 bid or 1600/ rtv 100 qd 200mg caps, 500mg tabs 3A, Pgp substrate; weak 3A inhibitor GI intolerance Nelfinavir (Viracept) (1) 1250 bid, 750mg tid 250mg, 625mg tabs, 50mg/g oral pwdr 2C19 (M83A) substrate; weak 3A inhibitor Diarrhea Lopinavir/ ritonavir (Kaletra) (1,2) 400/100 bid 200/50 mg tabs, 80/20mg/5mL soln 3A, Pgp substrate; 3A inhibitor; 2C9, 2C19 inducer Dyspepsia, Nausea, vomiting, diarrhea, flatulence Indinavir (Crixivan) (1-when taken with rtv) 800/ rtv 100 bid, 800mg tid 100, 200, 333, 400mg caps 3A, Pgp substrate; weak 3A inhibitor Nephrolithiasis  Drink 7-8 glasses of water per day; hyperbilirubinemia (1) Take with Food (2) Must be refrigerated ** All PIs except atazanavir can increase lipids and cause insulin resistance
Protease Inhibitors Standard Dose Dosage Forms Metabolism Common AEs** Atazanavir (Reyataz) (1) 400qd or 300/ rtv 100qd 100, 150, 200mg caps 3A substrate; 3A and UGT1A1 inhibitor Hyperbilirubinemia, PR prolongation Fosamprenavir (Lexiva) (1) 1400mg bid; 700/100 RTV mg bid; 1400/200 RTV mg qd 700mg tabs (Agenerase-APV liq available) 3A4, Pgp substrate; 3A4 inducer/ Inhibitor Rash, GI intolerance, caution with sulfur allergy Tipranavir (Aptivus) (1,2) 500/200 RTV mg bid 250mg caps 3A4, Pgp substrate; 3A4, inducer/ inhibitor??; Pgp inducer Hepatotoxicity, Increased bleeding caution with sulfur allergy Darunavir (Prezista) (1) 600/100 RTV mg bid 300mg tabs 3A4 substrate; 3A4 inhibitors Diarrhea, nausea, HA, nasopharyngitis Ritonavir (Norvir) (1,2) Used as a PK booster 100-200mg 100mg caps; 80mg/mL 2D6, 3A4, Pgp substrate; 3A4, Pgp inhibitor Nausea, vomiting, diarrhea, GI upset (1) Take with Food (2) Must be refrigerated ** All PIs except atazanavir can increase lipids and cause insulin resistance
Use of Ritonavir as a P450 Inhibitor with PIs
Lipids, Insulin Resistance (Lypodystrophy) Changes in fat metabolism Hypercolesterolemia – Can have increased LDL and decreased HDL – Treat with Fibric acid derivatives and certain HMGCoA reductase inhibitors Insulin Resistance – Treat with diet/exercise, metformin, sulfonylureas or insulin
Lipodystrophy Illustrations “Buffalo hump” “Protease paunch” “Facial wasting”
INTEGRASE INHIBITORS The process of Integration of viral DNA into host DNA occur in 6 steps 1.Binding of integrase to viral DNA, 2.3-prime processing (3'-P), 3.Nuclear translocation DNA-integrase pre-integration complex 4.Binding of the pre-integration complex to host DNA, 5.Strand Transfer (ST) 6.Repairing of the gaps formed during ST (gap repair) Current drugs inhibit Strand Transfer Raltegravir Dolutegravir Elvitegravir These are all DKA derivatives
Integrase Inhibitors MOA • CCD of HIV integrase contains 3 amino acids; D64, D116, E152 • For the enzyme to become active, the AA coordinate its binding with a divalent metal; Mg2+ or Mn2+ • The bound metals coordinate the bonding of the enzyme with viral DNA during the 3'-P and ST • DKAs interact with divalent metals at CCD leading to metal chelation Catalytc Core Domain (CCD) of the HIV1 Integrase Enyzme
THE INTEGRASE INHIBITORS  The integrase strand transfer inhibitors (INSTIs) are potent inhibitors of the HIV- encoded integrase enzyme, which incorporates pro-viral HIV-1 DNA into the host cell genome. Site of action of integrase inhibitors, adapted from Clinical pharmacology of integrase inhibitors
Integrase Inhibitors Drug Standard Dose Metabolism Common AEs Raltegravir (RAL) 400 mg tid Children 10mg/kg Phase II metabolism Major enzyme UGT1A1, minor UGT1A9 & UGT1A3 Minor: dizziness, headache, nausea, excessive tiredness and sleep disorders, life threatening skin reactions (SJ), toxic epidermal necrolysis, Elvitegravir (EVG) 150mg) (ELV/Cob+FT C+TDF) Mainly phase I metabolism CYP3A4/5, then UGT1A1/3 Resistance Mutations: T66I and E92Q, Dolutegravir 600 mg od Mainly Phase II metabolism Major: UGT1A1, Minor: CYP3A4, UGT1A3,1A9 Mutations: Y143C/R, Q148H/K/R and N155H
 Importance of gp120, gp41 glycoprotiens  Viral tropism (co-receptors on the CD4)  co-receptors CCR5, CXCR4  Varied use of CCR2, CCR3 HIV ENTRY INHIBITORS
Pharmacological targets of HIV Entry Inhibition of the interaction between the viral surface glycoprotein (gp120) and CD4 (Several Vaccine Trials) Inhibition of the interaction between gp120 and Co- receptor; CCR5 or CXCR4 (chemokines receptor antagonists) – CCR5-receptor blocker Maraviroc – Cenicriviroc in phase II/III trials (CCR5/CCR2) – Research in Agents with potential as CXCR4 receptor blockers Fusion inhibitors: Peptide derivatives of the gp41 that inhibit its transition to the fusion-active state – Enfuvirtide (T20) HIV-1 gp41 C- peptide derivative
Fusion Inhibitors Enfuvirtide, T-20 See Kilby and Eron, NEJM 2003;348:2228-38 Enfuvirtide
T-20 MOA First FDA-approved fusion inhibitor; Peptide with36 AA An analogue of heptad repeat 2 (HR2) of gp41 (C-terminal of gp41) It binds to HR1 (N-terminal), preventing the interaction between HR1 and HR2, thus inhibiting the conformational change that allows fusion of the viral cell envelope to the host cell membrane Used in combination therapy (HAART) Active against viruses that utilize the CCR5, CXCR4 and dual/mixed co-receptor tropic viruses
Fuzeon : Enfuvirtide (T-20) FDA-approved fusion inhibitor Dose: 90 mg bid side effects: – injection site rxn, hypersensitivity (rare) Resistance: changes in gp41 (cell surface protein)
PK of Enfurvitide  Has a bioavailability of 84.3%  SQ injection into the arm, thigh or abdomen is appropriate  The bioavailability differs slightly depending upon the site of administration, but this so has no clinical significance Highly protein bound (92%) to albumin & a-1 acid glycoprotein Small volume of distribution of 5.48L Enfurvitide is a protein, hence it undergoes catabolism Expected to undergo catabolism to its constituent AA, and subsequent the AA recycled in the body pool. T1/2 ~ 3.8 hrs
Resistance Resistance to enfuvirtide occurs rapidly A resistance associated mutation in the g41 protein
Chemokine Receptor Antagonists Marviroc; Blocks viral entry at CCR5 Dosed 300mg BID, Oral. MOA: Maravirocis is a selective and noncompetitive antagonist of CCR5 chemokine receptor. Interacts with the CCR5, inhibiting fusion and viral entry into host cells Chemokine receptors. [Internet]. IUPHAR database (IUPHAR-DB). 2014 [cited 17/06/2014]. Available from: http://www.iuphar- db.org/DATABASE/FamilyMenuForward?familyId=14.
