• Information
  1. Acyclovir
  2. Valacyclovir
  3. Famciclovir
  4. Penciclovir
  5. Ganciclovir
  6. Foscarnet
  7. Cidofovir
  8. Fomivirsen
  9. Zanamivir
  10. Oseltamivir
  11. Amantadine
  12. Rimantadine
  13. Lamivudine
  14. Ribavirin
  15. Interferon alpha
  16. Adefovir Dipovoxil
  17. Entecavir
  18. Telbivudine
  19. Docosanol
  20. Trifluridine

A. Acyclovir (Zovirax®) [1]

1. Acyclic guanosine analogue
   1. Competes with dGTP as a substrate for the viral DNA polymerase
   2. Herpes thymidine kinase (TK), but not human enzyme, phosphorylates acyclovir
   3. Acyclovir phosphate binds irreversibly to herpes polymerase, inactivates it
   4. Mainly active against herpes simplex (HSV) and varicella zoster (VZV) virus infections
2. Treatment of Mild to Moderate HSV and VZV
   1. Probably second line for orolabial HSV (1% penciclovir cream recommended)
   2. Genital HSV: 400mg po tid x 10d for mild, 5mg/kg q8hr x 5 days for severe
   3. Recurrent genital: 400mg tid x 5 days
   4. Suppression: 400mg bid effective for ocular and non-ocular disease [26]
   5. HSV Encephalitis: 10mg/kg iv q8 14-21 days
   6. Valacyclovir is an acyclovir prodrug with improved bioavailability (see below)
3. Immunocompromised Host
   1. Drug of choice for first line therapy in immunocompromised persons
   2. Resistance to acyclovir has been documented
   3. High dose acyclovir does not, however, prevent cytomegalovirus (CMV) infections
   4. Mucocutaneous HSV: 400mg 5X per day or 5mg/kg IV q8 hours x 10-14 days
   5. Severe: 5mg/kg q8hr iv x 7-10 days
4. Pharmacokinetics
   1. Acyclovir has ~20% bioavailability
   2. Very short half life
5. Topical acyclovir 5% does not appear to have any real activity over placebo [3]
6. Side Effects
   1. Extremely well tolerated overall
   2. Non-specific gastrointestinal symptoms
   3. Headache, rash
   4. High dose intravenous may precipitate in the renal tubules (crystal nephropathy)
   5. This can lead to azotemia; good hydration will reduce incidence of azotemia
   6. High doses may also cause confusion, agitation, disorientation, hallucinations
   7. Tremors and myoclonus very uncommon
   8. Not recommended during pregnancy, but appears to be safe
7. Acyclovir Resistance
   1. Resistance usually due to altered viral DNA polymerase or viral thymidine kinase
   2. Many HSV resistant strains have been recovered from persons with HIV
   3. Other immunodeficiencies can increase risk of developing resistant strains
   4. Foscarnet 40mg/kg IV q8 hr x 14-21 days is recommended for resistant strains

B. Valacyclovir (Valtrex®) [4,48]

1. L-valyl ester of acyclovir
   1. Metabolized to acyclovir after oral administration
   2. Improved bioavailablity, near 100%
2. Utility and Dosing
   1. Better serum levels than oral acyclovir
   2. Highly active against VZV, HSV1 and HSV2
   3. More rapid resolution of pain, reduced post-herpetic neuralgia than acyclovir [3]
   4. Approved for suppression of genital herpes (mainly HSV2) transmision [55,56]
   5. In HIV1+ patients with HSV, valacyclovir 500mg bid reduced HIV1 levels 0.53 log10/mL [10]
   6. Minimal activity against CMV, where valganciclovir is superior
3. Dosing
   1. Herpes zoster: 1000mg po tid x 7 days
   2. Treatment of orolabial HSV with 2gm po q12 hours x 1 day (2 doses) [48]
   3. Prevention of HSV transmission 500mg po qd (~75% effective) [56]
   4. Prevention of CMV disease in HIV at 2000mg po qid, but increased mortality
4. Side Effects
   1. Generally well tolerated, similar to acyclovir
   2. Valacyclovir may cause hemolytic anemia in immunocompromised persons
   3. This may be part of microangiopathic hemolytic uremia syndrome

