Nursing Pharmacology:  Antiviral Drugs

• Antiviral Drugs

  • Acyclovir and Related Drugs continued:

    • The broadest application of acyclovir is in the treatment of genital herpes simplex virus infections.² 

       

      • Herpes Simplex Virus:  Nursing Implications

        Attribution: Scholarly Nurse  Herpes Simplex Virus Nursing Interventions, Causes & Types (2023) https://www.youtube.com/watch?v=LGTF54K7Dz8 Scholarly Nurse:  https://www.youtube.com/@scholarlynurse

      • IV or oral acyclovir as well as oral valacyclovir reduce symptom duration, and viral shedding, while facilitating healing in primary genital HSV infection.² 

        • Both of these drugs, valacyclovir and acyclovir, have limited effect on recurrent genital HSV infections.

          • In considering either primary or recurrent genital HSV infection, neither drug changes the likelihood of subsequent recurrences, suggesting that acyclovir administration does not eliminate latent infection.

          • However, continual acyclovir oral administration (up to six years) or continual valacyclovir administration (greater than or equal to one year) decreases recurrence frequency during therapy; however, upon drug discontinuation, HSV lesions recur.

        • For patients with AIDS, chronic or episodic acyclovir administration promotes emergence of HSV and VZV resistant strains to acyclovir action.

          • Clinical failure results.² 

            • In this circumstance, the emergent isolate is likely deficient in virus-induced thymidine kinase which catalyzes initial phosphorylation step in activation of the pro-drug acyclovir.

            • Patients resistant to acyclovir with HSV or VZV infection often respond to foscarnet.² 

      • Topical acyclovir has limited clinical indications; however, this formulation may be beneficial in primary genital HSV infections and in mucocutaneous herpes simplex viral infections in immunocompromised individuals.

        • Herpes (Oral and Genital)

          Attribution:  Osmosis from Elsevier Herpes (oral & genital) - causes, symptoms, diagnosis, treatment, pathology (2017) https://www.youtube.com/watch?v=IOUnXeqNyMs Osmosis from Elsevier:  https://www.youtube.com/@osmosis

    • Varicella-Zoster Virus  (VZV) Infection

      • Oral acyclovir is therapeutically efficacious in treating varicella-zoster viral infections (VZV) in both children and adults.¹ 

        • Acyclovir in children decreases fever and new lesion formation by about 1 day.

        • Although acyclovir routine use in "uncomplicated" VZV infections is not recommended, the drug may be considered in individuals with:¹  

          • Risk of moderate-to-severe illness e.g. individuals greater than 12 years of age,

          • Individuals who would represent secondary household cases

          • Individuals with chronic pulmonary disorders or chronic cutaneous disorders

          • Individuals receiving corticosteroids or long-term salicylate treatment.

        • In adults treated within a day, oral acyclovir decreases time to lesion cresting by about two days.¹  

          • The drug also diminishes the maximum lesion number by about 50% and shortens fever duration.

        • IV acyclovir is likely effective in treating varicella-zoster pneumonia or encephalitis in previously healthy adults.¹  

          • Furthermore, as a preventive measure, oral acyclovir administered between one and two weeks following exposure may decrease risk of varicella infection.

          • For older adults with localized herpes zoster, orally acyclovir decreases pain and healing times when treatment is started within three days of rash onset.

          • Decreased ocular complications, especially keratitis and anterior uveitis due to zoster ophthalmicus, is associated with treatment.

          • Extended, concurrent administration of acyclovir and prednisone for three weeks accelerated zoster healing while improving quality-of-life measures when compared with each treatment regimen alone.¹  

        • Valacyclovir may provide quicker relief from zoster-associated pain compared to acyclovir in older adults (older than 50 years of age) with zoster.

        • Intravenous acyclovir administered in immunocompromised patients with herpes zoster reduces:¹ 

          • Length of hospitalization

          • Viral shedding

          • Healing time and

          • Risks of cutaneous dissemination and visceral complications.

        • For immunosuppressed children with their varicella, IV acyclovir decreases healing time and reduces visceral complication risk.¹ 

        • Acyclovir-resistant VZV isolates occasionally have been identified in HIV-infected children and adults manifesting chronic hyperkeratotic or verrucous lesions and occasionally meningioradiculitis.¹ 

          • VZV is likely the sole pathogenic agent in chronic verrucous (wart-like) lesions.^8,9

            •  

              Verrucous VZV lesions on the dorsum of the hand⁸

              "Multiple verrucous VZV lesions on the dorsum of the hand." Attribution:  Slightly cropped image from Figure 1A, reference 8.

