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43 Cards in this Set
- Front
- Back
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Nucleoside and Nucleotide analogues
Act via 2 mech: |
1. Competitive inhibition - competes with dTTP
2. Chain termination - once AZT-TP is incorporated into the growing DNA chain, natural dNTP cannot be added. (more affinity of these analogues for viral reverse transcriptase) |
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Acyclovir
Valacyclovir Famciclovir |
Used for HSV/VZV
Acyclovir - poor oral bioavailability, 10x more active against HSV than VZV Valacyclovir - oral prodrug of acyclovir, 2-5x more bioavailable Famciclovir - oral prodrug of penciclovir (which is used topically) |
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Ganciclovir
Valganciclovir Foscarnet |
Used for CMV
Ganciclovir - nucleoside analogue, low oral bioavailability, much better than acyclovir for CMV, granulocytopenia, thrompocytopenia (cut dose) Valganciclovir - oral prodrug of ganciclovir Foscarnet - pyrophosphate analogue inhibits DNA polymerase, IV only, nephrotox, anemia, active against acyclovir-resistant HSV and VZV, ganciclovir-resistant CMV |
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Practical Recommendations for Anti-retroviral therapy
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Use 3 drugs at once
Start and stop all at once Adherence improves virologic response CyP450 inducers/inhibitors, ALWAYS look up drug interactions |
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Initial therapy
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Typically two nucleoside analogues as cornerstone
Preferred: tenofovir + emtricitabine Alternative: abacavir + lamivudine zidovudine + lamivudine Nucleoside Analogues target viral reverse transcriptase |
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Tenofovir disoprovil fumarate, (TDF), Viread
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prodrug nucleotide analogue, prodrug, 10-50 hr half life, renal, inc creatine, proteinuria, dec bone density
more effective against 3TC/FTC (M184V) resistance than WT Resistance: K65R sensitizes virus to AZT Active vs. Hep B. Don't discontinue if co-treating |
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Lamivudine (3TC), Epivir
Emtricitabine (FTC), Emtriva |
1/day
renal few side effects rapidly develops M184V resistance 184 mutation sensitizes virus to ziduvodine and tenofovir Active vs. Hep B as well Share mutation class M184 Used also for HBV, inhibits DNA Pol at a lower dose. Be sure to increase dose for combo therapy. Emtricitabine not FDA approved, but also used here (Trivada) |
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Abacavir (ABC), Ziagen
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alcohol dehydrogenase metabolism, ethanol increases AUC
Hypersensitivity rxn in 5% fever, rash, fatigue, GI, resp, within 6wks, rechallenge may cause severe hypotension and death-- related to HLA-B*5701 genotype increase cardio disease, less active at high HIV load? |
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Zidovudine (ZDV, AZT) Retrovir
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2x/day
liver glucoronidation, renal excretion anemia, granulocytopenia, nausea Good CNS penetration Used in Prevention of Mother-to-Child Transmission (PMTCT)- IV use during labor and delivery CSF penetration helps with dementia Shares mutation class with Stavudine (TAMs- thymidine associated mutations) |
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Nucleoside side effects?
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Lactic acidosis, hepatic fat deposition (steatosis)-- all nrti, esp stavudine, didanosine
peripheral neuropathy-- zalcitabine, stavudine, didanosine Lipoatrophy, increase lipids-- stavudine Pancreatitis-- didanosine Side effects largely due to "d-drugs" ddC zalcitabine and d4t staudine (both fallen out of favor) |
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Truvada
EpziCom Combivir Trizivir |
emtricitabine + tenofovir QD
abacavir + lamivudine QD zidovudine + lamivudine BiD zidovudine + lamivudine + abacavir BiD (all one pill) |
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Non-nucleoside Reverse Transcriptase Inhibitors
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Inhibit HIV-1 not 2
Rash is most common side effect low genetic barrier to resistance- single point mutation causes resistance |
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Efavirenz (Sustiva)
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Induces some p450, Inhibits others
CNS/psychiatric in 50% of patients-- dizziness, somnolence, abnormal dreams, insomnia, generally resolves in 2-4 weeks Do not give in first trimester of pregnancy Rash in 27%, mild to moderate |
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Efavirenz appears in what combination therapy?