C. Famciclovir (Famvir®) [5]

1. Alternative to acyclovir
   1. Famciclovir is rapidly converted to penciclovir after oral intake
   2. Penciclovir is the active compound
   3. Herpes TK phosphorylates penciclovir to phosphate
   4. Penciclovir phosphate inactivates herpes polymerase
   5. Also inactivates hepatitis B virus (HBV) polymerase
2. Famciclovir has about 80% bioavailability
3. Utility
   1. Given within 72 hours, reduces duration but not incidence of postherpetic neuralgia
   2. Useful for all forms of HSV [7,8]
   3. Suppression of HSV infections in HIV infected persons [9]
   4. Shows good efficacy in subset of patients with recurrent HBV infection [23]
4. Dosing [3]
   1. Herpes Zoster (Shingles): 500mg po tid x 7 days
   2. Genital HSV: 250mg po tid x 5-10 days
   3. Recurrent genital HSV: 125mg po bid x 5 days
   4. Prophylaxis for genital HSV: 250mg po bid
   5. Consider use in HBV infection, possibly with IFNa or lamuvidine [23]

D. Penciclovir (Denavir®) [11]

1. FDA approved 1% topical cream for oral HSV
   1. Penciclovir cream significantly reduced pain, viral shedding, and healing in oral HSV
   2. However, the cream must be aplied every 2 hours, or ~9 times daily
2. Active metabolite of famciclovir
3. Also active against VZV and HBV

E. Ganciclovir (Cytovene®) [12] and Valganciclovir (Valcyte®) [1,45]

1. Ganciclovir is dihydrophosphoguanine (DHPG)
   1. Derivative of acyclovir with hydroxymethyl group at 3' position of acylic side chain
   2. Because of hydroxyl group on 3' carbon, this is not an absolute DNA chain terminator
   3. ~100X more effective than acyclovir against CMV in vitro
   4. Also effective against HHV-8, the etiologic agent of Kaposi's Sarcoma
   5. Viral phosphotransferases add phosphate group
   6. Oral ganciclovir has low bioavailability of ~9%
   7. Intraocular implant ganciclovir (Vitrasert®) very effective for ocular CMV disease [1]
   8. Valgancyclovir is L-valyl ester of ganciclovir with excellent oral availability
   9. Valgancyclovir should replace both IV and PO ganciclovir for CMV retinitis [45]
2. Indications
   1. CMV retinitis, other CMV infections except pneumonia
   2. Acyclovir resistant HSV
   3. Oral ganciclovir for CMV prevention in patients with HIV and CD4 <50/µL [13,14]
   4. Combination ganciclovir and foscarnet may be required in severe infections
   5. Oral or IV ganciclovir reduces risk of Kaposi's sarcoma in HIV+ persons >75% [29]
3. Gancyclovir Dosing
   1. Usually given as intravenous: 5mg/kg IV bid for 2-3 weeks (renal dosing)
   2. Oral therapy for prophylaxis in HIV with patients with CMV disease [14]
   3. Usual oral dose is 1500mg po bid but 1500mg po TID is probably more effective [29]
4. Valgancyclovir Dosing
   1. Induction 900mg po bid (usually for 3 weeks for CMV retinitis)
   2. Maintenance 900mg po qd
   3. Probably active in CMV pneumonia
5. Side Effects
   1. Myelosuppresion: granulocytopenia and thrombocytopenia mainly
   2. Severe pan-myelosuppression with AZT
   3. G-CSF and/or erythropoietin may be given for cytopenias
   4. Teratogenic, carcinogenic, and mutagenic in animals

F. Foscarnet (Foscavir®) [1]

1. Trisodium phosphonoformate
2. Inhibits DNA polymerases of all human herpesviruses (including HHV-6)
3. Probably blocks the pyrophosphate binding site (prevents chain elongation)
4. PFA also blocks influenza A RNA-dependent RNA polymerases and RT of HIV
5. Deposited in bone and may be hepatotoxic
6. Indications: acyclovir resistant HSV, VSV, CMV, possibly for HHV-8
7. Dosing
   1. Only intravenous formulation: 60mg/kg IV q8hr or 90mg/kg q12 hr for 2-3 weeks
   2. Adjustment for renal function required
8. Side Effects
   1. Nephrotoxic: azotemia (50%) and renal failure
   2. Nausea, vomiting
   3. Anemia and fatigue
   4. Electrolytes: low potassium and magnesium, abnormal calcium and phosphate
   5. Seizures - may be exacerbated by electrolyte disturbances
9. Drug of choice in patients with myelosuppression