PK of Maraviroc Poor biovailabilty; 300mg gives Vf=33% Volume of distribution of 194L Moderately protein bound (76%) to albumin & a-1-acid gp Tmax = 0.5 to 4 hrs, T 1/2 of 14-18 hours High fat diet can reduce Vf & plasma levels by 40-60%, but no clinical relevance Rapidly distribute into seminal/ virginal fluids, rectal tissue and the CNS; reach higher concentrate than in plasma Use limited by need for testing for CCR-Tropism
Metabolism Maraviroc is metabolized by the CYP450 3A isoenzymes to inactive metabolites – 8% is excreted unchanged in urine, – 25% is excreted unchanged in feces Maraviroc doesn’t induce or inhibit CYP450 But greatly affected by CYP450 modifiers – Normal dose 300mg BID, Oral. – 150mg BID with P450 inhibitors; Example ----- – 600mg BID with P450 inducers; ------- Drug Interactions
Clinical uses of ARVs Treating HIV in adults and children – Follow changes in guidelines Pre-exposure prophlaxis (Prep) – HIV-negative people who are at very high risk for HIV infection (HIV negative CSW, Partner in an ongoing relationship with an HIV-positive partner, homosexual/ bisexual man who has had anal sex with no condom – Truvada daily; reduces risk by 90% Post- exposure Prophylaxix (PEP) – HIV negative persons who have been exposed to infected fluids (Mostly exposed Health workers, Rape victims  Truvada+ Raltegravir/ or Dolutegravir for 28 days (start within 36h, prefferably 2h; test for HIV periodlically)  Alternatively; Truvada + ritonavir boosted PI (Dalv or ATV or FAMP)  Prevention of Mother to Child transmission (Option B +)
Research Updates Long acting antiviral agents (LAA) Long acting antiretroviral drugs including cabotegravir and rilpivirine, given in controlled release injections with long half- lives. Employment of nanotrchnology in HIV Nanotechnology-based drug delivery for HIV/AIDS treatment; Nanomedicine confers targeted delivery of drugs to specific cells or tissues and intracellular delivery of macromolecules. Research on targeted delivery of antiretroviral drugs to CD4+ T cells and macrophages,
Drug Interactions
Antiretroviral Metabolism, Induction, and Inhibition Drug Substrate Inhibits Induces Efavirenz 2B6, 3A4/5 3A4/5, 2B6 Nevirapine 3A4, 2B6 3A4 Ritonavir 2D6, 3A4, Pgp 3A4, 2D6, Pgp 2D6 (at high doses only) Saquinavir 3A4, Pgp 3A4 Nelfinavir 2C19 (M83A4) 3A4 Amprenavir 3A4, Pgp 3A4 (in vitro) 3A4 (in vivo) Fosamprenavir 3A4, Pgp 3A4 (in vitro) 3A4 (in vivo) Lopinavir/ritonavir 3A4, Pgp 3A4 2C9, 2C19, 1A2 Atazanavir 3A4, Pgp 3A4, UGT, 1A2 Tipranavir 3A4, Pgp 3A4 Other enzymes Darunavir 3A4, Pgp 3A4 Maraviroc 3A4, Pgp
Substrate Inhibitor Inducer 3A4 Macrolides,cyclosporine, CCB, statins, azoles, midazolam, triazolam Cimetidine, Macrolides, FQs, SSRIs, CCB, azoles, aprepitant rifamycins, phenytoin, carbamazepine, St. John’s wort, aprepitant, garlic 2D6 Opiates, nortriptyline, amitriptyline, tramadol, trazodone, paroxetine, metoprolol, propranolol, carvedilol Haldol, SSRIs, cimetidine, amiodarone rifamycins, phenytoin, CBZ, St. John’s wort 1A2 Amitriptyline, clozapine, caffeine, clozapine, imipramine, R-warfarin, theophylline, proprnaolol FQs, azoles, macrolides, rifamycins, phenytoin, CBZ, smoking, St. John’s wort 2C19 Omeprazole, phenytoin SSRIs, azoles, fluvastatin, omeprazole, topiramate rifamycins, CBZ, phenytoin 2C9 S-warfarin, sulfonylureas, phenytoin, carvedilol Amiodarone, SSRIs, azoles, amiodarone Phenytoin, CBZ, rifammycins, aprepitant Cytochrome P450: Non-Antiretrovirals
Dose Adjustments Between ARVs Drug A Drug B Recommendation Tenofovir Didanosine Dose ddI as 250mg od with TDF 300mg od Efavirenz (Nevirapine) Atazanavir Use RTV 100mg QD with ATV + EFV Efavirenz (Nevirapine) Fosamprenavir Use RTV with FPV Efavirenz (Nevirapine) Lopinavir/ritonavir Increase LPV/RTV to 3 tabs BID
Important Drug Interactions NNRTIs with: – Antimalarials, COCPs, AntitTB; levels are reduced by NNRTIs – Antiepileptics” Bilateral changes in drug concentrations – AntitTB drugs: Rif lowers conc of NNRTIs Maraviroc – Increase dose when combined with NNRTIs – Reduce dose if combined with PISs Do NOT use Simvastatin, Lovastatin, Antiarrthymics, Midazolam, Triazolam, Ergot derivatives, Rifamin, St. Johns Wort, or Garlic with most PIs or DLV Do NOT combine Rifampin with PIs – LPV/RTV may be dose increased and combined with Rifampin – Conflicting data with EFV and NVP Use other P450 inducers with CAUTION when combining with PIs and NNRTIs Do NOT use Fluticasone or Alfuzosin with Ritonavir Caution with Azoles, Clarithromycin, Oral Contraceptives, Phenytoin,
Importance of Adherence
Therapeutic Drug Monitoring Not widely used in the US Recommended in certain situations for PIs and NNRTIs What makes a drug a good candidate for TDM? When should TDM be performed for antiretrovirals?
