Antivirals

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Drug

Features

Antiviral agents

fewer options, limited MOAs, ideally works to inhibit viral-specific fxns and causes minimal host cell metabolic disturbances; target depends on type of virus

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Most viruses are obligate intracellular parasites

require host mechanisms for replication; difficult to design drugs to target viral replication w/o damaging host

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Non-HIV viral infections

herpes simplex virus (HSV), varicella-zoster virus (VZV), cytomegalovirus (CMV), influenza A & B, hepatitis B & C, papillomavirus, respiratory syncytial virus (RSV)

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Herpes simplex virus

dsDNA virus; skin/mucous membranes; vesicles; common STD; recurrent; a/w immunocompromised;

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HSV-1

localized mainly around oral region

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HSV-2

mainly localized around genital region

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Varicella-zoster virus

belongs to a group of herpes viruses including: HSV-1, HSV-2, VZV, CMV, EBV, HHV-6, HHV-7

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VZV disease manifestations: Varicella

"chicken pox" - 75-95% of cases occurs in kids <10yo

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VZV disease manifestations: Herpes Zoster

"shingles" - virus becomes active after bein latent usu face/trunk; occurs in 10-20% of those who had chickenpox; uknown cause of reactivation (age, immunosuppression, cancer)

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Antiviral Agents for HSV and VZV

nucleoside analogs (systemic) and topical/ocular agents

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Nucleoside analogs (guanosine derivatives)

acyclovir (zovirax), famciclovir (famvir), valcyclovir (valtrex); all have similar MOA/indications/but different pharmokinetics

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Drugs for HSV: Systemic Therapy - oral, genital, mucocutaneous HSV

acyclovir, famciclovir, valcyclovir

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Drugs for HSV: Systemic Therapy - HSV encephalitis

acyclovir

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Drugs for HSV: Systemic Therapy - Acyclovir-resistant HSV (severe infxn, immunocopromised)

Foscarnet (foscavir)

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Drugs for VZV: Systemic Therapy - Varicella

Acyclovir

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Drugs for VZV: Systemic Therapy - Herpes Zoster

acyclovir, famciclovir, valcyclovir

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Drugs for VZV: Systemic Therapy - Acyclovir-resistant VZV

Foscarnet

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Acyclovir

available topical, PO, IV (the ONLY IV in this class); primary use HSV1, HSV2, VZV, CNS, visceral, disseminated infxns; can dec risk of transmission to baby w/maternal genital herpes; Great data;

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Acyclovir MOA

requires 3 steps to be activated; enter cell (convert to acyclovir monophosphate by thymidine kinase); Add 2Ps (forms acyclovir triphopshate); Competes w/dGTP for viral DNA polymerase; Incorporated into viral DNA & stops elongation

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Acyclovir Pharmokinetics

oral dose 5x/day; short half-life; poor bioavailability (15-20%); renal clearance; large volume of distribution

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Acyclovir: Topical

treats oral herpes outbreaks; reduces duration by 1/2 day (must apply 5x/day for 4 days)

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Acyclovir: IV

encephalitis, disseminated disease

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Acyclovir: PO

genital herpes initial/recurrent outbreak and daily suppressive; Oral herpes; Herpes Zoster; Varicella

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Acyclovir: adverse effects

Oral (GI disturbances, headache); IV (phlebitis, renal dysfxn - crystalizes in kidney; make sure pt is hydrated; dose on IBW)

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Famciclovir

PO only! Used for: HSV-1, HSV-2, VZV; if HSV and VZV are resistant to acyclovir that are usually resistant to this drug too

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Famciclovir MOA

metabolized to penciclovir in the body, works in a similar manner to acyclovir

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Famciclovir Pharmokinetics

extensive first-pass metabolism to penciclovir (PCV); nucleoside analog similar to acyclovir; Improved bioavailability (77%); Longer intracellular half-life in PCV triphosphate form (10-20hrs) drops dose to 3x/d