G. Cidofovir (Vistide®) [15,16]

1. Nucleoside analog highly active against CMV given intravitreous or intravenous
2. Utility
   1. Intravitreous injections of 20µg cidofovir is safe and effective in CMV retinitis [17]
   2. Chronic suppression of CMV disease involving organs, including resistant strains
   3. Cidofovir gel (Forvade®) for topical treatment of acyclovir resistant HSV
   4. Activity against HHV-8; may be useful in Kaposi's sarcoma treatment
   5. Activity in vitro and in animal models against smallpox (variola virus) [44]
   6. Also active in vitro and in animals against progressive vaccinia (from smallpox vaccine) [51]
3. Dosing
   1. Intravenous dose 5mg/kg weekly for 2 weeks, then 3-5mg/kg every two weeks
   2. Given with probenecid (4gm peri-infusion) and saline hydration
4. Side Effects
   1. With IV therapy, 25% of patients have discontinued mdication
   2. Proteinuria, creatinine elevation, and metabolic acidosis occur
   3. Neutropenia may be marked
   4. Intravitreous: low risk of retinal detachment, ocular trauma, uveitis
5. Contraindicated for use with any other nephrotoxic agents
6. Ganciclovir and acyclovir resistant viruses are rarely resistant to cidofovir

H. Fomivirsen (Vitravene®) [1]

1. Antisense oligonucleotide for intravitreal treatment of CMV retinitis
2. Used for patients resistant to other therapies
3. Should not be used within 2-4 weeks of cidofovir treatment
4. Adverse effects: iritis, vitritis, increased intraocular pressure, vision changes
5. Development of resistance by CMV has not been documented

I. Zanamivir (Relenza®) [27,28,32,37,57]

1. Viral neuraminidase inhibitor
   1. Sialic acid analogue which inhibits influenza A and B virus
   2. Neuraminidase is the enzyme that cleaves sialic acid on target cells
   3. Cleavage required for release of new virus particles
2. Active against both Types A and B influenza (unlike amantadine/rimantadine)
3. Inhaled version is FDA approved
   1. Oral versions being developed
   2. However, low oral bioavailability (~10%)
   3. Rapid serum elimination by renal excretion
   4. Low volume of distribution
4. Both inhaled and oral improve influenza symptoms when started after onset of symptoms
5. Also highly protective in prophylactic setting
   1. Prevents flu-like symptoms when given prophylactically or 1-2 days after infection
   2. 50-90% reduction in symptoms of influenza infection and earlier return to work
   3. Effective (80%) for prophylaxis of family members exposed to influenza [39]
   4. Reduced requirements for antibiotics in high risk patients with influenza [28]
6. Dose is inhaled or intranasal 5mg bid
7. Recommended for use only in serious infections and epidemics [61]

J. Oseltamivir (Tamiflu®) [27,31,32,34,37,57]

1. Oral neuraminidase inhibitor
   1. Neuraminidase is the enzyme that cleaves sialic acid
   2. Oseltamivir is a carbocyclic transition state analog of sialic acid cleavage
   3. Neuraminidase mutations confer resistance to oseltamivir and can arise within 5 days of treatment in children [2]
2. Acute Influenza [36,38]
   1. Effective for acute influenza infection when initiated within 36 hours
   2. Reduced symptom scores: both duration and severity including fever and fatigue
   3. Likely to reduce incidence of secondary complications of influenza
   4. Cost effective treatment (without definitive diagnosis) in unvaccinated and high-risk vaccinated patients >65 years old [54]
   5. In other vaccinated patients age >65, diagnostic testing for influenza then treatment [54]
   6. Avian influenza H5N1 is usually sensitive to oseltamivir used at standard doses
   7. Oseltamivir resistance (neuraminidase mutation) can rarely emerge during treatment [59]
3. Prophylaxis in Influenza Outbreak Areas [34]
   1. Administered to healthy adults 18-65 years old in areas of influenza outbreaks
   2. Dosing qd or bid led to reduction of influenza from 4.8% (control) to 1.2-1.3%
   3. Rate of protection against culture-confirmed influenza was 87%
   4. Reduces new influenza ~90% in household contacts of cases used within 48 hours [42]
   5. Very well tolerated with mild nausea
   6. Prophylasis 75mg qd x 6 weeks in frail persons >64 years old reduces influenza complications 85% and is well tolerated [35]
4. Usual adult dose is 75-150mg po bid for treatment, 75mg po qd for prophylaxis
5. Side effects were only transient mild nausea and some vomiting
6. Recommended for use only in serious infections and epidemics [61]