HIV preventive approaches
Pre-exposure prophlaxis (Prep) Given to HIV-negative people who are at very high risk for HIV infection – Examples: HIV negative commercial sex workers (CSW), Partner in an ongoing relationship with an HIV-positive partner, homosexual/ bisexual man who has had anal sex with no condom – Truvada daily; reduces risk by 90% – Only effective if taken daily Post- exposure Prophylaxix (PEP) Given to HIV negative persons who have been exposed to infected fluids  Examples: Mostly exposed Health workers after contact with infected fluids, Rape victims  Truvada+ Raltegravir/ or Dolutegravir for 28 days  Alternatively; Truvada + ritonavir boosted PI (Dalv or ATV or FAMP) for 28 days (start within 72h, but the earlier the better prefferably 2h; test for HIV periodlically)  Rationale is to get the drugs into the body as fast as possible to kill the virus before it is able to make many copies, hence reducing chances of an established HIV infections
Prevention of Mother to Child transmission (Option B +) Use of antiretroviral therapy to prevent infections in babies born to HIV Positive mother Option B+: Start mother on treatment with recommended regimens and continue treating her for life Treatment as Prevention Treating HIV infected patients in discordant relationships (one of the partners is HIV negative). Rationale; Treating the infected member as early as possible reduces their viral load and hence reducing chances of infecting the discordant member.
Why TRUVADA in PREP and PEP Recall pharmacokientics of the drugs Both Tenofovir + Emtricitabine (Truvada) have long half-lives and concentrate highly in cervical, viginal, seminal, and rectal fluids This helps to kill the virus while attempting to replicate in these areas before spreading to cause an established HIV infection.
Comparison of concentraion of FTC in plasma and semina fluid Emtricitabin e
Fifteen health volunteers received a single dose of Truvada (Tenofovir +Emtricitabine) (300mgTDF + 200 FTC) Concentrations of Tenofovir (TDF or TFV) and Emtricitabine (FTC) were measured over 14 days in blood plasma (Graph A), Cervical-viginal fluid (Graph B), and in seminal fluid (Graph C). TDF and FTC concentrations were higher in cervicovaginal fluid (graph B), and seminal fluid (C) than in plasma (graph A) Note that the graphs are not drawn to the same scale (Y-axis scales differ) Comparison of Truvada in Plasama, Cervical-viginal and seminal fluids
From a study of tenofovir gel applied intraviginally; Tenofovir concentration of ≥100 ng/mL in CVF (cervical-viginal fluid) was associated with 65% protection against HIV, whereas ≥1000 ng/mL concentration correlated with 76% protection against HIV infection
Antiretroviral Drug Approval: 1987 - 2007 0 5 10 15 20 1987 1991 1993 1995 1997 1999 2001 2003 2006 AZT ddI ddC d4T 3TC SQV RTV IDV NVP NFV DLV EFV ABC APV LPV/r TDF T-20 ATV FTC FPV TPV DRV Maraviroc Raltegravir
Dose adjustments to consider Renally-eliminated NRTIs (except Abacavir) Adjust for CrCl <50 ml/min or dialysis Didanosine Emtricitabine Lamivudine Stavudine Tenofovir Zidovudine Reference: Drug product info and DHHS guidelines (see tables) Hepatic Metabolism  NNRTIs  PIs Adjust for certain inducers, substrates, or inhibitors of P450 system Adjust for insufficiency Indinavir Fosamprenavir Atazanavir Avoid Amprenavir oral soln Foasmprenavir (+/- ritonavir) Tipranavir

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Antiretroviral Agents-April 2021.ppt

  • 1.
  • 2.
    Viruses targeted bycurrent antiviral therapy Cytomegalovirus (CMV) Herpes simplex virus (HSV) Human immunodeficiency virus (HIV) Influenza: A, B, HIN Respiratory syncytial virus (RSV) Some VHF (Lassa Fever, CCHF)
  • 3.
    Viral Replication andPossible Sites of Drug Action Steps in Viral Replication Viral attachment Cell entry Transcription Translation Viral assembly Viruses are obligate, – Can only replicate after accessing host genome
  • 4.
    Antivirals: Mechanism ofAction Inhibit viral attachment Inhibit viral replication – May prevent viral uncoating/ release of genetic material for replication – May compete with DNA building blocks (nucleosides) – May target unique enzymes (Reverse Transcriptase) Prevent genetic copying of virus Prevent viral protein production Several Antiviral agents compete DNA building blocks
  • 5.
    Antivirals: Analogues ofDNA Nucleosides Purine Analo Antiviral Activity Adenosines Didanosine HIV Pyrimidine Analo Antiviral Activity Cytosines Lamivudine HIV Zalcitabine HIV Thymine Zidovudine (AZT) HIV Stavudine (d4T) HIV
  • 6.
  • 7.
    Understanding HIV and PossibleDrug targets DRUGS USED AGAINST HIV
  • 8.
    Mechanism of Actionof ARVs NNRTI NRTI Protease Inhibitor Illustration by David Klemm Entry Inhibitors: Fusion Inhibitor & Chemokine Receptor Antagonist Integrase Inhibitor
  • 9.
    Antiretroviral Classes  EntryInhibitors: Fusion Inhibitors  Entry Inhibitors: Chemokine Receptor Antagonists  NRTIs (Nucleoside OR Nucleotide Reverse Transcriptase Inhibitors, aka “Nukes”)  NNRTIs (Non-Nucleoside Reverse Transcriptase Inhibitors, aka “Non-Nukes”)  Integrase Inhibitors  PIs (Protease Inhibitors)
  • 10.