          •  For acyclovir-resistant VZV disease, IV foscarnet may be effective.

         

    • Acyclovir (Cyclovir, Zovirax and others)

      Acyclovir administration is associated with limited toxicity.2,7   The most likely toxicity is due to renal dysfunction secondary to drug crystallization. This effect occurs following either rapid IV drug administration or if patient hydration is inadequate. A thrombocytopenic purpura-hemolytic uremic syndrome (TTP/HUS) has been described in immunocompromised patients receiving acyclovir.  In immunosuppressed patients particularly, CNS changes may occur. In that setting these changes may not be related to acyclovir but rather to concurrent administration of other therapy or to underlying infection. Metabolism:2,7   Acyclovir is excreted mainly by the kidneys in an unmetabolized form following glomerular filtration and tubular secretion. About 15% of in an acyclovir dose is metabolized and about 20% of an orally administered acyclovir dose is absorbed. Acyclovir enters the CSF fairly easily and attains concentrations there about 50% of that noted in plasma. Pregnancy/Lactation7   Acyclovir has been assigned a pregnancy risk factor of "B". In animal reproduction studies teratogenic effects were not noted. Acyclovir crosses the human placenta; however analysis using a pregnancy registry (1984-1999) did not identify an increase in the number birth defects associated with acyclovir exposure when compared to those expected in the general population. Since the registry size was small and long-term data lacking, manufacturers recommend use during pregnancy with caution and only when clearly needed. According to the CDC (2010), acyclovir may be appropriate for genital herpes treatment in pregnant women. Since acyclovir enters breast milk, cautious use is recommended in that setting. Adverse Reactions:7   Concerning adverse reactions following oral administration: with frequency of greater than 10%: CNS effects including malaise. With frequency of 1%-10%: CNS symptoms of headache (about 2%). Gastrointestinal effects such as nausea, (about 3%), vomiting (less than 3%) and diarrhea (about 2.5%) have been described. With parenteral administration, adverse effects with frequency of 1%-10% include: Dermatologic with hives (2%), itching (2%), rash (2%). Gastrointestinal effects include nausea/vomiting with a frequency of about 7%. Hepatic effects as characterized by increased liver function test values occur with a frequency of about 1.5%. Drug injection site may exhibit inflammation or phlebitis with a frequency of about 10%. Renal effects after parenteral dosing, BUN and creatinine levels may increase. Drug Interactions:7   Mycophenolate may increase acyclovir-valacyclovir serum concentration; acyclovir-valacyclovir they in turn increase mycophenolate serum concentration. The risk is characterized as "C" and therapy should be monitored. Acyclovir-valacyclovir may reduce tenofovir excretion. The risk is characterized as "C" and therapy should be monitored. Acyclovir-valacyclovir may increase zidovudine CNS depressant effects. The risk is characterized as "C" and therapy should be monitored. Acyclovir-valacyclovir may reduce the therapeutic effect of zoster vaccine. To deal with this concern it is suggested that viral agents with anti-zoster activity, including acyclovir, valacyclovir and famciclovir, be discontinued for about a day prior to and for about two weeks following live attenuated zoster vaccine.

    • Ganciclovir (Cytovene, Cymevene)

      • Ganciclovir (Cytovene, Cymevene) is an effective drug for cytomegalovirus (CMV) prophylaxis in immunocompromised individuals.¹ 

        • Acyclovir is not effective in established CMV infections.¹   

        • High-dose IV acyclovir and CMV-seropositive bone marrow transplant recipients reduces risk (about 50% reduction) of CMV disease.

          • When combined with long-term oral acyclovir, survival is enhanced. Following engraftment, valacyclovir is likely equally effective compared to IV ganciclovir prophylaxis in this patient subset.

          • Oral acyclovir or valacyclovir at high dose suppression for three months seems to decrease CMV disease risk in some cases.

            • However, oral valganciclovir appears preferred for mismatched graft recipients.

              • Valganciclovir is the valine ester of ganciclovir, which has limited oral bioavailability.

