The pace of development of new antiviral drugs has been accelerated by the human immunodeficiency virus (HIV) epidemic. Progress in our understanding of the molecular biology and pathogenesis of viral diseases has been remarkable. This chapter focuses on the antiviral drugs most likely to be used by dermatologists, as well as those that cause cutaneous side effects. The age of effective antiviral therapy is here, and they are used throughout all disciplines of medicine. We need to be prepared to evaluate patients on a wide variety of antiviral drugs, especially those currently used to treat HIV.

(See Chapters 193 and 194)

Acyclovir

Mechanism of Action

Acyclovir, 9-[(2-hydr-oxyethoxy) methyl] guanine, was the first orally available drug to be widely used for the treatment of herpes simplex virus (HSV) and varicella-zoster virus (VZV) infections. The triphosphate form of the drug is the active form, which has a potent inhibitory effect on herpesvirus-induced DNA polymerases but relatively little effect on host cell DNA polymerase. As such, it has a tremendous margin of safety when used to treat herpetic infections. Acyclovir triphosphate causes premature termination of the nascent viral DNA chain. HSV- and VZV-induced thymidine kinases result in efficient phosphorylation of acyclovir to acyclovir monophosphate, the first step in drug metabolism. This step is not accomplished efficiently by normal cellular kinases, resulting in greater concentrations of active drug in infected cells.

Pharmacokinetics

While acyclovir is available in oral, intravenous, and topical formulations, the oral bioavailability is only in the range of 15%–30%. Excretion is almost entirely renal, with approximately 85% of renally excreted drug being unmetabolized. Because of this reliance on renal excretion, the dose must be reduced for patients with a creatinine clearance of less than 50 mL/min. Acyclovir is water soluble and achieves good levels in a variety of body fluids, including the contents of vesicles, cerebrospinal fluid, and vaginal secretions. Acyclovir has been marketed as a 5% ointment, but the efficacy is limited compared with systemic administration.

Indications

• Treatment of symptomatic primary or recurrent mucocutaneous HSV-1 or HSV-2 infection
  
• Suppression of recurrent HSV-1 and HSV-2 infections
  
• Treatment of mucocutaneous HSV infections in immunocompromised patients
  
• Prevention of perinatal HSV-1 and HSV-2 infection and treatment of neonatal HSV infection
  
• Treatment of primary VZV infection in adults and immunocompromised children
  
• Treatment of VZV infection to reduce the risk of postherpetic neuralgia
  
• Treatment of HSV-1 encephalitis
  
• Postexposure prophylaxis and treatment for Herpes simiae in the setting of a monkey bite

It has been suggested that suppression of genital HSV recurrences may reduce the risk of acquisition of HIV. It is common for those with HIV-1 infection to have outbreaks of HSV and frequent reactivation is associated with increased plasma and genital levels of the HIV-1 virus. Unfortunately, a randomized, placebo-controlled trial of suppressive acyclovir did not reduce the risk of disease transmission in couples in whom only one was initially seropositive for HIV-1. The failure to prevent transmission occurred despite a reduction in plasma HIV-1 RNA of 0.25log(10) copies per milliliter as well as a 73% reduction in the occurrence of genital HSV.1 Acyclovir can produce direct suppression of HIV-1.2 Newer monophosphorylated acyclovir derivatives (including those with the phosphate group masked by lipophilic groups) have greater potential to prevent viral transmission, as they suppress both HIV-1 and HSV-2 more effectively.3 It is important to note that acyclovir can select for the HIV-1 V75I reverse transcriptase variant in vitro. While this variant has decreased sensitivity to some nucleoside analogs, it demonstrates an increased sensitivity to zidovudine.4 [See Section “Drugs for the Treatment of Human Immunodeficiency Virus (HIV) Infection.”]

Acyclovir given in late pregnancy to women with recurrent genital herpes has been shown to decrease the frequency of genital lesions as well as subclinical viral shedding. This can result in a decrease in the number of Caesarean sections performed.

Unfortunately, breakthrough lesions and viral shedding can still occur and recent evidence suggests that standard oral dosing of acyclovir in late pregnancy often results in insufficient levels at delivery to prevent viral shedding.5

Resistance is a growing problem, and data from corneal HSV-1 isolates suggests that infections commonly represent mixtures of acyclovir-sensitive and resistant viruses with different thymidine kinase gene sequences. The acyclovir-resistant HSV-1 can establish latency and reactivate intermittently to cause acyclovir-refractory disease.6

Dosing Regimens

Compliance with five times daily dosing regimens is poor, so the dosing regimens commonly used in clinical practice differ from those reflected in drug labeling (Table 231-1).