    Generic Name Yearof FDA Approval Nucleoside Reverse Transcriptase Inhibitors (NRTI) Emtricitabine (FTC) 2003 Enteric coated didanosine (ddI EC) 2000 Abacavir sulfate (ABC) 1998 Lamivudine (3TC) 1995 Stavudine (d4T) 1994 Zalcitabine dideoxycytidine (ddC) No longer marketed 1992 Didanosine (ddI) 1991 Zidovudine (AZT) 1987 Nucleotide Reverse Transcriptase Inhibitors (NtRTI) Tenofovir disoproxil fumarate ((TDF) 2001 Non-nucleoside Reverse Transcriptase Inhibitors Rilpivirine 2011 Etravirine 2008 Efavirenz (EFV) 1998 Delavirdine (DLV) 1997 Nevirapine Immediate release (NVP) 1996 Nevirapine extended release 2011 Protease Inhibitors (PI Rilpivirine if VL<100,000 Amprenavir (APV) (no longer marketed) 1999 Tipranavir (TPV) 2005 Indinavir (IDV) 1996 Saquinavir mesylate (SQV) 1995 Lopinavir + Ritonavir (LPV/RTV) 2000 Fosamprenavir Calcium(FOS-APV) 2003 Ritonavir (RTV) 1996 Darunavir 2006 Atazanavir sulphate (ATV) 2003 Atazanavir + Ritonavir Nelfinavir mesylate (NFV) 1997 HIV Entry Inhibitors Enfuvirtide (T-20) 2003 Maraviroc 2007 Integrase Inhibitors Raltegravir 2007 Elvitegravir Dolutegravir 2013 Others Cobicistat (Booster)
  • 11.
    What do Ido with all these drugs? Student: Which of these drugs should I master? Clinician: Which of these drugs should I prescribe?
  • 12.
    Class Drugs Entry Inhibitors: FusionInhibitor: Enfuvirtide, Chemokinine Receptor Antagonist (CCR5): Maraviroc Nucleoside/tide Reverse Transcriptase Inhibitors (NRTIs) Abacavir, Zidovûdine, Emtricitabine, Lamivudine, Stavudine, Didanosine, NtRTI:Tenoforvir, Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) Efavirenz, Niverapine, Delavirdine, Etravrine, Lilprivine Integrase Inhibitors (ISTIs) Raltegravir, Elvitegravir, Dolutegravir Protease Inhibitors (PIs) Ritonavir, Lopinavir, Saquinavir, Indinavir, Amprenavir, Fosampranavir, Nelfinavir, Darunavir Abbreviations MVC = maraviroc ENF = enfuvirtide (T-20) ABC= Abacavir AZT= Zidovudine 3TC = Lamivudine FTC = Emtricitabine d4T = Stavudine ddC = Zalcitabine ddI = Didanosine TDF = Tenofovir EFV = Efavirenz NVP = Nevirapine ETR = Etravirine DLV= Delavirdine RAL = Raltegravir EVG = Elvitegravir DTG = Dolutegravir RTV = Ritonavir LPV = Lopinavir APV = Amprenavir ATV = Atazanavir DRV = Darunavir FPV = Fosamprenavir IDV = Indinavir LPV/r = lopinavir/ritonavir NFV = nelfinavir /r = ritonavir, low dose SQV = saquinavir
  • 13.
    Population Preferred first-line regimen Alternativefirst-line Regimen Special circumstances Adults and adolescen ts TDF + 3TC (or FTC) + DTG TDF + 3TC + EFV 400 mg TDF + 3TC (or FTC) + EFV 600 mg AZT + 3TC + EFV 600 mg TDF + 3TC (or FTC) + PI/r TDF + 3TC (or FTC) + RAL TAF + 3TC (or FTC) + DTG ABC + 3TC + DTG Children ABC + 3TC + DTG ABC + 3TC + LPV/r ABC + 3TC + RAL TAF + 3TC (or FTC) + DTG ABC + 3TC + EFV (or NVP) AZT + 3TC + EFV (or NVP) AZT + 3TC + LPV/r (or RAL) Neonates AZT + 3TC + RAL AZT + 3TC + NVP AZT + 3TC + LPV/r
  • 14.
  • 15.
    REVERSE TRANSCRIPTASE INHIBITORS NNRTI –Efavirenz (EFV) – Niverapine (NVP) – Delavirdine – Etravirine – Rilpivirine NRTI – Zidovudine (AZT) – Lamivudine (3TC) – Abacavir – Emtricitabine (FTC) – Didanosine – Stavudine ( OL) d4T NtRTI – Tenofovir (TDF) Highlighted for first line ISTI Dolutegravir Raltegravir Elvitegravir
  • 16.
    NRTI Combinations FDC DrugsStandard Dose* Dosage forms Combivir Lamivudine/ Zidovudine 1 Tablet bid * 150/300mg tabs Trizivir Abacavir/Lamivudine/Zidovudine 1 Tablet bid* 300/150/300mg tabs Truvada Tenofovir/Emtricitabine 1 Tablet qd* 300/200mg tabs Epzicom Abacavir/Lamivudine 1 Tablet qd* 600/300mg tabs Atripla Tenofovir/Emtricitabine/Efavirenz 1 Tablet qd* 300/200/600 mg tabs *dose reduce for renal dysfunction
  • 17.
    Newer FDCs  Tenofovir/Lamivudine/Dolutegravir Tenofovir/Emtricitabine/Rilpivirine  Tenofovir/Emtricitabine/Cobicistat/Elvitegravir
  • 18.
    NRTIs Mechanism of Action Nucleoside analogs (like AZT which is a thymidine analogue)  Analog of thymidine, cytosine, adenine, or guanine  Triphosphorylated inside lymphocytes to active compound  Incorporate into the growing HIV viral DNA strand by reverse transcriptase  Nucleotide analog  Currently only tenofovir (TDF)  Does NOT need to be tri-phosphorylated only di-phosphorylated to active compound After incorporation of the NRTI, viral DNA synthesis will be terminated.
  • 19.
    NRTI- Class PK Generallylow protein binding Most have low volume of distribution Bioavailability varies, highest with 3TC, lowest wih TDF Short T1/2 except Emtricitabine and Tenofovir Largely Renal elimination and phase II metabolism No CYP metabolism
  • 20.
    PK of someNRTI NRTI Generic Name Bioavailability (%) VD (L/kg) Protein Binding Metabolism / Elimination Half-Life, h Abacavir 83 0.86 50% Phase II Metabolism by Alcohol dehydrogenase and glucuronyl transferase 1.5 Didanosine 30-40 1.08 <5% Renal 30-50% Hepatic up o 50% 1.5 Emtricitabine 93 Unknown <4% Glomerular Filtration and Tubular Secretion 10 Lamivudine Adults- 93% Children 68% 1.3 <36% 70% Renal Elimination 5.6% to trans-sulfoxide metabolite 5-7 Tenofovir 25 1.2-1.3 7% Active tubular secretion and Glomerular filtration 17 Zidovudine Up to 70% 1.6 25%-38% Hepatic glucuronidation 1
  • 21.