              • Valganciclovir is later converted by valACVase to release the parent drug, ganciclovir.

            • High-dose valacyclovir, compared with acyclovir, decreases CMV disease in advanced HIV infection; however, such administration is associated with higher toxicity and perhaps shorter survival.¹  

        • Oral acyclovir along with systemic corticosteroids may be helpful in treating Bell's palsy.¹  

          •  

            Bell's Palsy^10,11 

            Bell's palsy is a type of facial paralysis due to cranial nerve VII (facial nerve) dysfunction.  This dysfunction results in lack of facial muscle control on the affected side.11 Figure above shows "A person attempting to show his teeth and raise his eyebrows with Bell's palsy on his right side (left side of the image)."10

             

    • Ganciclovir (Cytovene, Vitrasert, Zirgan)¹⁴

      Ganciclovir (Cytovene, Vitrasert, Zirgan), a synthetic, nucleoside analog, exhibits antiviral activity against herpes simplex infections. This agent is also used in both prevention and treatment of cytomegalovirus (CMV infections). Oral ganciclovir appears comparably effective to IV ganciclovir for secondary prophylaxis with respect to CMV retinitis. Oral ganciclovir is available for maintenance therapy for CMV retinitis and for primary prophylaxis of CMV retinitis in patients testing positive for HIV. An intraocular implant version of ganciclovir, Vitrasert, allows for slow ganciclovir release over a period of up to 8 months. Ganciclovir in an ophthalmic gel formulation may be used for managing acute herpetic keratitis. Mechanism of Action:  Ganciclovir is a prodrug which requires several phosphorylation steps for conversion to the active form. The first phosphorylation step is catalyzed by a viral protein kinase (pUL97); whereas, the subsequent two phosphorylation steps utilize host cellular kinases. Ganciclovir triphosphate is a competitive inhibitor of viral DNA polymerase and its incorporation into viral DNA effectively terminates viral DNA elongation. Ganciclovir Contraindications:  Ganciclovir is contraindicated for patients demonstrating either ganciclovir or acyclovir hypersensitivity; furthermore ganciclovir likely should not be used in patients with valganciclovir hypersensitivity, famciclovir hypersensitivity, valacyclovir hypersensitivity or penciclovir hypersensitivity. This concern is due to structural similarities between these drugs suggestive of cross sensitivity. Ganciclovir as an intravitreal implant is contraindicated in individuals with severe thrombocytopenia, also a contraindication for intra-ocular surgery. Patients with bone marrow suppression and individuals receiving suppressive chemotherapy or radiation therapy should be administered ganciclovir only cautiously. Ganciclovir intravitreal implant is also contraindicated for individuals with external infection, also a contraindication for intra-ocular surgery. Intravitreal ganciclovir is not a treatment for systemic cytomegaloviral (CMV) infection. Most patients will experience a decrease in visual acuity in the implanted eye; however, this change, although immediate, is also temporary. Administration of ganciclovir in patients with cytomegaloviral retinitis should have ophthalmologic examinations, checking for possible progression recurrence of CMV retinitis. Ganciclovir Toxicity:  Ganciclovir toxicity may be increased following rapid administration which causes inappropriately high plasma drug levels. Accordingly, ganciclovir should not be given by rapid IV bolus. Instead, slow, constant rate IV infusion over 1 hour would be more appropriate. Systemic ganciclovir dosage may require adjustment for individuals with renal impairment, since the drug is mainly eliminated from the body unchanged by the kidney. Maintenance of appropriate renal elimination during ganciclovir treatment is important and supported by sufficient hydration and fluid intake.  Patients with renal impairment experience elevated risk of toxic reactions due to ganciclovir administration. Pregnancy / Lactation:  Ganciclovir is described as a pregnancy risk category "C" drug. This drug may be a potential teratogen in humans and might cause birth defects. Ganciclovir use during pregnancy must take into account potential benefit versus risk to the unborn. Possible ganciclovir excretion into breast milk remains to be assessed; accordingly, the manufacturer suggests mothers to stop or not to start breast-feeding if they are taking ganciclovir. Drug Interactions:  Concerning drug interactions: ganciclovir should be used only with caution with probenecid. Probenecid may inhibit renal tubular secretion ganciclovir which thus may increase ganciclovir toxicity. An interaction involving ganciclovir and imipenem (antibiotic) + cilastatin can result in generalized seizures by unknown mechanisms. Many other drugs interact with ganciclovir. Concerns include drugs which may inhibit renal function, thus interfering with ganciclovir clearance, as well as drugs that inhibit rapidly dividing cell populations. These latter drugs may cause additive toxicity. It is recommended that the reader utilize the manufacturer's package insert materials and related materials to obtain a comprehensive description of ganciclovir-drug interactions. Adverse Reactions:  Ganciclovir administration may be associated with significant hematological adverse effects including anemia, neutropenia, pancytopenia, leukopenia and thrombocytopenia. Manifestations of this toxicity may involve disposition to bleeding and bruising. Hematologic toxicities appear more likely to occur early in therapy and is typically dose-related and reversible. Sometimes, however, this toxicity can be either prolonged or irreversible. The most common G.I. adverse effect of systemic ganciclovir involves abdominal pain, anorexia, diarrhea, nausea, vomiting, dysgeusia (abnormal sense of taste) and flatulence. The reader is referred to the manufacturers package insert materials and other primary sources for a complete listing. Adverse CNS effects are not unusual during ganciclovir treatment. These CNS effects may include abnormal dreams, anxiety, drowsiness, peripheral neuropathy (about 10%) tremor and rarely, seizures. Again the reader should consult the manufacturer's package insert and other primary reference materials for a complete description of possible adverse CNS effects, including sources that track post-marketing surveillance reports. Systemic ganciclovir appears somewhat nephrotoxic (renal toxicity). This toxicity may appear as "mild to moderate" increases in serum creatinine. This renal effect appears early in treatment and is reversible; however, should renal function deteriorate during therapy, adjustment of ganciclovir dosage may be needed. Special clinical circumstances e.g. posttransplantation, appears associated with increased ganciclovir nephrotoxicity and the reader is referred to the manufacturer's insert materials or related reference materials for a comprehensive description of these interactions. Other ganciclovir adverse reactions include dermatological adverse effects, possible carcinogenic effects, possible reproductive effects, possible teratogenic effects, predisposition to infection and others. For a comprehensive description and discussion of ganciclovir adverse effects the reader should consult the manufacturer's insert materials and associated primary reference materials.