K. Amantadine (Symmetrel®) [18,32,57]

1. Adamantane which Interferes with early step in Influenza A replication
   1. Blocks viral M2 protein ion channel
   2. Thus, reduces effect of this viral protein on viral uncoating and cellular pH regulation
2. No activity against Influenza B or Parainfluenza virus and increasing resistant influenza A
3. Must be started prior to exposure or symptoms to be most effective
   1. Amantadine ~80% effective in preventing illness
   2. May reduce symptoms duration after onset of symptoms
   3. 92% of influenza isolates in 2005-6 had mutation that confers adamantane resistance [62]
4. Dosing
   1. Dose is100mg po bid with
   2. Reduce dose in with any renal impairment
   3. Avoid (reduce dose) with severe hepatic disease
5. Side Effects
   1. Neurotoxicity (anxiety, agitation), insomnia, dizziness, hallucination,
   2. Coma has been reported in the elderly, especially with renal insufficiency
   3. Teratogenic; contraindicated in pregnancy
6. Not recommended for treatment of influenza A in 2006 [60,61,62]

L. Rimantadine (Flumadine®) [1,32,57]

1. Methyl amantadine with same mechanism of action as amantadine
2. Much improved side effect profile compared with amantadine
3. Decrease for renal insufficiency only if creatinine clearance <10mL/min
4. Excellent for influenza prophylaxis with 70-90% prevention rate
5. Dose 200mg po qd
6. No activity against Influenza B or Parainfluenza Virus and increasing resistant influenza A
7. Not recommended for treatment of influenza A in 2006 [60,61]

M. Lamivudine (LAM, Epivir®) [19,20]

1. Oral dideoxynucleoside inhibitor, nucleoside analog
   1. Blocks HIV reverse transcriptase
   2. Blocks HBV DNA synthesis by RNA-DNA polymerase
2. Efficacy in Chronic HBV Infection [19,23,33]
   1. Single agent treatment in chronic HBV led to HBV DNA reduction to undetectable levels in ~50% of patients as well as improvement in liver histology
   2. Also increases seroconversion in HBeAg carriers
   3. After drug discontinuation, viral DNA reappears after drug is stopped
   4. May be used pre-transplant in patients with cirrhosis and active HBV infection [20]
   5. Treatment through 42 months with LAM 100mg qd reduces hepatic decompensation and hepatocellular carcinoma in chronic HBV with advanced liver disease [25]
   6. Combination therapy with IFNa is generally not beneficial
   7. Well tolerated with some response in children with chronic HBV [46]
   8. In HBsAg+ patients receiving cancer chemotherapy, LAM prophylaxis prevents reactivation by >80% and may eliminate HBV-related hepatic failure [6]
3. Dosing
   1. Usual anti-HBV dose in chronic carriers is 100mg/day, up to 300mg/day
   2. For prophylaxis in liver transplantation, 100mg/d 4 weeks before and indefinitely after
   3. For HIV, dose is 150mg po bid in combination therapy
4. Side Effects
   1. Generally well tolerated
   2. Fatigue, headache, gastrointestinal complaints, muscle aches
   3. Pancreatitis infrequent, mainly in children

N. Ribavirin (Virazole®, others) [21,22]

1. Synthetic nucleoside
   1. Antiviral agent with anti-HCV activity
   2. Aerosolized form (Virazole®) has some against respiratory syncytial virus (RSV)
2. HCV [22,43]
   1. Showed significant reduction in aminotransferase levels in HCV disease
   2. However, aminotransferase levels remained normal in ~7% after drug stopped
   3. Serum HCV RNA levels did not change during or after therapy
   4. Syngergistic combination with IFNa shows in HCV, increases repsonse rates [22,47]
   5. Ribavirin alone is of little value in chronic HCV infection and is not recommended [63]
3. Utility
   1. Aerosolized agent for children with RSV and pneumonia/bronchiolitis
   2. IV for prophylaxis or treatment of Lassa fever and Hantavirus Hemorrhagic Fever [44]
   3. Also appears active against Argentine hemorrhagic fever [44]
   4. Investigations ongoing in Hantavirus Pulmonary Syndrome [3]
4. Dosing
   1. Oral 800-1200mg per day in combination with interferon alpha (Rebetron®)
   2. Aerosolized agent (Virazole®)
   3. Intravenous formulation available from Centers for Disease Control (CDC) in USA
5. Obtaining Oral Ribavirin Capsules [43]
   1. Ribavirin oral is not marketed in the USA
   2. However, compounding pharmacies provide the drug in USA
   3. Fisher Pharmacy (Pittsburgh) 888-347-3416
   4. International Academy of Compounding Pharamcists 800-927-4227 (www.iacprx.org)

