Antiviral agents I: drugs for non-HIV viral infections

CHAPTER 93


Antiviral agents I: drugs for non-HIV viral infections


Antiviral drugs are discussed in this chapter and the one that follows. In this chapter, we consider drugs used to treat infections caused by viruses other than HIV. In Chapter 94, we consider drugs used against HIV infection. Drugs for non-HIV infections are summarized in Table 93–1.



Although antiviral therapy has made significant advances, our ability to treat viral infections remains limited. Compared with the dramatic advances made in antibacterial therapy over the past half-century, efforts to develop safe and effective antiviral drugs have been less successful. A major reason for this lack of success resides in the process of viral replication: Viruses are obligate intracellular parasites that use the biochemical machinery of host cells to reproduce. Because the viral growth cycle employs host-cell enzymes and substrates, it is difficult to suppress viral replication without doing significant harm to the host. The antiviral drugs used clinically act by suppressing biochemical processes unique to viral reproduction. As our knowledge of viral molecular biology expands, additional virus-specific processes will be discovered, giving us new targets for drugs.



Drugs for infection with herpes simplex viruses and varicella-zoster virus


Herpes simplex virus (HSV) and varicella-zoster virus (VZV) are members of the herpesvirus group. HSV causes infection of the genitalia, mouth, face, and other sites. VZV is the cause of varicella (chickenpox) and herpes zoster (shingles), a painful condition resulting from reactivation of VZV that had been dormant within sensory nerve roots. Both conditions are discussed further in Chapter 68, along with the vaccine used to prevent chickenpox. Drugs for infection with HSV and VZV are summarized in Table 93–2. Genital herpes is discussed in Chapter 95.





Acyclovir


Acyclovir [Zovirax] is the agent of first choice for most infections caused by herpes simplex viruses and varicella-zoster virus. The drug can be administered topically, orally, and intravenously. Serious side effects are uncommon.




Mechanism of action

Acyclovir inhibits viral replication by suppressing synthesis of viral DNA. To exert antiviral effects, acyclovir must first undergo activation. The critical step in activation is conversion of acyclovir to acyclo-GMP by thymidine kinase. Once formed, acyclo-GMP is converted to acyclo-GTP, the compound directly responsible for inhibiting DNA synthesis. Acyclo-GTP suppresses DNA synthesis by (1) inhibiting viral DNA polymerase and (2) becoming incorporated into the growing strand of viral DNA, which blocks further strand growth.


The selectivity of acyclovir is based in large part on the ability of certain viruses to activate the drug. HSVs are especially sensitive to acyclovir because the drug is a much better substrate for thymidine kinase produced by HSVs than it is for mammalian thymidine kinase. Hence, formation of acyclo-GMP, the limiting step in the activation of acyclovir, occurs almost exclusively in cells infected with HSV. Cytomegalovirus is inherently resistant to the drug because acyclovir is a poor substrate for the form of thymidine kinase produced by this virus.




Therapeutic uses






Adverse effects


Intravenous therapy.

Intravenous acyclovir is generally well tolerated. The most common reactions are phlebitis and inflammation at the infusion site. Reversible nephrotoxicity, indicated by elevations in serum creatinine and blood urea nitrogen, occurs in some patients. The cause is deposition of acyclovir in renal tubules. The risk of renal injury is increased by dehydration and by use of other nephrotoxic drugs. Kidney damage can be minimized by infusing acyclovir slowly (over 1 hour) and by ensuring adequate hydration during the infusion and for 2 hours after.


Neurologic toxicity—agitation, tremors, delirium, hallucinations, and myoclonus—occurs rarely, primarily in patients with renal impairment. In patients on dialysis, very low doses can cause severe neurotoxicity, characterized by delirium and coma.



Oral and topical therapy.

Oral acyclovir is devoid of serious adverse effects. Renal impairment has not been reported. The most common reactions are nausea, vomiting, diarrhea, headache, and vertigo. Topical acyclovir frequently causes transient local burning or stinging; systemic reactions do not occur. Oral acyclovir is safe during pregnancy, and hence can be used to suppress recurrent genital herpes near term.







Preparations, dosage, and administration





Oral.


Oral acyclovir [Zovirax] is available in capsules (200 mg), tablets (400 and 800 mg), and a suspension (200 mg/5 mL). Dosages for patients with normal kidney function are given below. Dosages must be reduced for patients with renal impairment.




Intravenous.