      • Famciclovir (Famvir and generic)

        • As noted below, famciclovir (Famvir) is a prodrug which is, upon deacetylation and hepatic oxidation (oxidation in the liver), converted to penciclovir (Denavir).³ 

          • Famcyclovir via penciclovir exhibits antiviral activity (in vitro) against:³ 

            • Herpes simplex virus (HSV-1; HSV-2)

            • Varicella-zoster virus (VZV)

            • Epstein-Barr virus (EBV)

            • Hepatitis B virus (HBV).

          • Antiviral activation requires an initial phosphorylation step as described previously for acyclovir.³  

            • This step is catalyzed by a viral thymidine kinase found in infected cells.

              • Additional phosphorylation steps, catalyzed by host cell kinases, add two additional phosphate groups leading to the ultimate active drug form, penciclovir triphosphate.

                • This agent inhibits viral DNA polymerase, thus diminishing viral replication.³  

                  • As described in more detail in the section on antiviral drug resistance, the most frequently encountered resistant HSV mutant isolates exhibit viral thymidine-kinase deficiencies.

                    • Accordingly, cross-resistance between acyclovir and famciclovir (penciclovir) are expected.

          • Oral famciclovir is efficacious both for initial and recurrent management of genital herpes as well as for chronic genital herpes suppression.³  

            • Also, the drug may be used for "cold sores" as well as for treatment of acute zoster (VZV).³ 

        • Penciclovir (Denavir)

          • Penciclovir (Denavir) applied as a 1% cream, reduces both symptoms and signs of herpes labialis (a.k.a cold sore, fever blister, etc)  in immunocompetent patients.

          • This finding was based on a randomized, placebo-controlled, double-blind, patient-initiated, clinical trial.¹³ 

            • For the study, patients were prospectively provided study medication with the treatment being initiated by the patient within 1 hour of the first sign or symptom of herpes simplex labialis (cold sore) recurrence.

            • About 2200 immunocompetent individuals were enrolled in the study and given study medication with about 1570 patients initiating application of topical 1% penciclovir cream for recurrence.