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Famciclovir: PO

genital herpes initial outbreak/recurrent outbreak and daily suppressive; Oral herpes; Herpes Zoster

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Famciclovir: adverse effects

headache, nausea, diarrhea

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Valacyclovir

PO only! HSV-1, HSV-2, VZV (HSV and VZV acyclovir-resistant strains also resist this drug)

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Valacyclovir: MOA and Pharmokinetics

same as acyclovir; Valine ester prodrug of acyclovir metabolized to acyclovir; Results in blood levels 3-5x higher than acyclovir; less frequent dosing

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Valacyclovir: PO

genital herpes initial/recurrent oubreak and daily suppression (once daily dosing; reduces transmission risk); Oral herpes (once daily dose); Herpes zoster

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Valacyclovir: Adverse Effects

GI disurbances, HA; TTP/HUS (thrombotic thrombocytopenic purpura/hemolytic uremic syndrome in HIV pts w/high dose)

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Topical Therapy for Orolabial HSV

acyclovir (zovirax), penciclovir (denavir), docosanol (abreva)

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Ocular Therapy for Keratoconjunctivitis (ocular herpes)

Trifluridine (viroptic)

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Zovirax

prescription only, similar to systemic product; apply 5x/day for 4 days

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Denavir

prescription only, similar MOA to acyclovir; apply every 2hrs while awake for 4days; decresaes healing time by 0.7days

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Abreva

available OTC; inhibits fusion btw HSV and plasma membrane preventing entry into cells; apply 5x/day ($16); if started w/in 12hrs it decreases healing time by 1/2day

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Trifluridine

nucleoside analog; **active against Acyclovir-Resistant Strains of HSV;** irreversible inhibition of thymidylate synthetase (incorporates thymidine into viral DNA); incorporates into cellular DNA (precludes systemic use)

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Acyclovir Resistance

mostly limited to immunocompromised (5-10% in AIDS pts; 18% in bone marrow transplants; 0.6% in immunocompetent); Mechanisms: Viruses deficient in TK/altered substrate specificity of TK (can't recognize ACV or ACV-3P/altered viral DNA polymerase enzymes

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CMV

infects 50-85% of adults in US by age 40 (frequ transmitted to child b/f birth); more widespead in low class; some experience mono-like syndrome; virus stays dormant for life (recurs rarely unless immunocompromised)

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Drugs for CMV

Systemic: ganciclovir (cytovene), valganiciclovir (valcyte), foscarnet (foscavir), cidofovir (visitide); Ocular: ganciclovir (vitrasert), fomivirsen (vitravene)

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Ganciclovir

PO, IV, intra-ocular implant; Mostly used for CMV (also effective but toxic for resistant HSV, VZV but foscarnet is more active)

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Ganciclovir MOA

similar to acyclovir, except it is initially phosphorylated by enzyme UL97 (NOT thymidine kinase (TK))

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Ganciclovir Pharmokinetics

poor oral bioavailability (5% inc to 9% w/food); Renal excretion; dose adjust

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Ganciclovir Place in Therapy

Tx of systemic CMV (lungs, colon, esophagus); CMV retinitis; prevention of CMV in transplant, immunosuppressed pts

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Ganciclovir Adverse Effects

teratogenic, carcinogenic, mutagenic; myelosuppression (esp. neutropenia 20-40%); fever, rash, HA; liver/kidney dysfxn

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Valganciclovir

PO only!! Used for activity against CMV; MOA like ganciclovir

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Valganciclovir: Pharmokinetics

oral prodrug of ganciclovir; converted in body to ganciclovir; improved bioavailability (61%); achieves concentrations similar to IV ganciclovir; dosed less frequently

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Valganciclovir: Place in Therapy

mostly replaced oral ganciclovir; CMV retinitis; prevention of CMV in transplant/immunosuppressed pts; maintenance Tx of systemic CMV