For IV dosing, acyclovir is available in solution (50 mg/mL). Administration is by slow infusion (over 1 hour or more). Parenteral acyclovir must not be given by IV bolus or by IM or subQ injection. To minimize the risk of renal damage, hydrate the patient during the infusion and for 2 hours after. Dosages for patients with normal kidney function are given below. Dosages should be reduced for patients with renal impairment.




Valacyclovir




Actions and uses.


Valacyclovir [Valtrex], a prodrug form of acyclovir, has three approved indications: (1) herpes zoster (shingles), (2) herpes simplex genitalis, and (3) herpes labialis (cold sores). In all three infections, benefits depend on conversion of valacyclovir to acyclovir, its active form. In a clinical trial in patients with herpes zoster, valacyclovir (1000 mg 3 times a day for 7 or 14 days) was somewhat more effective than acyclovir (800 mg 5 times a day for 7 days) in reducing the duration of pain and the duration of postherpetic neuralgia. In trials for patients with initial or recurrent herpes genitalis, valacyclovir (1000 mg twice a day) and acyclovir (200 mg 5 times a day) produced similar results. In another study, valacyclovir was shown to reduce—but not eliminate—the risk of transmitting genital herpes between monogamous heterosexual partners.


In patients receiving immunosuppressive drugs following a kidney transplant, prophylaxis with valacyclovir (2 gm 4 times a day for 90 days) can reduce the risk of CMV disease, a major complication of transplantation surgery.






Famciclovir


Famciclovir [Famvir] is a prodrug used to treat acute herpes zoster and genital herpes infection. Benefits are equivalent to those of acyclovir. Adverse effects are minimal.









Topical drugs for herpes labialis


We have three topical drugs for recurrent herpes labialis (cold sores). Two of these drugs—penciclovir and docosanol—are discussed below. The third drug—acyclovir—is discussed above.




Docosanol cream


Docosanol [Abreva] is a topical preparation indicated for recurrent herpes labialis. The drug is available over the counter as a 10% cream. Application is done 5 times a day, beginning at the first sign of recurrence. Benefits are modest. In one trial, treatment reduced the time to healing from 4.8 days down to 4.1 days—about the same response seen with penciclovir. Docosanol cream appears devoid of adverse effects.


Docosanol has a broad antiviral spectrum and a unique mechanism of action. Unlike penciclovir, which inhibits viral DNA synthesis (and thereby suppresses replication), docosanol blocks viral entry into host cells. The drug does not kill viruses and does not prevent them from binding to cells. As a result, viable virions can remain attached to the cell surface for a long time. Because docosanol does not affect processes of replication, it is unlikely to promote resistance.



Topical drugs for ocular herpes infections



Trifluridine ophthalmic solution


Trifluridine [Viroptic] is indicated only for topical treatment of ocular infections caused by HSV-1 and HSV-2. The drug is given to treat acute keratoconjunctivitis and recurrent epithelial keratitis. Antiviral actions result from inhibiting DNA synthesis. The most common side effects are localized burning and stinging. Edema of the eyelid occurs in about 3% of patients. Systemic absorption is minimal following topical administration, and hence the drug is devoid of systemic toxicity. Trifluridine is supplied as a 1% ophthalmic solution. Treatment consists of placing 1 drop on the cornea every 2 hours while the patient is awake, for a maximum of 9 drops/day. Once re-epithelialization of the cornea has occurred, the dosage is reduced to 1 drop every 4 hours. Treatment continues for 7 days.






Drugs for cytomegalovirus infection


Cytomegalovirus (CMV) is a member of the herpesvirus group, which includes herpes simplex virus types 1 and 2, varicella-zoster virus (the cause of chickenpox), and Epstein-Barr virus (the cause of infectious mononucleosis). Transmission of CMV occurs person to person—through direct contact with saliva, urine, blood, tears, breast milk, semen, and other body fluids. Infection can also be acquired by way of blood transfusion or organ transplantation. Infection with CMV is very common: Between 50% and 85% of Americans age 40 and older harbor the virus. After the initial infection, which has minimal symptoms in healthy people, the virus remains dormant within cells for life, without causing detectable injury or clinical illness. Hence, for most healthy people, CMV infection is of little concern. By contrast, people who are immunocompromised—owing to HIV infection, cancer chemotherapy, or use of immunosuppressive drugs—are at high risk of serious morbidity and even death, both from initial CMV infection and from reactivation of dormant CMV. Common sites for infection are the lungs, eyes, and GI tract. Among people with AIDS, CMV retinitis is the principal reason for loss of vision (see Chapter 94). The four drugs used against CMV are discussed below.