              • Vehicle control cream represented placebo.

            • If recurrence occurred, topical 1% penciclovir cream or vehicle control cream was applied every two waking hours for 4 consecutive days.

            • The primary efficacy variable was lesion healing; however, secondary endpoints involved time to loss of lesion pain and time to cessation of viral shedding.

            • Results indicated that healing of typical lesions, such as ulcers, vesicles and/or crusts occurred about 0.7 day faster in the penciclovir-treated patient group.¹³

            • Penciclovir cream is the first treatment that clearly demonstrated in effect on the course of recurrent herpes labialis in immunocompetent patients.

              • Efficacy was noted in both clinical and laboratory measures of disease.¹³

          •  

            Herpes Simplex Lesion of the Lower Lip

            Hermann CDC Herpes simplex lesion of lower lip, second day after onset. HSV cold sore, 1964 http://phil.cdc.gov/Phil/details.asp

          • The extent of the reduction is from a half to one day.

            • This indication has been approved by the FDA.

References

Acosta EP Flexner C Antiviral Agents (Nonretroviral) Chapter 58 in Goodman & Gilman's The Pharmacological Basis of Therapeutics, 12th edition (Brunton LL Chabner BA Knollmann BC, eds; Brunton LL, ed; Blumenthal DK  Murri N Hilal-Dandan R, assoc eds, Knollmann BC, consulting ed, on-line edition) The McGraw-Hill Companies, 2011. Baden LR Dolin R, Chapter 178, Antiviral Chemotherapy, Excluding Antiretroviral Drugs, in Harrison's Online   (Dan L. Longo, Anthony S. Fauci, Dennis L. Kasper, Stephen L. Hauser, J. Larry Jameson, Joseph Loscalzo, Eds.),  Harrison's Principles of Internal Medicine, 18th edition, The McGraw-Hill Companies, Inc. 2012. Safrin S Antiviral Agents, Chapter 49 in Basic & Clinical Pharmacology, 12 e (Katzung BG Masters SB Trevor AJ) The McGraw-Hill Companies, 2012 (on-line edition) Piret J Boivin G Minireview:  Resistance of Herpes Simplex Viruses to Nucleoside Analogues:  Mechanisms, Prevalence, and Management. Antimicrobial Agents and Chemotherapy, 55(2):  p. 459-472, Feb. 2011. Gilbert C Bestman-Smith J Goivin G Resistance of herpesviruses to antiviral drugs:  clinical impacts and molecular mechanisms.  Drug Resistance Updates 5:  88-114, 2002. Siegel R Viruses, HIV, Prions, and related topics, Human Virology (Stanford) http://web.stanford.edu/group/virus/ ; Foscarnet section: http://web.stanford.edu/group/virus/astro/2000/foscarnet.htm Acyclovir (Systemic) Drug Monographs Access Medicine Nikkels AF SnoeckR Rentier B Pierard Chronic verrucous varicella zoster virus skin lesions:  clinical, histological, molecular and therapeutic aspects.  Clinical dermatology Review Article.  Clinical and Experimental Dermatology, 24, 346-353, 1999. http://www.researchgate.net/publication/12737524_Chronic_verrucous_varicella_zoster_virus_skin_lesions_clinical_histological_molecular_and_therapeutic_aspects Tsao H Tahan SR Johnson RA Chronic varicella zoster infection mimicking a basal cell carcinoma in an AIDS patient. J Am Acad Dermatol 36:  831-833, 1997. Heilman J Bell's palsy http://commons.wikimedia.org/wiki/File:Bellspalsy.JPG ; Bell's palsy http://en.wikipedia.org/wiki/Bell's_palsy De Clercq E Field HJ Antiviral prodrugs-the development of successful prodrug strategies for antiviral chemotherapy.  British Journal of Pharmacology 147:  1-11, 2006. Spruance SL Rea TL Thoming C Tucker R Saltzman R Boon R Penciclovir cream for the treatment of herpes simplex labialis.  A randomized, multicenter, double-blind, placebo-controlled trial.  Topical Penciclovir Collaborative Study Group JAMA 277(1):  1374-1379, May 7, 1997. Drug Monograph Ganciclovir:  Drug information (ClinicalKey) provided by Gold Standard.

 

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