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Valganciclovir

same as ganciclover, except more anemia and diarrhea

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Resistance to Ganciclovir

Mutation in UL97 (not x-resistant with cidofovir or foscavir); Mutation in DNA polymerase (may be x-resistant with cidofovir...use foscavir instead)

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Foscavir

IV only!! Requires slow infusion and large fluid volume; Used for CMV (also good for non-resistant and resistant HSV & VZV); Toxicity prevents use as first-line for CMV; Toxicity limits use to resistant HSV, VZV only; Try cidofovir if foscavir-resistant

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Foscavir MOA

pyrophoshate analog; doesn't require TK activation or phosphorylation; Inhibits DNA and RNA polymerase

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Foscavir Pharmokinetics

poor bioavailability and GI intolerance prevent oral dosing; primarily renally cleared; can be deposited in bone

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Foscavir Place in Therapy

2nd line for CMV (retinitis, systemic infxn, ganciclovir-resistant CMV, prevention in transplant/immunosuppressed pts); Resisant HSV and VZV

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Foscavir Adverse Effects

nephrotoxic, electrolyte disturbance (hypocalcemia, hypophosphatemia, hypokalemia, hypomagnesemia); GI effects; Bone marrow suppression (anemia, neutropenia; less than ganciclovir??)

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Cidofovir

IV only!! cytosine nucleoside analog; used for CMV, resistant HSV/VZV, and rare viruses

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Cidofovir MOA

2 stages of phosphorylation (cellular enzymes: Monophosphate Kinase and Pyruvate Kinase; not TK); Forms cidofovir diphosphate; similar to nucleotides (competitive inhibitor of alternate substrate for CMV DNA polymerase)

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Cidofovir Pharmokinetics

primarily renally excreted (plasma half-life 2.5hrs; clinical intracellular duration of action up to 60hrs); Given once a week for 2 weeks

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Cidofovir Place in Therapy

Primarily used for CMV activity (also resistant HSV/VZV; adenoviruses, papillomaviruses, poxviruses); not available commercially, but compounded as topical cream for genital warts

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Cidofovir Adverse Effects

Nephrotoxic (always give w/NS and probenecid to decrease nephrotoxicity; avoid use of nephrotoxic meds and pts w/renal insufficiency); Neutropenia; Metabolic acidosis

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Fomivirisen (vitravene)

given intravitreally every 2-4wks (half-life 55hrs); used for CMV retinitis (for those unresponsive to other therapies); Unique MOA (binds to mRNA)

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Ganciclovir (vitrasert)

small capsule-like device containing a drug core encased in permeable and impermeable polymer layers for surgical implantation in the back of the eye

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Influenza virus nomenclature

type of nucleoprotein (virus type, geographic origin, strain number and year of isolation); Hemagglutinin and Neuraminidase indicates the virus subtype based on surface antigens

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Drugs for Influenza: M2 Inhibitors

prevention and treatment of influenza A; Rimantadine (flumadine), Amantadine (symmetrel)

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Amantadine & Rimantadine

prevents/treates influenza A; if Tx begins in 48hrs it decreases fever/symptoms by 1day; resistance develops in 3-5days

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M2 Inhibitor MOA

blocks M2 protein channel in influenza A; disrupts H transport, viral uncoating in host cell and therefore viral RNA transcription

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M2 Inhibitor Pharmokinetics

both are renal excretion (adjust dose); Rimantadine is hepatically metabolized before excretion (dose adjust)

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M2 Inhibitor Place in Therapy

control institutional outbreaks, protect high risk pts immunized after epidemic begins; prophylactic for immunosuppressed/those at high risk for flu

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M2 Inhibitor Adverse Effects

GI (anorexia, nausea); CNS effects (nervous/anxiety, confusion, concentration; Amantadine > Rimantadine dt release of DA; rarely use in Parkinsons Dx)

