Non HIV Anti Virals Prof. Mary Klotman

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1 Mary Klotman, M.D. Professor of Medicine and Microbiology Mount Sinai School of Medicine New York, NY 1 Nucleoside analogues: first line herpes antivirals Parent Oral prodrug Valganciclovir 2 Phosphorylation of acyclic nucleoside analogues: specificity of herpes antivirals Initial phosphorylation limits toxicity Aciclovir Penciclovir Ganciclovir Nature Reviews Microbiology, 2: The screen versions of these slides have full details of copyright and acknowledgements 1

2 Acyclovir (zovirax) Acyclic deoxyguanasine derivative oral, intravenous and topical Valacyclovir is an oral ester prodrug of acyclovir that is cleaved to acyclovir in GI tract Related derivatives: famciclovir (oral) and penciclovir (topical and IV) Target: DNA polymerase HSV-1/HSV-2 (0.1 µm), VZV (2.6 µm) >>> CMV (47.1 µm), EBV Active form is tri-phosphate; First phosphorylation mediated by viral thymidine kinase 4 Mechanism of action of acyclovir Figure 2. Mechanism of action of acyclovir in cells infected by herpes simplex virus Acyclovir competes with deoxyguanasine for binding to polymerase and permanently terminates DNA chain elongation (NEJM, 340: 1262, 1999) 5 Pharmacokinetics of acyclovir and valacyclovir Acyclovir: 10-20% bioavailability/peak serum concentrations between 1 and 2 µg/ml with 200 and 800 µg, respectively Oral form limited activity against VZV Half-life three hours CSF: 50% serum levels Cleared by glomerular filtration; must be dose adjusted with renal insufficiency Valacyclovir: 48-54% bioavailability allowing oral therapy with less frequent dosing 6 The screen versions of these slides have full details of copyright and acknowledgements 2

3 Toxicities of acyclovir and valacyclovir Reversible crystalline nephropathy Crystallization of drug in tubules Avoid with hydration and slow infusion Gastrointestinal, local irritation and headache Encephalopath y In setting of renal insufficiency Thrombotic microangiopath y Valacyclovir in setting of immunodeficiency 7 Antiviral resistance Occurs with virus replication in the presence of partially suppressing concentrations of drug Must have replication to generate mutations Usually seen in immunocompromised patients with prolonged exposure to acyclovir Mutations in thymidine kinase more frequent than mutations in DNA polymerase Suspect in absence of clinical response TK alterations result in resistance to all acyclovir-lik e drugs but not to other anti-herpes drugs that are not dependent on this step, i.e., foscarnet 8 Clinical application of acyclovir Prophylaxis and treatment of HSV and VZV Choice of drug and formulation depends on virus, host, manifestations and cost Normal host Treatment: shortens clinical course/viral shedding o HSV Primary genital/recurrent genital herpes: decrease symptoms by 2 days and virus shedding by 7 days Herpes labialis: can decrease symptoms 1/2 to 1 day with topical or oral treatment Herpes encephalitis: intravenous acyclovir markedly alters mortality o VZV Chickenpox: high dose oral acyclovir or valacyclovir in patients at risk for more severe course, i.e., adults and immunocompromised Zoster especially in elderly Suppression to prevent recurrence Frequent recurrent genital herpes 9 The screen versions of these slides have full details of copyright and acknowledgements 3

4 Neonatal herpes Clinical application continued Intravenous acyclovir Immunocompromised hosts Treatment o HSV o VZV Prophylaxis Treat all mucocutaneous No clinical response, consider resistance - foscarnet Chickenpox: intravenous acyclovir Zoster (shingles): intravenous acyclovir or valacyclovir o Those at risk for severe disease, particularly during active immunosuppression 10 Herpes gingivostomatitis/labialis Primary HSV gingivostomat itis Oral acyclovir, valacyclovir, famciclovir Primary HSV 1, normal host Herpes labialis in immunocompromised Acyclovir (consider IV), valacyclovir, famciclovir Recurrent HSV in HIV+, lesion 1 month Herpes labialis in normal host Treatment optional: oral or topical, short course Recurrent in normal host, day 2 of lesion 11 First episode or recurrent genital herpes: normal and immunocompromised host Treatment of first and recurrent episodes Oral acyclovir, valacyclovir or famciclovir Severe/immunocompromised- IV acyclovir Primary HSV 2 Suppressive therapy (especially in setting of HIV): for frequent recurrences Acyclovir, valacyclovir or famciclovir Recurrent HSV 2 12 The screen versions of these slides have full details of copyright and acknowledgements 4