Ganciclovir


Ganciclovir [Cytovene, Vitrasert, Zirgan] is a synthetic antiviral agent with activity against herpesviruses, including CMV. Because the drug can cause serious adverse effects, especially granulocytopenia and thrombocytopenia, it should be used only for prevention and treatment of CMV infection in the immunocompromised host.






Therapeutic use.

Ganciclovir is used only to prevent and treat CMV infection in immunocompromised patients, including those with HIV infection and those receiving immunosuppressive drugs. Specific uses include:



In patients with AIDS, CMV retinitis has an incidence of 15% to 40%. Although most AIDS patients respond initially, the relapse rate is high. Accordingly, for most patients, maintenance therapy should continue indefinitely. The risk of relapse is higher with oral ganciclovir than with IV ganciclovir. Since viral resistance can develop during treatment, this possibility should be considered if the patient responds poorly.



Adverse effects. 


Granulocytopenia and thrombocytopenia.


The adverse effect of greatest concern is bone marrow suppression, which can result in granulocytopenia (40%) and thrombocytopenia (20%). These effects, which are usually reversible, are more likely with IV therapy than with oral therapy. These hematologic responses can be exacerbated by concurrent therapy with zidovudine. Conversely, granulocytopenia can be reduced with granulocyte colony-stimulating factors (see Chapter 56). Because of the risk of adverse hematologic effects, blood cell counts must be monitored. Treatment should be interrupted if the absolute neutrophil count falls below 500/mm3 or if the platelet count falls below 25,000/mm3. Cell counts usually begin to recover within 3 to 5 days. Ganciclovir should be used with caution in patients with pre-existing cytopenias, in those with a history of cytopenic reactions to other drugs, and in those taking other bone marrow suppressants (eg, zidovudine, trimetrexate).



Reproductive toxicity.


Ganciclovir is teratogenic and embryotoxic in laboratory animals and probably in humans. Women should be advised to avoid pregnancy during therapy and for 90 days after ending treatment. At doses equivalent to those used therapeutically, ganciclovir inhibits spermatogenesis in mice; sterility is reversible with low doses and irreversible with high doses. Female infertility may also occur. Patients should be forewarned of these effects.









Preparations, dosage, and administration. 



Intravenous.


Ganciclovir [Cytovene] is available as a powder (500 mg) to be reconstituted for IV infusion. Solutions are alkaline and must be infused into a freely flowing vein to avoid local injury. For treatment of CMV retinitis, the initial dosage for adults with normal renal function is 5 mg/kg (infused over 1 hour) every 12 hours for 14 to 21 days. Two maintenance dosages can be used: (1) 5 mg/kg infused over 1 hour once every day of the week or (2) 6 mg/kg infused over 1 hour once a day, 5 days a week. Dosages must be reduced for patients with renal impairment. Since many patients with AIDS must continue maintenance therapy for life, they need a permanent IV line and equipment for home infusion. Adequate hydration must be maintained in all patients to ensure renal excretion of ganciclovir.






Valganciclovir




Basic and clinical pharmacology.


Valganciclovir [Valcyte] is a prodrug version of ganciclovir [Cytovene] with greater oral bioavailability (60% vs. 9%). Following absorption from the GI tract, valganciclovir is rapidly metabolized to ganciclovir, its active form—and eventually undergoes excretion as unchanged ganciclovir in the urine. Indications are CMV retinitis and prevention of CMV disease in high-risk organ transplant recipients. In patients with active CMV retinitis, oral valganciclovir is just as effective as intravenous ganciclovir—and much more convenient. In addition to its use against CMV, valganciclovir has been used off-label to reduce transmission of genital herpes (see Chapter 95).


Adverse effects are the same as with ganciclovir. The principal concern is blood dyscrasias—granulocytopenia (27%), anemia (26%), and thrombocytopenia (6%)—secondary to bone marrow suppression. In addition, valganciclovir frequently causes diarrhea (41%), nausea (30%), vomiting (21%), fever (31%), and headache (22%). Valganciclovir is presumed to pose the same risks of mutagenesis, aspermatogenesis, and carcinogenesis as ganciclovir.



Preparations, dosage, and administration.