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Drugs for Influenza: Neuraminidase Inhibitors

Prevention and Treatment of influenza A & B: Oseltamivir (tamiflu), Zanamivir (relenza)

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Oseltamivir & Zanamivir

prevent/treat influenza A&B; Must Tx w/in 48hrs for Zanamivir, 36hrs for Oseltamivir to decrease sx by 1-2days; Decreases risk of complications (respiratory, hospitalization, antibiotic use);

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Drugs for Influenza: Neuraminidase Inhibitors Resistance

Oseltamivir (1-9% emergence during therapy); Zanamivir (rare resistance; active agains strains resistant to other agents)

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Neuraminidase Inhibitors MOA

virion has already infected host cell and looks to bud from infected cell; Surface of virus has neuramidase ptns (neuramidase breaks bonds holding viruses to outside of infected cells); If Neuramidase is inhibited ==> new virus insn't released/spread

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Oseltamivir Pharmokinetics

PO only; pro-drug activated in body; renal excretion (dose adjust)

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Zanamivir Pharmokinetics

Inhalation only! up to 25% bioavailable (17% is systemically absorbed)

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Drugs for Influenza: Neuraminidase Inhibitors Place in Therapy

same pt population as M2 agents; prevention of complications; effective against most strains of influenza; less resistance; better tolerated

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Oseltamivir Adverse Effects

nausea/vomiting (give w/food)

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Zanamivir Adverse Effects

nasal/throat discomfort; bronchospasm (avoid in asthmatics)

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HBV: Drugs for chronic hepatitis

Lamivudine (epivir HBV); Interferon alfa-2b (intron A); Peginterferon alfa-2a (pegasys); Adefovir (hepsera); Entecavir (baraclude)

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HCV: Drugs for Chonic Hepatitis

Peginterferon alfa-2b (PEG-Intron) + Ribavirin (rebetol), Peginterferon alfa-2a (Pegasys) + Ribavirin (copegus)

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HCV: Drugs for Acute Hepatitis

Interferon alfa-2b (intron A)

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Hepatitis Drugs by Class: Interferons

Interferon alfa-2b (Intron A), Peginterferon alfa-2b (PEG-intron), Peginterferon alfa-2a (pegasys)

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Hepatitis Drugs by Class: Ribavirin

rebetol, copegus

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Interferons - just know they have various effects on body

ptns w/many actions: 1. Antiviral/immunomodul. effects RNA/ptn synth; 2. Binds membrane receptors/initiates cascade (enzyme induction, suppress cell prolif, inhibit viral replication, immunomodulate); 3. Given SC or IM; 4. w/Ribavirin for HCV

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Interferons (IFN): Adverse Effects

Management of adverse effects/logistics (up to 66% of pts discontinue therapy b/c of "minor side effect hurdles"; some adverse effects can be managed while on therapy; Dr must play role in management/prevention of adverse effects

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IFNs: flu-like symptoms

fever/chills, malaise/fatigue, muscle aches; occur in 75% of pts; usu occur 3-4hrs after injection and improve in 24hrs or in first 2-3months

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IFN Management

start dose low and titrate slowly; temporarily reduce dose; give at bedtime w/ prophylactic ASA, APAP or NSAIDs; give w/low-dose glucocorticoid

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IFN: Injection Site Reaction

50% of pts given SC injections (erythema, skin lesions, atrophy/necrosis/secondary infxn (can require abx/surgery and d/c of drug)); Necrosis occus in 5%

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IFNs: Management of Injection Site Rxns

proper technique (rotate sites, proper depth, massage); use autoinjectors for SC; pretreat w/ice; ensure drug is completely dissolved at room temp; avoid excess sunlight exposure

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IFN Adverse Effects: Increased muscle spasticity

worsens during first months w/in 3-24hrs after injection lasting hrs-days); give NSAIDs or muscle relaxant (baclofen); reducing dose is not helpful