Initiation of Therapy

Treatment for mucocutaneous HSV disease should begin as early as possible. For recurrent disease, treatment may be in the form of continuous suppression or episodic treatment beginning during the prodromal period. Treatment for varicella is most effective if it can be started within 24 hours of onset of vesicles. In immunocompetent patients, treatment for zoster has proven benefit if started within 72 hours of onset of the eruption.

Monitoring of Therapy

The dose should be adjusted for patients with a creatinine clearance level of less than 50 mL/min, but drug level assays are not routinely performed.

Risks and Precautions

Renal (5% incidence of adverse reactions)

• Crystallization in renal tubules leading to obstructive nephropathy
  
• Interstitial nephritis

Central nervous system (1% incidence)

• Lethargy
  
• Tremors
  
• Confusion
  
• Seizures

Miscellaneous

• Phlebitis with intravenous administration
  
• Rash
  
• Recall dermatitis
  
• Fixed drug eruption
  
• Elevated liver function tests
  
• Neutropenia

Complications

Acyclovir is generally very well tolerated. The major risk is renal tubular crystallization with rapid intravenous administration. Caution must be exercised with high doses and in the setting of dehydration. Interstitial nephritis has also been reported. Central nervous system toxicity is uncommon, but may manifest as lethargy, tremors, or seizures. Patients with these side effects commonly have underlying diseases involving the central nervous system. Thrombophlebitis is a known complication of infusion, and appears to be related to the high pH of the reconstituted solution (pH 11). The plasma half life is only 2.5 hours, requiring repeated administration, but newer nanoparticle preparations are being developed with an increased half-life to reduce the need for repeat parenteral administration.7 Nanoparticle technology is also being used to improve the bioavailability of oral forms of the drug.8 In the future, antiviral susceptibility testing may allow selection of the optimal drug in those at increased risk for adverse reactions.9 These assays show the greatest potential in the setting of concurrent HIV infection.10

Valacyclovir

Mechanism of Action and Pharmacokinetics

Valacyclovir, the l-valine ester of acyclovir, was developed to provide increased oral bioavailability of the active drug acyclovir.11 Valacyclovir is readily absorbed from the gastrointestinal tract and almost entirely converted to acyclovir by intestinal and hepatic esterases. The mechanism of action and spectrum of activity of valacyclovir are identical to those of acyclovir. Following a 1-g oral dose of valacyclovir, peak plasma concentrations of acyclovir in the range of 5.7 μg/mL are achieved in 1.75 hours, and area-under-the-curve (AUC) concentrations are similar to those achieved with 5 mg/kg of acyclovir given intravenously.

Indications

• Treatment of initial and recurrent HSV genital infections
  
• Suppression of frequently recurring genital HSV infections
  
• Treatment of herpes zoster

The cost-effectiveness of long-term herpes suppression and intermittent therapy has been debated, but patients are generally quite appreciative of therapy.12,13 Treatment decreases the frequency of clinical outbreaks as well as the incidence of viral shedding. In the setting of HSV-2 seropositive subjects without a history of symptomatic genital herpes infection, 84% of subjects had no shedding while receiving 1 g daily of valacyclovir versus 54% of subjects on placebo (P <0.001).14 Recent data suggest a higher frequency of total and subclinical HSV-2 shedding following newly diagnosed HSV-2 infection than reported in earlier studies. Valacyclovir 1 g daily resulted in a 78% reduction in viral shedding in this population compared to placebo, and 79% of subjects had no clinical recurrences while receiving valacyclovir compared with 52% of subjects receiving placebo (P <0.01).15

The drug has been used to suppress recurrence of ocular disease.16 In the setting of oral herpes simplex, valacyclovir has been used alone or combined with oral corticosteroids. In one study, there were more aborted lesions in the valacyclovir-clobetasol arm than in the placebo group (50% vs. 15.8%, P = 0.04)17, but further study is needed to assess the independent contribution of the corticosteroid.