    NRTI Class Toxicities LacticAcidosis – Elevated lactate, low pH/bicarbonate, N/V, shortness of breath, if untreated can lead to death – Results from damage to mitochondria in cells Hepatomegaly with Steatosis – Enlarged liver – Results from build up of fat droplets inside liver cells
  • 22.
    Emtricitabine Nucleoside analog ofcytidine Dose: Adult 200mg, pediatric 6mg/kg od; usually 3TC+TDF Oral bioavailability, up to 93%. AUC approx 10 h*µg/ml; Cmax is 1.8 +_0.7 µg/ml , Cmin 0.09 +_ 0.07 µg/ml T1/2 estimated at 10 hours; Longer Intracellular T1/2 Undergoes glomerular filtration and active tubular secretion, and limited hepatic oxidation/conjugation Avoided if creatine clearance <50mL/min
  • 23.
    NtRTI- Tenofovir Tenofovir-diphosphate: analogueof the natural 2′- deoxyadenosine-triphosphate 300mg oral dose, Oral bioavailability of 25% Peak concentration 326 ng/ml; AUC 3324 ng*hr/ml Undergoes active tubular secretion mainly with OAT-1 and OAT-3 organic anion transporters T1/2=17hrs; ionised triphosphate form is trapped intracellularly prolonging T1/2 to 150 hours main toxicity is damage of proximal renal tubule due to accumulation following uptake by transporters
  • 24.
    NRTIs Drug Standard Dose*Dosage forms Common Side Effects Metabolism/ Elimination Zidovudine (ZDV/AZT) Retrovir 300mg bid* 300mg tab, 100mg cap, iv, oral soln Fatigue, malaise, HA myalgia, anemia, GI Mainly Phase II Renal Lamivudine (3TC) Epivir 150mg bid* or 300mg od 150, 300mg tab, solution Well tolerated Renal Emtricitabine (FTC) Emtriva 200mg od 200mg cap Well tolerated Renal Didanosine (ddI) Videx 400mg EC qd ( 60kg) 250mg EC qd <60kg)* 125,200,250, 400mg cap, pwdr for soln Pancreatitis, peripheral neuropathy, LA/HS Renal Lactic acidosis can occur with any NRTIs; * reduce dose for renal dysfunction Stavudine (d4T) Zerit No longer in first line 40mg bid ( 60kg) 30mg bid (<60kg) 15,20,30,40 mg cap,oral soln Peri neuropathy, Pancreatitis, LA/HS, Lipoatrophy, facial wasting Renal Abacavir (ABC) Ziagen 300mg bid, 600mg qd 300mg tabs, oral soln Severe Hypersensitivity Due to HLA-B*5701 Highest in India and least in SSA Hepatic by alcohol dehydrogenase and glucuronyl transferase Tenofovir (TDF) Viread 300mg qd* 300mg tabs Renal toxicity, bone resorption Renal
  • 25.
    NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS(NNRTIs)  NNRTI bind to reverse transcriptase to an allosteric site, causing structural alterations that prevents addition of new nucleosides to the growing DNA chain  NNRTIs do not require phosphorylation to be active RT
  • 26.
    NNRTIs Drug Standard Dose Dosage forms Common AEs Metabolism CYP450 (enoughfor undergraduates) Delavirdine (DLV) Rescriptor 400 mg tid 100mg tab, 200mg cap Rash Potent CYP3A inhibitor; 3A4 substrate Nevirapine (NVP) Viramune 200 mg qd x 14 d then 200 mg bid 200mg tabs, Oral susp Rash (SJ), hepatotoxicity, CNS toxicity CYP3A inducer, auto inducer; 3A4, 2B6 substrate Efavirenz* (EFV) Sustiva 600 mg qhs 50, 100, 200mg cap, 600mg tab Abnormal dreams, drowsiness or insomnia, rash (SJ), hyperlipidemia Substrate and inducer; CYP3A, 2B6, 3A5, UGT, Pgp Rilpivirine dizziness, abnormal dreams, depression CYP3A4, 2C19, 1A2, Weak inducer CYP3A4, 2B6 and 2C19 May inhibit CYP2B6, 1A2
  • 27.
    NNRTIs-Class Chracteristics No activityon HIV2 Generally High protein binding Long T1/2 CYP450 Metabolism, minimal additional phase II rxn CYP450 Modification, including autoinduction CNS toxicity: sleep disturbances, depression, hallucinations Cross resistance: K103,
  • 28.
    Efavirenz Adult dose is600mg OD; Oral bioavailability is 45% Time to steady state 6-10 days Cmax is12.9 ± 3.7μmol/l, Cmin) 5.6 ± 3.2μmol/l Oral clearance of 0.18 ± 0.072L/h/kg Linear PK; AUC increases proportionally with increasing dose T1/2 is 52-76hrs for single dose; drops to 40-55H due to AI Metabolised primarily by CYP2B6, also CYP3A4/5 and UGT Substrate of ABCB1 Primary and major metabolite is 8-hydroxyefavirenz, and 7- hydroxyefavirenz is the minor metabolite Efv induces several (3A4, 2B6, UGT2B7, ABCB1) Resistance and cross resistance with other NNRTIs
  • 29.
    Etravirine 200mg bd Shares manyproperties with efavirenz – Highly protein binding (>99.8%) – Metablised mainly by CYP3A4, – Mainly Induces CYP3A4, Inhibits CYP2C9, Lower rates of rash and CNS adverse events Has inherent molecular flexibility permitting some affinity to RT despite NNRTI resistance mutations
  • 30.
    Comparison of PKProfiles 0 5 10 15 20 25 30 Mean EFV (95%CI) conc in µmol/l 0 1 2 3 4 6 8 16 24 Time of blood draw PKDay 1 PKDay 14 Zidovudine Emtricitabine Abacavir Efavirenz
  • 31.
    Fifteen health volunteersreceived a single dose of Truvada (Tenofovir +Emtricitabine) (300mgTDF + 200 FTC) Concentrations of Tenofovir (TDF or TFV) and Emtricitabine (FTC) were measured over 14 days in blood plasma (Graph A), Cervical-viginal fluid (Graph B), and in seminal fluid (Graph C). TDF and FTC concentrations were higher in cervicovaginal fluid (graph B), and seminal fluid (C) than in plasma (graph A) Note that the graphs are not drawn to the same scale (Y-axis scales differ) Comparison of Truvada in Plasama, Cervical-viginal and seminal fluids
  • 32.
    Integrase Inhibitors Raltegravir (Isentress™) Dosed400mg BID (1 tab BID) No modification of CYP450 enzymes or Pgp Metabolized by UGT1A1 – Only affected by drugs that inhibit/ induce UGTs ( Rif) Mutation in any of the AA causes resistance:
  • 33.