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IFN Adverse Effects: Lab abnormalities

anemia, neutropenia, thrombocytopenia, LFT elevation (rarely persistant if d/c drug); get baseline LFT, CBC and repeat at 1 and 3 months of therapy)

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IFN Adverse Effects: Depression

inc suicide risk? depression could be dt many mechanisms? trials show no added risk, but monitor and treat for depression as appropriate

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Ribavirin

Nucleoside analog (inhibits synthesis of viral RNA or DNA); used in combo for HCV infxn (Primary, but never monotherapy for HCV); Also used nebulized as Tx for RSV (rarely); possibly for SARS/lassa fever; Primary toxicity: Hemolytic Anemia; Pregnancy X

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Imiquimod (Aldara)

available as cream; use for HPV (regular and genital warts); actinic keratosis, superficial basal cell carcinoma; MOA unknown

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Palivizumab (synagis)

monoclonal antibody; prevent RSV (respiratory syncytial virus - most common pneumonia in infants); NOT a vaccine; given to high-risk infants (lund Dx, premature) during RSV season to prevent infxn

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HAART

combo HIV Tx - highly active antiretroviral therapy; must monitor CD4 cell count & HIV RNA levels (viral load); Inc in viral load or dec in CD4 may indicate drug resistance (susceptibility testing; change Tx regimen); different toxicity/efficacy

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HIV Fusion Inhibitors: Enfuvirtide (fuzeon; aka T-20)

linear 36 amino acid synthetic peptide; only member in class; given as SC injection; not a first-line therapy (recommended in Tx experienced pts w/ongoing HIV replication despite current antiretroviral use)

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Fusion Inhibitor MOA

after HIV binds to host surface a conformational change occurs in gp41; change allows fusion of membranes allowing entry into host cell; Fusion Inhibitors bind gp41 and block conformational change

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Fusion of HIV virion w/ a host cell is a multi-step process

1. HIV virion approaches CD4 cell w/gp41 and gp120 subunits in its glycoprotein spikes; 2. CD4 interacts w/gp120 for initial attachment; 3. When gp120 interacts w/CD4 receptors, a conformation allows interaction w/cell co-receptors CXCR4 or CCR5

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Conformational changes in gp120 following binding w/co-receptors causes:

gp41 to be exposed; fusion is mediated by gp41 (which contains 2 heptad repeat domains, HR1 and HR2)

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As gp41 is exposed, a further structural change occurs in gp120 facilitatin insertion of gp41 into the:

Tcell membrane; HR2 domain begins to coild into the exposed grooves of the HR1 region; this zipping process destabilizes both Tcell and viral membranes allowing HIV RNA to pass into CD4 Tcell

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Fuzeon

a peptide homolog of part of the HR2 region of gp41; it binds to portion of HR1 and blocks HR1-HR2 zipping interaction to prevent fusion

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Fuzeon: Adverse Effects

injection site reactions (pain, induration, nodules, cysts); hypersensitivity

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NRTIs "Nukes": NucleoSIDE reverse transcriptase inhibitors

Abacavir (ziagen, ABC), Didanosine (videx, videx EC, ddl), Emtricitabine (emtriva, FTC), Lamivudine (epivir, 3TC), Stavudine (zerit, d4T), Zalcitabine (hivid, ddC), Zidovudine (retrovir, AZT, ZDV)

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NRTIs "Nukes": NucleoTIDE reverse transcriptase inhibitor

Tenofovir (viread, TDF)

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NRTIs: Combination Products

Zidovudine/lamivudine (Combivir), Zidovudine/lamivudine/abacavir (trizivir), Abacavir/lamivudine (epzicom), Emtricitabine/tenofovir (truvada)

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NRTI: MOA

reverse transcriptase converts HIV ssRNA into dsDNA; drugs competetively inhibits enzyme RT; synthetic analogs incorporated into viral DNA (viral DNA cannot produce fxnl DNA, elongation is stopped dt "dummy building blocks")