5 Severe HSV disease: IV high-dose acyclovir Neonatal herpes HSV encephalitis Disseminated in immunocompromised 13 Chicken pox in adult or immunocompromised host Adult: oral acyclovir (high dose) or valacyclovir Immunocompromised: IV acyclovir high dose Zoster in normal and immunocompromised IV acyclovir, valacyclovir or famciclovir, high dose oral acyclovir Reduces duration of shedding, decrease in new lesions, decrease acute pain Decrease in post-herpetic neuralgia Prevent dissemination in the immunocompromised Varicella zoster 14 Other anti-hsv drugs Idoxuridine (herplex) and trifluridine (viroptic) Inhibit polymerase of virus as well as cellular polymerases, little specificity HSV and VZV Topical only, i.e., ophthalmic cream/ointment for herpes kerato-conjunctivit is 15 The screen versions of these slides have full details of copyright and acknowledgements 5

6 Anti-CMV drugs: ganciclovir (cytovene) and valganciclovir (valcyte) Ganciclovir Acyclic deoxyguanasine analog; Addition of hydroxyl-methyl group Oral, intravenous and intraocular implant CMV, HSV, VZV, EBV, HHV-8 Triphosphorylat ed The CMV kinase (UL97) phosphorylates more efficiently than acyclovir Also phosphorylated by TK Valganciclovir 16 Mechanism and pharmacokinetics of ganciclovir Competitive inhibition of polymerase, not an absolute chain terminator Bioavailability of ganciclovir is 6-9%, valganciclovir is 60% 5 mg/kg/d of IV ganciclovir equivalent to 900 mg/d valganciclovir Serum half-life of 2-4 h and intracellular half-life of triphosphate up to 12 h CSF penetration 50% Cleared by kidneys so needs dose adjustment 17 Toxicities of ganciclovir Myelosuppression, especially neutropenia Can be worse with other suppressive drugs, i.e., bone marrow transplant setting Dose reduction, GMCSF Renal insufficiency: crystals Hydration and proper dose adjustment Fever, headache Encephalopathy Rash Elevation in liver enzymes Retinal detachment from corneal implant 18 The screen versions of these slides have full details of copyright and acknowledgements 6

7 Ganciclovir resistance Primarily UL97 (CMV kinase) mutations (foscarnet/cidofovir still sensitive) or rarely polymerase mutations (some cross resistant) Usually seen with prolonged exposure to the drug, i.e., in AIDS patients or transplant patients 19 Clinical indications for ganciclovir Treatment CMV disease in immunocompromised ; IV ganciclovir or oral valganciclovir o May delay engraftment CMV retinitis in AIDS patients o Induction and maintenance phase: high dose IV or high dose oral valganciclovir followed by lower dose maintenance o Alternative: ocular implant: at risk for disease in other eye without systemic therapy Prophylaxis for those at risk, particularly in transplant setting Usually used after engraftment in bone marrow transplant setting Combination protocols of IV ganciclovir followed by valganciclovir 20 CMV retinitis in AIDS Pre-treatment Post-treatment at 6 weeks 21 The screen versions of these slides have full details of copyright and acknowledgements 7

8 Alternative anti-herpes drugs: foscarnet (foscavir) Organic analog of pyrophosphat e: trisodium phosphonoformat e Intravenous only HSV, VZV, CMV, EBV, HHV-6 and 8 No phosphorylation required: toxicity Target: binds directly to DNA polymerase at the pyrophosphat e binding site: prevents cleavage and chain extension 22 Foscarnet: pharmacokinetics and toxicities Poor bioavailability therefore IV only CSF: up to 67% of serum Plasma half-life: 6.8 h, bone up to months Renal clearance therefore must be dose adjusted Renal insufficiency: common/tubule damage Hydration and careful monitoring of function Dose adjustment Electrolyte imbalances: common/ch elator Hypocalcemia, careful monitoring and replacement Gastrointestinal: common Anemia, penile ulcers (accumulation of drug) and seizures 23 Foscarnet: resistance and clinical indications Resistance: point mutations in polymerase Usually not resistant to ganciclovir-resistant isolates but foscarnet resistant isolates usually cross resistant to other CMV drugs Indications: severe CMV disease/ret initis especially when caused by an isolate with a UL97 mutation or patient can not tolerate ganciclovir (bone marrow transplant) Hydration and monitoring of renal function 24 The screen versions of these slides have full details of copyright and acknowledgements 8