    Ugandan MOH ARTrecommendations Patient category Recommended ART regimens Alternative ART regimens Adults and adolescents ≥30Kg, including pregnant and breastfeeding women TDF+3TC+DTG ABC+3TC+DTG (if TDF is contraindicated) TDF +3TC+ EFV400 (if DTG is contraindicated) ABC +3TC+ EFV400 (if DTG is contraindicated) TDF +3TC+ATV/r (if DTG and EFV, are contraindicated) ABC + +3TC+ATV/r (if DTG and EFV, are contraindicated) Children ≥ 20Kg - <30Kg ABC+3TC+DTG (AZT or TAF) +3TC+DTG (if ABC is contraindicated (ABC or AZT or TAF)+3TC+LPV/r (if DTG is contraindicated) (ABC or AZT or TAF)+3TC+EFV (if DTG is contraindicated) Children< 20Kg ABC+3TC+DTG AZT+3TC+DTG (if ABC is contraindicated) (ABC or AZT or RAL) +3TC+LPV/r (if DTG is contraindicated) Tripple NRTI (ABC or AZT ) +3TC + RAL
  • 34.
    Data in favorof Integrase Strand Transfer Inhibitors Research shows that when compared to the current NNRTI-based regimens, ISTIs Have a high virological efficacy, Low resistance rate given their high genetic barrier to resistance Excellent safety and tolerability profile that can salvage prior treatment failures to be included in the “first line regiments”. Minimal drug-drug interactions as opposed to NNRTIs
  • 35.
    PROTEASE INHIBITORS (PIs) Mechanismof Action  Protease enzyme cleaves HIV precursor proteins (gag/pol polyproteins) into active proteins that are needed to assemble a new, mature HIV virus.  PIs bind to protease preventing the cleavage and inhibiting the assembly of new HIV viruses PI HIV-1 Protease X HIV
  • 36.
    Protease Inhibitors Standard Dose Dosage FormsMetabolism CYP450 Common AEs** Saquinavir (Invirase) (1) 1000/ rtv 100 bid or 1600/ rtv 100 qd 200mg caps, 500mg tabs 3A, Pgp substrate; weak 3A inhibitor GI intolerance Nelfinavir (Viracept) (1) 1250 bid, 750mg tid 250mg, 625mg tabs, 50mg/g oral pwdr 2C19 (M83A) substrate; weak 3A inhibitor Diarrhea Lopinavir/ ritonavir (Kaletra) (1,2) 400/100 bid 200/50 mg tabs, 80/20mg/5mL soln 3A, Pgp substrate; 3A inhibitor; 2C9, 2C19 inducer Dyspepsia, Nausea, vomiting, diarrhea, flatulence Indinavir (Crixivan) (1-when taken with rtv) 800/ rtv 100 bid, 800mg tid 100, 200, 333, 400mg caps 3A, Pgp substrate; weak 3A inhibitor Nephrolithiasis  Drink 7-8 glasses of water per day; hyperbilirubinemia (1) Take with Food (2) Must be refrigerated ** All PIs except atazanavir can increase lipids and cause insulin resistance
  • 37.
    Protease Inhibitors Standard Dose Dosage FormsMetabolism Common AEs** Atazanavir (Reyataz) (1) 400qd or 300/ rtv 100qd 100, 150, 200mg caps 3A substrate; 3A and UGT1A1 inhibitor Hyperbilirubinemia, PR prolongation Fosamprenavir (Lexiva) (1) 1400mg bid; 700/100 RTV mg bid; 1400/200 RTV mg qd 700mg tabs (Agenerase-APV liq available) 3A4, Pgp substrate; 3A4 inducer/ Inhibitor Rash, GI intolerance, caution with sulfur allergy Tipranavir (Aptivus) (1,2) 500/200 RTV mg bid 250mg caps 3A4, Pgp substrate; 3A4, inducer/ inhibitor??; Pgp inducer Hepatotoxicity, Increased bleeding caution with sulfur allergy Darunavir (Prezista) (1) 600/100 RTV mg bid 300mg tabs 3A4 substrate; 3A4 inhibitors Diarrhea, nausea, HA, nasopharyngitis Ritonavir (Norvir) (1,2) Used as a PK booster 100-200mg 100mg caps; 80mg/mL 2D6, 3A4, Pgp substrate; 3A4, Pgp inhibitor Nausea, vomiting, diarrhea, GI upset (1) Take with Food (2) Must be refrigerated ** All PIs except atazanavir can increase lipids and cause insulin resistance
  • 38.
    Use of Ritonaviras a P450 Inhibitor with PIs
  • 39.
    Lipids, Insulin Resistance (Lypodystrophy) Changesin fat metabolism Hypercolesterolemia – Can have increased LDL and decreased HDL – Treat with Fibric acid derivatives and certain HMGCoA reductase inhibitors Insulin Resistance – Treat with diet/exercise, metformin, sulfonylureas or insulin
  • 40.
  • 41.
    INTEGRASE INHIBITORS The processof Integration of viral DNA into host DNA occur in 6 steps 1.Binding of integrase to viral DNA, 2.3-prime processing (3'-P), 3.Nuclear translocation DNA-integrase pre-integration complex 4.Binding of the pre-integration complex to host DNA, 5.Strand Transfer (ST) 6.Repairing of the gaps formed during ST (gap repair) Current drugs inhibit Strand Transfer Raltegravir Dolutegravir Elvitegravir These are all DKA derivatives
  • 42.
    Integrase Inhibitors MOA •CCD of HIV integrase contains 3 amino acids; D64, D116, E152 • For the enzyme to become active, the AA coordinate its binding with a divalent metal; Mg2+ or Mn2+ • The bound metals coordinate the bonding of the enzyme with viral DNA during the 3'-P and ST • DKAs interact with divalent metals at CCD leading to metal chelation Catalytc Core Domain (CCD) of the HIV1 Integrase Enyzme
  • 43.
    THE INTEGRASE INHIBITORS The integrase strand transfer inhibitors (INSTIs) are potent inhibitors of the HIV- encoded integrase enzyme, which incorporates pro-viral HIV-1 DNA into the host cell genome. Site of action of integrase inhibitors, adapted from Clinical pharmacology of integrase inhibitors
  • 44.