O. Interferon alpha (IFNa) [22,23]

1. Recombinant human alpha IFN
   1. IFNa-2a (Roferon®) and IFN-2b (IntronA®) - given thrice weekly subcutaneously
   2. PEG-Interferon alpha 2a (Pegasys®) - IFN-2a covalented attached to 40K PEG molecule
   3. PEG-IFNa-2a (Pegasys®) once weekly; more effective than IFNa for HCV [40,41]
   4. PEG-IFNa-2b (PEG-Intron®) once weekly is FDA approved for HCV infection [43]
2. Utility
   1. HBV ~40% prolonged responses (higher with lamuvidine)
   2. HCV ~50% initial response with ~60% relapse after stopping drug
   3. Combination therapy with ribavirin
   4. Hepatitis D Virus - ~50% complete response during therapy, with ~50% relapse [24]
   5. Human Papillomavirus (HPV)
   6. Human Herpesvirus 8 (HHV 8)
   7. Also used in various cancers (CML, Multiple Myeloma, Hairy Cell Leukemia)
3. Combination with famciclovir is also promising
4. Dosing - typically 3-6 MU sc 3X per week for antiviral effects
5. Side Effects
   1. Flu-like syndrome including fevers
   2. Injection site inflammation
   3. Thrombocytopenia
   4. Neutropenia
   5. Autoimmune Thyroiditis
   6. Depression exacerbation

P. Adefovir Dipovoxil (Hepsera®) [49]

1. Nucleoside analog (prodrug) with broad antiviral activity (mainly anti-HIV and HBV)
2. Activated by phosphorylation to adefovir diphosphate which is a DNA chain terminator
3. Dose 10mg po qd for HBV (60mg/d in HIV has many side effects)
4. HIV Negative Patients for 48 Weeks [52,53]
   1. In HBeAg- patients, reduces HBV DNA levels to <400 copies/mL in 50%
   2. In HBeAg- patients, improves liver histology in 64% (versus 33% with placebo)
   3. In HBeAg+ patients, causes seroconversion to HBeAb+ in 12-14%
   4. In HBeAg+ patients, histologic improvement occurred in ~55% (25% with placebo)
   5. In HBeAg+ patients, appears less effective at 24 and 52 weeks than telbivudine [64]
5. In HIV+ HBV patients, 48 weeks of adefovir reduced lamivudine resistant HBV levels [50]
6. Severe hepatitis exacerbations can occur after cessation of therapy in ~25% patients
7. Causes creatinine elevation and can be nephrotoxic
8. Caution in patients with pre-existing renal dysfunction
9. Dose in HBV is 10-30mg/d, generally well tolerated

Q. Entecavir (Baraclude®) [58]

1. Nucleoside analog with HBV activity (no HIV activity)
2. Guanosine analog, extremely potent, effective aginst YMDD mutants
3. Slightly superior to LAM in LAM naive patients (~9% overall superior ALT normalization)
4. Good activity in LAM resistant patients (61% normalize ALT)
5. Generally well tolerated; some lactic acidosis and hepatomegaly steatosis reported
6. Dose is 0.5mg po qd

R. Telbivudine (Tyzeka®) [64]

1. Nucleoside analog reverse transcriptase inhibitor, anti-HBV
2. Dose 600mg qd x 1 year superior for HBV DNA negativity against lamivudine 100mg qd
3. HBV DNA negative at 52 weeks: 60% of HBeAg+, 88% of HBeAg- patients
4. In HBeAg+ persons, superior viral suppression at 24 and 52 weeks versus adefovir [64]
5. No activity against HIV or HCV
6. Fatigue, malaise, fever, joint pain, GI upset, elevated muscle enzyme levels

S. Docosanol (Abreva®)

1. Long chain fatty acid for treatment of recurrent herpes labialis
2. Available in USA as 10% cream over the counter (without prescription)
3. Prevents infection by lipid-enveloped viruses
4. Inhibits fusion between plasma membrane and viral envelope
5. Improves healing time with recurrent herpes; requires 5X / day application
6. Adverse effects similar to placebo cream

T. Trifluridine (Viroptic®) [1]

1. Nucleoside analog active against herpesviruses
2. Approved as ophthalmic preparation for treating HSV ocular infections
3. HSV Keratoconjunctivitis dose: 1 drop 1% solution topically q2 hours, up to 9 drops/d

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