Valacyclovir demonstrates in-vitro activity against Epstein-Barr virus (EBV). It is being studied in the settings of infectious mononucleosis, hepatitis, encephalopathy, and post-transplant lymphoproliferative disease. Unfortunately, in a recent trial, valacyclovir treatment was not effective in decreasing peripheral blood EBV viral loads in pediatric liver transplantation patients.18 In healthy volunteers, long-term administration of valacyclovir effectively reduces the number of EBV-infected B cells, although it does not reduce the number of EBV DNA copies per B cell.19

Dosing Regimens

Standard doses for adults with herpetic infections are listed in Table 231-2.20 The drug has also been evaluated in children with malignancy.21 In this setting, valacyclovir (15 mg/kg) was well tolerated and demonstrated excellent bioavailability.22 Those less than 3 months of age demonstrate decreased clearance of the drug. Among children 3 months through 11 years of age, a 20-mg/kg dose of an extemporaneously compounded valacyclovir oral suspension produced favorable acyclovir blood levels and was well tolerated. The authors noted that among children 2 through 5 years of age, a dose increase from 20–25 mg/kg resulted in near doubling of the peak concentration [C(max)] and the area under the curve (AUC)23

Initiation of Therapy

As with acyclovir, valacyclovir therapy should be initiated as soon as possible after the onset of an HSV or VZV infection.

Risks and Precautions

In addition to side effects noted with acyclovir, thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS) can occur in patients with advanced HIV disease and in transplant recipients receiving dosages of 8 g/day. The drug has also been reported to produce both immediate hypersensitivity and a symmetrical drug-related intertriginous and flexural exanthem.24,25

Complications

Most adverse effects are those that also occur with acyclovir, including a potential for CNS effects.26 Severe and even fatal cases of TTP/HUS have been reported in patients with acquired immunodeficiency syndrome (AIDS) and transplant recipients who were given high dosages of valacyclovir. The basis for and causal relationship have not been completely established, and TTP/HUS has not been reported in patients taking conventional dosages (up to 3 g/day) of valacyclovir. In a study of high-dose valacyclovir administered to six subjects with normal renal function and three subjects with chronic renal impairment (CrCl approximately 15–30 mL/min), average steady-state concentrations of acyclovir and its metabolites, 9-[(carboxymethoxy) methyl]guanine and 8-hydroxy-acyclovir were greater in both serum and CSF among the subjects with impaired renal function. In contrast, the CSF penetration of each metabolite did not differ based on renal function. This suggests that it is simply the higher concentrations in the systemic circulation that result in proportionally higher concentrations in the CSF.27

Famciclovir and Penciclovir

Mechanism of Action

Famciclovir, [9-(4-hydroxy-3-hydroxy-methylbut-1-yl) guanine, is the prodrug of penciclovir, [9-(4-hydroxy-3-hydroxy-3-hydroxymethylbut-1-yl) guanine]. Once absorbed, penciclovir is phosphorylated to penciclovir triphosphate. The initial phosphorylation of penciclovir to penciclovir monophosphate is efficiently carried out by HSV- or VZV-induced thymidine kinases in a manner similar to that of the initial phosphorylation of acyclovir. Phosphorylation to diphosphate and triphosphate forms of penciclovir then occurs via cellular kinases. Penciclovir triphosphate inhibits viral DNA polymerases and inhibits extension of the nascent viral DNA chain in a manner similar to acyclovir; however, because of the presence of the hydroxyl group on the acyclic side chain of penciclovir, some DNA chain extension may occur.

Pharmacokinetics

Famciclovir is marketed as an oral formulation, which is converted to penciclovir by deacetylation and oxidation in the liver and intestine. The bioavailability of oral famciclovir is 77%, with a peak plasma concentration of 3.3 μg/mL reached 1 hour after oral administration of 500 mg of famciclovir. The plasma half-life of penciclovir is 2 hours, and 60%–70% of the drug is excreted unchanged in the urine. This occurs via both glomerular filtration and tubular secretion. As with acyclovir, the dose of penciclovir should be reduced in patients with advanced renal dysfunction. Compared with the intracellular half-life of acyclovir triphosphate, that of penciclovir triphosphate is markedly prolonged in both HSV-infected cells (10–20 hours) and VZV-infected cells, allowing the drug to be administered two to three times daily. Penciclovir is available as a 1% ointment for the treatment of recurrent oral HSV. At least in some vehicles, topical penetration of penetration of penciclovir is superior to that of acyclovir.28 Microemulsion and nanoparticle formulations are being evaluated.29,30,31