    Integrase Inhibitors Drug StandardDose Metabolism Common AEs Raltegravir (RAL) 400 mg tid Children 10mg/kg Phase II metabolism Major enzyme UGT1A1, minor UGT1A9 & UGT1A3 Minor: dizziness, headache, nausea, excessive tiredness and sleep disorders, life threatening skin reactions (SJ), toxic epidermal necrolysis, Elvitegravir (EVG) 150mg) (ELV/Cob+FT C+TDF) Mainly phase I metabolism CYP3A4/5, then UGT1A1/3 Resistance Mutations: T66I and E92Q, Dolutegravir 600 mg od Mainly Phase II metabolism Major: UGT1A1, Minor: CYP3A4, UGT1A3,1A9 Mutations: Y143C/R, Q148H/K/R and N155H
  • 45.
     Importance ofgp120, gp41 glycoprotiens  Viral tropism (co-receptors on the CD4)  co-receptors CCR5, CXCR4  Varied use of CCR2, CCR3 HIV ENTRY INHIBITORS
  • 46.
    Pharmacological targets ofHIV Entry Inhibition of the interaction between the viral surface glycoprotein (gp120) and CD4 (Several Vaccine Trials) Inhibition of the interaction between gp120 and Co- receptor; CCR5 or CXCR4 (chemokines receptor antagonists) – CCR5-receptor blocker Maraviroc – Cenicriviroc in phase II/III trials (CCR5/CCR2) – Research in Agents with potential as CXCR4 receptor blockers Fusion inhibitors: Peptide derivatives of the gp41 that inhibit its transition to the fusion-active state – Enfuvirtide (T20) HIV-1 gp41 C- peptide derivative
  • 47.
    Fusion Inhibitors Enfuvirtide, T-20 SeeKilby and Eron, NEJM 2003;348:2228-38 Enfuvirtide
  • 48.
    T-20 MOA First FDA-approvedfusion inhibitor; Peptide with36 AA An analogue of heptad repeat 2 (HR2) of gp41 (C-terminal of gp41) It binds to HR1 (N-terminal), preventing the interaction between HR1 and HR2, thus inhibiting the conformational change that allows fusion of the viral cell envelope to the host cell membrane Used in combination therapy (HAART) Active against viruses that utilize the CCR5, CXCR4 and dual/mixed co-receptor tropic viruses
  • 49.
    Fuzeon : Enfuvirtide(T-20) FDA-approved fusion inhibitor Dose: 90 mg bid side effects: – injection site rxn, hypersensitivity (rare) Resistance: changes in gp41 (cell surface protein)
  • 50.
    PK of Enfurvitide Has a bioavailability of 84.3%  SQ injection into the arm, thigh or abdomen is appropriate  The bioavailability differs slightly depending upon the site of administration, but this so has no clinical significance Highly protein bound (92%) to albumin & a-1 acid glycoprotein Small volume of distribution of 5.48L Enfurvitide is a protein, hence it undergoes catabolism Expected to undergo catabolism to its constituent AA, and subsequent the AA recycled in the body pool. T1/2 ~ 3.8 hrs
  • 51.
    Resistance Resistance to enfuvirtideoccurs rapidly A resistance associated mutation in the g41 protein
  • 52.
    Chemokine Receptor Antagonists Marviroc;Blocks viral entry at CCR5 Dosed 300mg BID, Oral. MOA: Maravirocis is a selective and noncompetitive antagonist of CCR5 chemokine receptor. Interacts with the CCR5, inhibiting fusion and viral entry into host cells Chemokine receptors. [Internet]. IUPHAR database (IUPHAR-DB). 2014 [cited 17/06/2014]. Available from: http://www.iuphar- db.org/DATABASE/FamilyMenuForward?familyId=14.
  • 53.
    PK of Maraviroc Poorbiovailabilty; 300mg gives Vf=33% Volume of distribution of 194L Moderately protein bound (76%) to albumin & a-1-acid gp Tmax = 0.5 to 4 hrs, T 1/2 of 14-18 hours High fat diet can reduce Vf & plasma levels by 40-60%, but no clinical relevance Rapidly distribute into seminal/ virginal fluids, rectal tissue and the CNS; reach higher concentrate than in plasma Use limited by need for testing for CCR-Tropism
  • 54.
    Metabolism Maraviroc is metabolizedby the CYP450 3A isoenzymes to inactive metabolites – 8% is excreted unchanged in urine, – 25% is excreted unchanged in feces Maraviroc doesn’t induce or inhibit CYP450 But greatly affected by CYP450 modifiers – Normal dose 300mg BID, Oral. – 150mg BID with P450 inhibitors; Example ----- – 600mg BID with P450 inducers; ------- Drug Interactions
  • 55.
    Clinical uses ofARVs Treating HIV in adults and children – Follow changes in guidelines Pre-exposure prophlaxis (Prep) – HIV-negative people who are at very high risk for HIV infection (HIV negative CSW, Partner in an ongoing relationship with an HIV-positive partner, homosexual/ bisexual man who has had anal sex with no condom – Truvada daily; reduces risk by 90% Post- exposure Prophylaxix (PEP) – HIV negative persons who have been exposed to infected fluids (Mostly exposed Health workers, Rape victims  Truvada+ Raltegravir/ or Dolutegravir for 28 days (start within 36h, prefferably 2h; test for HIV periodlically)  Alternatively; Truvada + ritonavir boosted PI (Dalv or ATV or FAMP)  Prevention of Mother to Child transmission (Option B +)
  • 56.
    Research Updates Long actingantiviral agents (LAA) Long acting antiretroviral drugs including cabotegravir and rilpivirine, given in controlled release injections with long half- lives. Employment of nanotrchnology in HIV Nanotechnology-based drug delivery for HIV/AIDS treatment; Nanomedicine confers targeted delivery of drugs to specific cells or tissues and intracellular delivery of macromolecules. Research on targeted delivery of antiretroviral drugs to CD4+ T cells and macrophages,
  • 57.
  • 58.
    Antiretroviral Metabolism, Induction, andInhibition Drug Substrate Inhibits Induces Efavirenz 2B6, 3A4/5 3A4/5, 2B6 Nevirapine 3A4, 2B6 3A4 Ritonavir 2D6, 3A4, Pgp 3A4, 2D6, Pgp 2D6 (at high doses only) Saquinavir 3A4, Pgp 3A4 Nelfinavir 2C19 (M83A4) 3A4 Amprenavir 3A4, Pgp 3A4 (in vitro) 3A4 (in vivo) Fosamprenavir 3A4, Pgp 3A4 (in vitro) 3A4 (in vivo) Lopinavir/ritonavir 3A4, Pgp 3A4 2C9, 2C19, 1A2 Atazanavir 3A4, Pgp 3A4, UGT, 1A2 Tipranavir 3A4, Pgp 3A4 Other enzymes Darunavir 3A4, Pgp 3A4 Maraviroc 3A4, Pgp
  • 59.