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Atripla:
emtricitabine + tenofovir + efavirenz "One pill once a day" Preferred regimen for naive patients |
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Nevirapine (Viramune)
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2x/day, approved 1x/day if dosed with FTC/TDF in Truvada
Induces P450-- induces its own metabolism. Use dose escalation Rash, elevated transaminases, avoid with higher CD4 counts Also used for Mother to Child Transmission Alternative preferred for naive patients Ziduvodine + Lamivudine + Nevirapine |
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Etravirine (Intelence)
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2nd gen
2x/day hepatic metabolism,Cyp450 inducer/inhibitor rash and nauasea, no CNS effects (like new and improved efavirenz) Active vs K103N virus (resistant to EFV, NVP) Resistance requires multiple NNRTI mutations, Y181C is the key mutation Use in treatment-experienced patients only, in combination with a protease inhibitor |
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NNRTI mutations
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K103N - Efavirenz and Nevirapine
Y181C - Etravirine and both the above |
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Protease Inhibitors
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target viral protease- create non infectious progeny virions
All inhibit cyp450, some also induce Ritonavir boosting-- small doses of ritonavir inhibit p450 metabolism, increase trough and AUC of a second PI boosted PIs have low rate of resistance in breakthrough virus due to high trough concentrations |
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Initial Therapy Guidelines
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2 NRTI or NtRTI plus
Preferred: Atazanavir/rtv Darunavir/rtv Alternative: Fos-amprenavir/rtv Lopinavir/rtv |
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Atazanavir (Reyataz)
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indirect unconjugated hyperbilirubinemia due to inhibition of UDP-glucuronosyl transferase
decreased trough with TDF, must use boosted ATV/rtv proton pump inhibitors, h2 blockers, and antacids reduce absorption |
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Darunavir (Prezista)
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active against viruses resistant to multiple other protease inhibitors
Diarrhea, nausea, headache, skin rashes, SULFA allergy |
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Fos-amprenavir (Lexiva)
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prodrug of amprenavir with more bioavailability
headache, nausea, vomiting, hyperlipidemia, and rash (SULFA) |
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Lopinavir + ritonavir (Kaletra- same pill)
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BID, fixed dose combo pill, 4 pills per day
active against 1st gen PI mutations diarrhea, nauasea, hyperlipidemia more ritonavir/day Part of preferred PMTCT |
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Protease Inhibitor Mutations
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Atazanavir- I50L
Fosamprenavir, Darunavir I50V Lopinavir/ritonavir, Indinavir and all of above V82 and I84V |
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Lipodystrophy syndrome
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Subcu fat wasting (lipoatrophy)
Intra-abdominal fat, breast enlargement, buffalo hump Dyslipidemia, Insulin resistance, diabetes mellitus |
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Enfuvirtide (T20), Fuzeon
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HIV Entry Inhibitor
36 amino acid peptide, corresponds to gp41 of HIV envelope glycoprotein inhibits fusion of virus subcu injection BID injection site rxns, low patient enthusiasm however, NO cross resistance with other classes |
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Maraviroc (Selzentry)
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CCR5 Antagonist
Only active against R% virus, must send tropism test (Trofile) before starting-- BID CYP34A and P-glycoprotein resistance mech - aa +/- in V3 loop of HIV-1, tropism shift, emergence of X4 virus or dual mixed however, again, NO cross resistance with other classes approved for treatment naive |
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Raltegravir (Isentress)
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Integrase Inhibitor
Great drug, glucuronidation via UGT BID, well tolerated Low barrier to resistance compared to boosted PIs, use will 2 other fully active agents Cross resistance with elvitegravir (investigational integrase inhibitor) approved for treatment naive |
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Oseltamivir (Tamiflu)
Zanamivir (Relenza) |
Neuramindase Inhibitors
Osetamivir- high bioavailability, take with food, renal excretion Zanamivir - dry powder inhalation, low oral and systemic bioavailability, NO PREGNANCY USE, can cause bronchospasm |
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Amantadine
Rimantidine |
viral uncoating - blocks ion movement into endocytotic vesicles through M2 proteins - mutation in HA protein gene allows virus to uncoat at higher pH
influenza A, not B |
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Ribavirin
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hypermutation and inhibition of RNA Pol
inhaled aerosol used for acute Respiratory Syncytial Virus pneumonia in children can cause bronchospasn, teratogenic to exposed healthcare workers oral form used in combo with interferon for hep C |
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Interferon
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normally produced in response to viral infection
antiviral- induces enzymes that lead to inhibition of protein synth in virus infected cells immunomodulator PEG- polyethylene glycol conjugated |
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Interferon Alpha
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side effects - flu like fever chills, fatigue, headache, myalgias (50%)
inflam at injection site depression, insomnia bm suppression thyroid function eye tox chronic hep B or C subcu injection |
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Hep B
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Lamivudine, Adefovir, Tenofovir, Entecavir, Telbivudine, Interferon Alpha,
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Lamivudine (Epivir-HBV)
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see other slide
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Adefovir (Hepsera)
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Same company as tenofovir
nucleotide analogue effective against lamivudine resistant less potent, but high threshold for resistance second line treatment option |
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Tenofovir (Viread)
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nucleotide analogue
active against lamivudine resistant HBV, but not adefovir-resistant better tolerated than adefovir co-formulated with emtricitabine as Truvada FIRST LINE- MOST POTENT FOR HBV |
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Entecavir (Baraclude)
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nucleoside analogue
less effective for lamivudine-resistant virus active against HIV, so DON'T use alone in HIV co-infection unless HIV RNA fully suppressed FIRST LINE treatment option |
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Telbivudine (Tyzeka)
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Second line option
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Interferon Alpha for HBV
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FIRST LINE OPTION
no benefit to adding oral agents to interferon Peg-IFN alpha more convenient dosing potential long term AB responses possible |
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New Agents for Hep C-- Direct Acting Agents
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Protease Inhibitors - inhibit NS3/4 protease of HCV, active only against genotype 1.
Add ribavirin to dec emergence of resistance and inc response rate Boceprevir Telaprevir |
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Boceprevir
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4 pills TID = 12 pills/day
side effects (many discontinue) anemia and dysgeusia (abnormal taste) |
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Telaprevir
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2 pills TID = 6 pills/day
side effects (many discontinue) anemia, rash, pruritis, nausea |