9 Cidofovir (vistide) Cytosine nucleotide analog Intravenous CMV, HSV, VZV, EBV, HHV-6 and 8, adenovirus, poxviruses Phosphorylated to active diphosphate by cellular kinases Competitively binds to polymerase, incorporated into DNA chain 25 Cidofovir: pharmacokinetics and toxicities Half-life of 2.6 h, however active diphosphate intracellular half-life of h Given every 7-14 days Given with probenecid Blocks tubular secretion, decreases nephrotoxicity Poor CNS penetration Cleared by renal tubular secretion Dose adjustment and hydration Dose-dependent renal toxicity Hydration, avoid with significant renal insufficiency, avoid other nephrotoxic drugs 26 Cidofovir: clinical indications and resistance CMV retinitis: induction (q7 days) and maintenance (q14 days) dosing Severe CMV disease with contraindications to other drugs Can be used with UL97 mutant isolates resistant to ganciclovir 27 The screen versions of these slides have full details of copyright and acknowledgements 9

10 Fomivirsen (vitravene) Antisense oligodeoxynucleotide Intraocular only CMV specific Hybridizes with CMV RNA Intraocular half-life of 55 h Indication: CMV retinitis in AIDS Complications: CMV in other eye, intraocular inflammation 28 Influenza: orthmyxoviridae family Enveloped (-) strand RNA viruses Eight single stranded segments, can be re-assorted, exchanged and engineered; 10 polypeptides Four genera; Human pathogens A and B Subtypes based on hemagglutinins (H1-H15) and neuraminidases (N1-N9), drift within subtypes, shift when major change in subtypes Major animal reservoirs, especially aquatic birds, can jump hosts and re-assort 29 Antiviral targets in influenza Neuraminidase and M2 channel Schematic representation of influenza A virion Influenza virus replication cycle 30 The screen versions of these slides have full details of copyright and acknowledgements 10

11 NEJM, 343: 177, Anti-influenza drugs: M2 inhibitors Amantadine (symmetrel): cyclic amine, 1-aminoadamantane hydrochloride Influenza A only Targets the M2 viral ion channel and prevents ion flux necessary for uncoating in the endosome Oral: 90% bioavailable, h half-life Excreted in urine unchanged: dose adjustment especially in elderly Toxicities: CNS in elderly, gastrointestinal Resistance: frequent, mutations in M2 protein 32 Anti-influenza drugs: M2 inhibitors Clinical indications Treatment of influenza A in patients at risk for complications (200 mg/day, 100 mg/day in elderly); Shortens duration of symptoms and time of viral shedding Benefit within h of symptoms Presently limited value due to resistance Prevention; exposed at risk and non-vaccinated individuals 33 The screen versions of these slides have full details of copyright and acknowledgements 11

12 Anti-influenza drugs: neuraminidase inhibitors Oseltamivir Chemical structure N-acetylneuraminic acid analogs: oseltamivir (tamiflu), zanamivir (relenza) Target: viral neuraminid ase, preventing virus release Influenza A and B Zanamivir 34 Oseltamivir pharmacokinetics and toxicities Oral prodrug 80% bioavailable (zanamivir not absorbed, therefore inhaled) Activated in gut and liver Plasma half-life of 6-8 h (standard dose is 75 mg twice/day) Cleared by kidneys, therefore must be dose adjusted, especially in elderly Toxicity: gastrointestinal, better with food Resistance not as frequent as M2 inhibitors but can occur, mutations in neuraminidase or hemagglutinin 35 Oseltamivir: clinical indications Treatment Prevention Patients at risk for complications: elderly, chronic disease Patients with severe disease, i.e., pneumonia Normal host to modestly reduce duration of symptoms In general treatment must be started within h to have a benefit Those in high risk groups and not vaccinated o Nursing home outbreak 36 The screen versions of these slides have full details of copyright and acknowledgements 12

13 Oseltamivir vs. placebo for laboratoryconfirmed influenza in normal adults (The Lancet, 355: 1845, 2000) Treated within 36 h of illness, 66% were confirmed cases (475) Treatment with 150 mg 2X/day resulted in a shorter duration of illness by 35 h (30% reduction, 81 vs. 116 h) Treatment within 24 h even faster resolution Treatment associated with less viral shedding, improved symptom scores 37 Figure 2: Time (h) to resolution of all symptoms in influenza-infected patients 38 Six week prevention trial: community influenza outbreak NEJM, 341: 1339, 1999 Protection 82-89% 39 The screen versions of these slides have full details of copyright and acknowledgements 13

14 Anti-hepatitis B drugs Lamivudine Cytidine Lamivudine (3TC or epivir): nucleoside (cytidine) analog Phosphorylated to triphosphate in cell HBV, HIV Competitively inhibits polymerase (in the case of HIV-reverse transcriptase) Oral bioavailability: 80% Prolonged intracellular half-life of h CSF: 20% of plasma Renal clearance; dose adjustment 40 Lamivudine for hepatitis B Toxicities and resistance Few toxicities: headache, fatigue, insomnia Resistance: frequent with chronic administration A rate of 20%/year YMDD mutation in polymerase Associated with viral rebound 41 Lamivudine for hepatitis B Clinical indications In patients with chronic active hepatitis: chronic suppression with 100 mg/day Can be used in patients with decompensation of liver function Marked and rapid decrease in circulating viral DNA within 2 weeks Slows progression of liver fibrosis Majority (80%) rebound off therapy 20% will convert from e antigen positive to negative 42 The screen versions of these slides have full details of copyright and acknowledgements 14