    Substrate Inhibitor Inducer 3A4Macrolides,cyclosporine, CCB, statins, azoles, midazolam, triazolam Cimetidine, Macrolides, FQs, SSRIs, CCB, azoles, aprepitant rifamycins, phenytoin, carbamazepine, St. John’s wort, aprepitant, garlic 2D6 Opiates, nortriptyline, amitriptyline, tramadol, trazodone, paroxetine, metoprolol, propranolol, carvedilol Haldol, SSRIs, cimetidine, amiodarone rifamycins, phenytoin, CBZ, St. John’s wort 1A2 Amitriptyline, clozapine, caffeine, clozapine, imipramine, R-warfarin, theophylline, proprnaolol FQs, azoles, macrolides, rifamycins, phenytoin, CBZ, smoking, St. John’s wort 2C19 Omeprazole, phenytoin SSRIs, azoles, fluvastatin, omeprazole, topiramate rifamycins, CBZ, phenytoin 2C9 S-warfarin, sulfonylureas, phenytoin, carvedilol Amiodarone, SSRIs, azoles, amiodarone Phenytoin, CBZ, rifammycins, aprepitant Cytochrome P450: Non-Antiretrovirals
  • 60.
    Dose Adjustments BetweenARVs Drug A Drug B Recommendation Tenofovir Didanosine Dose ddI as 250mg od with TDF 300mg od Efavirenz (Nevirapine) Atazanavir Use RTV 100mg QD with ATV + EFV Efavirenz (Nevirapine) Fosamprenavir Use RTV with FPV Efavirenz (Nevirapine) Lopinavir/ritonavir Increase LPV/RTV to 3 tabs BID
  • 61.
    Important Drug Interactions NNRTIswith: – Antimalarials, COCPs, AntitTB; levels are reduced by NNRTIs – Antiepileptics” Bilateral changes in drug concentrations – AntitTB drugs: Rif lowers conc of NNRTIs Maraviroc – Increase dose when combined with NNRTIs – Reduce dose if combined with PISs Do NOT use Simvastatin, Lovastatin, Antiarrthymics, Midazolam, Triazolam, Ergot derivatives, Rifamin, St. Johns Wort, or Garlic with most PIs or DLV Do NOT combine Rifampin with PIs – LPV/RTV may be dose increased and combined with Rifampin – Conflicting data with EFV and NVP Use other P450 inducers with CAUTION when combining with PIs and NNRTIs Do NOT use Fluticasone or Alfuzosin with Ritonavir Caution with Azoles, Clarithromycin, Oral Contraceptives, Phenytoin,
  • 62.
  • 63.
    Therapeutic Drug Monitoring Notwidely used in the US Recommended in certain situations for PIs and NNRTIs What makes a drug a good candidate for TDM? When should TDM be performed for antiretrovirals?
  • 64.
  • 65.
    Pre-exposure prophlaxis (Prep) Givento HIV-negative people who are at very high risk for HIV infection – Examples: HIV negative commercial sex workers (CSW), Partner in an ongoing relationship with an HIV-positive partner, homosexual/ bisexual man who has had anal sex with no condom – Truvada daily; reduces risk by 90% – Only effective if taken daily Post- exposure Prophylaxix (PEP) Given to HIV negative persons who have been exposed to infected fluids  Examples: Mostly exposed Health workers after contact with infected fluids, Rape victims  Truvada+ Raltegravir/ or Dolutegravir for 28 days  Alternatively; Truvada + ritonavir boosted PI (Dalv or ATV or FAMP) for 28 days (start within 72h, but the earlier the better prefferably 2h; test for HIV periodlically)  Rationale is to get the drugs into the body as fast as possible to kill the virus before it is able to make many copies, hence reducing chances of an established HIV infections
  • 66.
    Prevention of Motherto Child transmission (Option B +) Use of antiretroviral therapy to prevent infections in babies born to HIV Positive mother Option B+: Start mother on treatment with recommended regimens and continue treating her for life Treatment as Prevention Treating HIV infected patients in discordant relationships (one of the partners is HIV negative). Rationale; Treating the infected member as early as possible reduces their viral load and hence reducing chances of infecting the discordant member.
  • 67.
    Why TRUVADA inPREP and PEP Recall pharmacokientics of the drugs Both Tenofovir + Emtricitabine (Truvada) have long half-lives and concentrate highly in cervical, viginal, seminal, and rectal fluids This helps to kill the virus while attempting to replicate in these areas before spreading to cause an established HIV infection.
  • 68.
    Comparison of concentraionof FTC in plasma and semina fluid Emtricitabin e
  • 69.
    Fifteen health volunteersreceived a single dose of Truvada (Tenofovir +Emtricitabine) (300mgTDF + 200 FTC) Concentrations of Tenofovir (TDF or TFV) and Emtricitabine (FTC) were measured over 14 days in blood plasma (Graph A), Cervical-viginal fluid (Graph B), and in seminal fluid (Graph C). TDF and FTC concentrations were higher in cervicovaginal fluid (graph B), and seminal fluid (C) than in plasma (graph A) Note that the graphs are not drawn to the same scale (Y-axis scales differ) Comparison of Truvada in Plasama, Cervical-viginal and seminal fluids
  • 70.
    From a studyof tenofovir gel applied intraviginally; Tenofovir concentration of ≥100 ng/mL in CVF (cervical-viginal fluid) was associated with 65% protection against HIV, whereas ≥1000 ng/mL concentration correlated with 76% protection against HIV infection
  • 71.
    Antiretroviral Drug Approval: 1987- 2007 0 5 10 15 20 1987 1991 1993 1995 1997 1999 2001 2003 2006 AZT ddI ddC d4T 3TC SQV RTV IDV NVP NFV DLV EFV ABC APV LPV/r TDF T-20 ATV FTC FPV TPV DRV Maraviroc Raltegravir
  • 72.
    Dose adjustments toconsider Renally-eliminated NRTIs (except Abacavir) Adjust for CrCl <50 ml/min or dialysis Didanosine Emtricitabine Lamivudine Stavudine Tenofovir Zidovudine Reference: Drug product info and DHHS guidelines (see tables) Hepatic Metabolism  NNRTIs  PIs Adjust for certain inducers, substrates, or inhibitors of P450 system Adjust for insufficiency Indinavir Fosamprenavir Atazanavir Avoid Amprenavir oral soln Foasmprenavir (+/- ritonavir) Tipranavir