Indications

• Treatment of initial and recurrent HSV genital infections
  
• Suppression of frequently recurring genital HSV infections
  
• Treatment of herpes zoster

Dosing Regimens

Standard adult doses are given in Table 231-3.32 In one study of recurrent genital HSV, a 2-day course of 500 mg initially, then 250 mg twice daily was noninferior to the standard 5-day course of 125 mg twice daily.33 In another study, single-day famciclovir (1,000 mg administered twice daily) was similar in efficacy to 3-day valacyclovir (500 mg administered twice daily) for the treatment of recurrent genital herpes.34 Single day treatment is associated with high patient satisfaction.35 Some data suggest that suppressive treatment may be superior to episodic treatment.36 Studies in children are ongoing, and currently the drug is used less commonly in this population.37,38 While famciclovir has shown efficacy in general populations, one study of patient-initiated episodic treatment of recurrent genital herpes in immunocompetent black patients showed efficacy similar to that of placebo.39

Risks and Precautions

Like acyclovir and valacyclovir, famciclovir is generally well tolerated. The dose should be reduced for patients with a creatinine clearance less than 60 mL/min. The drug has been used safely along with hydration in patients with prior renal toxicity related to acyclovir.40 Leukocytoclastic vasculitis has been reported with the drug.41 Common side effects include:

• Headache
  
• Nausea
  
• Diarrhea
  
• Dizziness

Complications

Serious toxicity is uncommon. Prolonged high-dose administration of famciclovir to rats has been associated with an increased incidence of mammary adenocarcinomas in females, but the clinical significance of this observation for humans treated with the drug is unknown.

Trifluridine

Mechanism of Action and Pharmacokinetics

Trifluridine, 5-trifluoromethyl-2′-deoxyuridine, is a pyrimidine nucleoside analog. Trifluridine monophosphate acts as an irreversible competitive inhibitor of thymidylate synthetase, and trifluridine triphosphate inhibits HSV DNA polymerase. Trifluridine triphosphate also inhibits cellular DNA polymerases, although it does so to a lesser extent than viral DNA polymerases. Because of systemic toxicity, trifluridine is approved only for topical application in the form of a 1% ophthalmic aqueous solution. The elimination half-life for the ophthalmic solution is 12–18 minutes.

Indications

• Treatment of primary HSV conjunctivitis
  
• Treatment of recurrent HSV keratitis
  
• Treatment of acyclovir-resistant mucocutaneous HSV infections in patients with AIDS

Efficacy

A recent meta-analysis of data from 99 randomized trials including a total of 5,363 participants concluded that the topical application of trifluridine, vidarabine, acyclovir, or ganciclovir all resulted in a high proportion of participants healing within 1 week of therapy and no agent emerged as significantly better than the others for the treatment of dendritic epithelial keratitis.42 Other authors have suggested that although the drug is effective, it may result in delays in re-epithelialization.43 There may be additional benefit from topical interferon in those treated with this agent.44

Dosing Regimens

Standard dosing regimens are given in Table 231-4.

Risks and Complications

• Mild burning
  
• Palpebral edema
  
• Punctate keratopathy
  
• Stromal edema

Ganciclovir and Valganciclovir

Mechanism of Action and Pharmacokinetics

Valganciclovir, l-valine 2-[(2-amino-1,6-dehydro-6-oxo-9H-purin-9-yl) methoxy]-3-hydroxypropyl ester, is the l-valyl ester of ganciclovir. It is more efficiently absorbed and acts as a prodrug for ganciclovir. After oral administration, valganciclovir is converted to ganciclovir by intestinal and hepatic esterases. The oral availability of valganciclovir is approximately 60% and is increased by administration with food. After a 900-mg dose of valganciclovir, the maximum plasma concentration of ganciclovir is 5.61 μg/mL, and the plasma concentration–time curve is similar to that achieved with ganciclovir given intravenously at a dose of 5 mg/kg.

Indications

• Treatment of CMV retinitis in patients with AIDS
  
• Suppression and prevention of CMV disease in transplant recipients

Viral clearance varies, even in the face of adequate plasma levels, so patients should be monitored for clinical response.45,46 The drug has some activity against herpesvirus 6, but resistance has been reported.47

Dosing Regimens

Standard dosing regimens are provided in Table 231-5. Pediatric dosing regimens have also been published.48

Risks and Complications

Potential side effects include diarrhea, nausea, loss of appetite, headache, dizziness, confusion, nervousness, vivid dreams, tremor, weakness, peripheral edema and pain at the injection site.