15 Adefovir dipivoxil (hepsera) Adefovir Adefovir dipivoxil Acyclic nucleotid e analog of adenosine monophosph ate Oral prodrug becomes adefovir Phosphorylated by cellular enzyme to active diphosphate Competitively inhibits HBV polymerase/chain termination HIV, HBV, herpesviruses Higher doses required for HIV/unacceptable renal toxicity 43 Adefovir dipivoxil Pharmacokinetics and resistance Prodrug 59% bioavailability; serum half-life of 7.5 h Cleared by glomerular filtration/t ubular secretion, therefore must be dose adjusted Higher anti-hiv doses associated with renal toxicity: renal tubule dysfunction Active against lamivudine-resistant HBV Resistant isolates relatively rare Toxicity: dose dependent renal tubule dysfunction, lactic acidosis, hepatic steatosis 44 Adefovir dipivoxil (hepsera) Clinical indications Chronic active hepatitis B, especially when resistant to lamivudine; 10 mg/day Suppresses HBV DNA Associated with improvement in liver histology and liver enzymes Viral rebounds when stop therapy 45 The screen versions of these slides have full details of copyright and acknowledgements 15

16 Entecavir: hepatitis B antiviral Guanasine nucleosid e analog Intracellular phosphorylation to active triphosphate Inhibits HBV polymerase Inhibits priming of polymerase, reverse transcriptase activity of polymerase and the synthesis of positive strand DNA Greater in vitro potency than lamivudine, active against lamivudine resistant virus Intracellular 1/2 life of 15 hours/daily dosing 46 Entecavir continued Tablet and solution 100% bioavailable on empty stomach Renally cleared, dose adjustment Standard dose mg 1X/day Superior histologic, virologic and biochemical response when compared to lamivudine in clinical trials Resistance rare compared to lamivudine 47 A summary of the resistance rates for lamivudine, adefovir dipivoxil, and entecavir Mohanty SR, et al., (2006), Treatment of chronic hepatitis B, Nat. Clin. Pract. Gastroenterol. Hepatol., 3: , doi: /ncpgasthep The screen versions of these slides have full details of copyright and acknowledgements 16

17 Recombinant interferon α Active against a number of viruses, particularly hepatitis B and C Acts by inducing expression of antiviral genes Recombinant α-2b (rebetron or intron-a) and 2a (roferon) Pegylated 2a (pegasys) and 2b (PEG-intron) Natural host antiviral that works via cell surface receptors inducing signaling 49 Recombinant interferon Subcutaneous injection gives maximum serum concentrations in 7 h, half-life of 2-5 h Pegylated: branched polyethylene glycol covalently bound to interferon Slower clearance and sustained absorption Peak levels h and sustained up to 168 h, half-life 40 h Cleared by glomerular filtration, no dose adjustment usually necessary Toxicities; flu-like syndrome, neuropsychiatric with severe depression, thrombocytopenia, granulocytopenia, elevated liver enzymes 50 Recombinant interferon Clinical indications Chronic active hepatitis B Subcutaneously daily or 3X/week Decline in HBV DNA and improved liver histology and enzymes Virus rebounds with stopping Effective against lamivudine-resistant isolates 51 The screen versions of these slides have full details of copyright and acknowledgements 17

18 Recombinant interferon Clinical indications Chronic active hepatitis C Best results seen when pegylated form used with ribavirin Sustained viral response in majority in absence of HIV with clearing of plasma HCV RNA and improvement in liver histology Poorer response with genotype 1 and with HIV 52 Ribavirin: role in HCV infection Guanasine analog Hepatitis C, RSV, influenza A and B, parainfluenza Phosphorylated by cellular kinases Interferes with guanasine triphosphate Inhibits capping of mrna and RNA polymerase 53 Ribavirin Oral bioavailability: 64% Cleared by the kidneys, therefore needs dose adjustment Toxicities: hemolytic anemia - dose related, depression, fatigue, teratogenic Contraindicated with severe anemia or renal insufficiency, severe heart disease and pregnancy Indications: improves response to interferon in HCV, severe RSV disease via aerosolization 54 The screen versions of these slides have full details of copyright and acknowledgements 18

19 Conclusions A number of therapeutic options with proven clinical benefit In the near future, there will be increasing options against new viral targets, that when given alone or in combination will have enhanced clinical benefit The screen versions of these slides have full details of copyright and acknowledgements 19