Valganciclovir [Valcyte] is available in (1) 450-mg tablets and (2) a powder that makes a 50-mg/mL oral solution when reconstituted with 91 mL of purified water. All doses should be taken with food to enhance bioavailability.


For treatment of CMV retinitis, the adult dosage is 900 mg twice daily for 21 days, followed by 900 mg once daily for maintenance. Dosage must be reduced for patients with renal impairment.


For prevention of CMV disease in transplant recipients, the adult dosage is 900 mg once daily, starting within 10 days of transplantation and continuing until 100 days post-transplantation (or 200 days post-transplantation in kidney recipients).


Because valganciclovir has the potential for mutagenesis and carcinogenesis, the powder and tablets should be handled carefully. Tablets should be ingested intact, without crushing or chewing. Direct contact with the powder or broken tablets should be avoided. If contact does occur, the area should be washed with soap and water. When handling or disposing of the drug, healthcare workers should follow the same guidelines established for cytotoxic anticancer drugs.



Cidofovir


Cidofovir [Vistide] is an IV drug with just one indication: CMV retinitis in patients with AIDS who have failed on ganciclovir or foscarnet. Alternative drugs for this infection are foscarnet, which is given IV, and ganciclovir, which may be administered IV, PO, or by ocular insert. Compared with IV foscarnet or IV ganciclovir, cidofovir has the distinct advantage of needing fewer infusions: Whereas foscarnet and ganciclovir must be infused daily, cidofovir is infused just once a week or every other week. The major adverse effect of the drug is kidney damage.







Adverse effects. 





Preparations, dosage, and administration.


Cidofovir [Vistide] is supplied in solution (75 mg/mL) in 5-mL ampules. To reduce the risk of renal injury, cidofovir infusions must be accompanied by IV hydration therapy and PO probenecid.


Each cidofovir dose—for induction or maintenance—consists of 5 mg/kg infused IV over 1 hour. For induction, two doses are given 1 week apart. For maintenance, one dose is given every 2 weeks. The size of each dose must be reduced for patients with renal impairment. If impairment is severe, cidofovir should be withheld.


Oral probenecid must accompany each infusion. The dosage is 2 gm given 3 hours before the infusion, 1 gm given 1 hour after the infusion, and another 1 gm given 8 hours after that. Ingesting food before each dose can decrease probenecid-induced nausea and vomiting. An antiemetic may also be used.


Hydration is accomplished by infusing 1 L of 0.9% saline solution over 1 to 2 hours immediately before infusing cidofovir. For patients who can tolerate it, 1 L more can be infused over 1 to 3 hours, beginning when the cidofovir infusion begins or as soon as it is over.



Foscarnet


Foscarnet, formerly available as Foscavir, is an IV drug active against all known herpesviruses, including CMV, HSV-1, HSV-2, and VZV. Compared with ganciclovir, foscarnet is more difficult to administer, less well tolerated, and much more expensive (the cost to the pharmacy is about $20,000 a year). The major adverse effect is renal injury.







Adverse effects and interactions.


In general, foscarnet is less well tolerated than ganciclovir. However, unlike ganciclovir, foscarnet does not cause granulocytopenia or thrombocytopenia.








Drugs for hepatitis


Viral hepatitis is the most common liver disorder, affecting millions of Americans. The disease can be caused by six different hepatitis viruses, labeled A, B, C, D, E, and G. All six can cause acute hepatitis, but only B, C, and D also cause chronic hepatitis. Acute hepatitis lasts for 6 months or less and is characterized by liver inflammation, jaundice, and elevation of serum alanine aminotransferase (ALT) activity. In most cases, acute hepatitis resolves spontaneously, and hence intervention is generally unnecessary. In contrast, chronic hepatitis can lead to cirrhosis, hepatocellular carcinoma, and life-threatening liver failure, and hence treatment should be considered.


Most cases (90%) of chronic hepatitis are caused by either hepatitis B virus (HBV) or hepatitis C virus (HCV). Accordingly, our discussion focuses on hepatitis B and hepatitis C. About 1.5% of Americans are infected with HBV or HCV, which is 5 times more than the number infected with HIV. Comparisons between hepatitis A, B, and C are summarized in Table 93–3. Vaccines for hepatitis A and B are discussed in Chapter 68. Drugs for hepatitis B and C are discussed below.

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Jul 24, 2016 | Posted by in NURSING | Comments Off on Antiviral agents I: drugs for non-HIV viral infections

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