Foscarnet

Mechanism of Action

Foscarnet, trisodium phosphonoformate, is a pyrophosphate-containing antiviral drug that noncompetitively inhibits viral DNA polymerases at the pyrophosphate binding site. In contrast to the nucleoside analogues, foscarnet does not require phosphorylation and is therefore active against many strains of virus that are resistant to acyclovir, famciclovir, or ganciclovir as a result of absent or reduced kinase activity.49–51 Salvage therapy with foscarnet plus a thymidine analog has been shown to be effective in patients with advanced-stage HIV disease and viruses harboring multiple drug-resistance mutations including thymidine-associated mutations.52 Unfortunately, resistance to combined ganciclovir and foscarnet therapy has been reported in the setting of dual-strain cytomegalovirus coinfection.53 Valproic acid has been reported to impair the antiviral activity of ganciclovir, cidofovir, and foscarnet.54

Pharmacokinetics

Foscarnet is available as an intravenous preparation that has poor solubility and must be administered by an infusion pump in a dilute solution over 1–2 hours. The plasma half-life of the drug includes an initial phase of 4–8 hours and a terminal component of 88 hours or longer, which reflects a deposition in bone of up to 20% of the dose. Eighty percent of the dose is excreted unaltered by the kidney. The dose must therefore be reduced in patients with renal dysfunction.

Indications

• Treatment of CMV retinitis in patients with AIDS
  
• Treatment of CMV colitis
  
• Treatment of CMV polyradiculopathy in combination with ganciclovir
  
• Treatment of acyclovir-resistant HSV infections
  
• Treatment of ganciclovir-resistant CMV infections

Dosing Regimens

Standard dosing schedules are provided in Table 231-6.

Risks and Complications

Renal (30% incidence)

• Increased creatinine levels
  
• Proteinuria
  
• Nephrogenic diabetes insipidus
  
• Hypokalemia, hypocalcemia, hypomagnesemia

Miscellaneous

• Headache
  
• Fatigue
  
• Fever
  
• Seizures
  
• Low white blood cell count, anemia

Monitoring of Therapy

Renal toxicity is the major risk with foscarnet, and close monitoring of renal function is required. Saline hydration before administration and slow infusion of the drug may reduce nephrotoxicity. Electrolyte and metabolic abnormalities including hypocalcemia and hypercalcemia, hypophosphatemia and hyperphosphatemia, hypomagnesemia, and hypokalemia have been described.

Cidofovir

Mechanism of Action

Cidofovir, (S)-1-[3-hydroxy-2(phosphonylmethoxy)-propyl] cytosine, is a phosphonate nucleotide analog.55 In contrast to the nucleoside analogues, it does not require initial phosphorylation by virus-induced kinases. Rather, it is converted by host cell enzymes to cidofovir diphosphate, a competitive inhibitor of viral DNA polymerases.

Pharmacokinetics

Cidofovir is approved for intravenous administration. A topical formulation has been developed and compounded formulas have been used. An intravenous dose of 5 mg/kg results in a peak plasma concentration of 11.5 μg/mL. The plasma half-life of cidofovir is 2.6 hours, and the drug is excreted almost entirely by the kidney. Cidofovir diphosphate has a markedly prolonged intracellular half-life (in excess of 48 hours), and may be given at a dose of 5 mg/kg twice a week for the first 2 weeks, followed by one dose every 2 weeks.

Indications

• CMV retinitis in AIDS
  
• Treatment of resistant HSV and CMV infections

Cidofovir also has antiviral activity against pox and parapoxviruses, including vaccinia and variola (small pox), orf, monkeypox, and molluscum contagiosum.56,57 It has been used successfully off-label in topical form for the treatment of the lesions of human papillomavirus infection, Kaposi sarcoma, and HSV infection.58–64 Coadministration of cidofovir with smallpox vaccine reduced the incidence of side effects but interfered with the vaccine-elicited immune responses and immunity to monkeypox.65

Dosing Regimens

Standard dosing regimens are provided in Table 231-7. Data regarding the use in pediatric patients are accumulating.66