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NRTI: Class Adverse Effects

1. Mitochondrial Toxicity: lactic acidosis (never give stauv+dida), hepatic steatosis, peripheral neuropathy, pancreatitis (esp stauvudine/didanosine/zalcitabine/zidovudine); Lamivudine and Tenofovir are well tolerated; 2. Lipoatrophy: unnatural fat loss

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NRTI: Points of Note

few drug interactions

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NRTI: Points of Note - Didanosine

the only NRTI that must be taken w/regard to food (30min b/f, 2hr after)

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NRTI: Points of Note - Abacavir

not toxic to mitochondria or causative of lipoatrophy (interacts w/alcohol); Hypersensitivity rxn in 3-9% (rash, fever, fatigue, respiratory/GI symptoms; can be fatal)

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NRTI: Points of Note - Zalcitabine

rarely used

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NNRTIs: "non-nukes" - Non-nucleoside reverse transcriptase inhibitors

Delavirdine (rescriptor, DLV), Efavirenz (sustiva, EFV), Nevirapine (viramune, NVP)

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NNRTI: MOA

binds directly to enzyme RT (binds near active site; doesn't compete with viral nucleosides, alters active site and inactivates enzyme); viral RNA cannot produce any DNA

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NNRTI: Adverse Effects

all can cause a serious rash

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NNRTI: Adverse Effects - Efavirenz

CNS effects (dizziness, HA, insomnia, vivid dreams, nightmares, hallucinations w/in 3hrs of each dose and may stop in a few wks)

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NNRTI: Adverse Effects - Nevirapine

severe hepatotoxicity (esp in pts w/liver probs at baseline); Highest incidence of rash

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NNRTI: Points of note

more drug rxns than NRTIs; Cross-resistance w/in class is common (not across classes); Efavirenz and Nevirapine are used most commonly

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Protease Inhibitors

Amprenavir (agenerase, APV), Atazanavir (reyataz, ATV), Fosamprenavir (lexiva), Indinavir (crixivan, IDV), Lipoinavir/ritonavir (kaletra, LPV/RTV), Nelfinavir (viracept, NFV), Ritonavir (norvir, RTV), Saquinavir hard/soft gel cap (invirase, SQV hgc/sgc)

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Protease Inhibitor: MOI

protease enzymes cleave ptn into smaller functional mature virions; PIs inhibit this enzyme; ptn cannot be cleaved into fxnl ptn (cannot be assembled or released); cannot infect new cells or replicate further

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Protease Inhibitor: Class Adverse Effects

inc serum glucose/cholesterol/TGs (inc risk of coronary artery disease); Lipodystrophy (inc fat deposition in back/abdomen and wasting in arms/face); Hepatotoxicity; GI side effects

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Protease Inhibitors: Points of Note

class has revolutionized treatment; most drug interactions of HIV meds (substrates for CYP 3A4 except *Nelfinavir*); new regimens are combining 2 PIs together

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PI: Nelfinavir

not a substrate for CYP 3A4

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PI: Atazanavir

lacks effect on cholesterol

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HIV and Pregnancy: Best way to prevent perinatal transmission

Optimal Therapy: Nevirapine or Zidovudine + NRTI + PI

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Single dose nevirapine

often used to prevent perinatal transmission in developing countries

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Efavirenz

never use in pregnancy!!!

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HAART: complicated therapy

drug interactions, resistance, additive toxicities from concomitant meds; guidelines continually updated

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HAART: Initial Regimen - 2NRTIs + NNRTI

Zidovudine OR Tenofovir + Lamivudine OR Emtricitabine + Efavirenz

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HAART: Initial Regimen - 2NRTIs + PI

Zidovudine OR Tenofovir + Lamivudine OR Emtricitabine + Lopinavir/Ritonavir

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HAART: Build combinations with at least 3 medications

one of which is a NNRTI or PI!

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