NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.

Arvin A, Campadelli-Fiume G, Mocarski E, et al., editors. Human Herpesviruses: Biology, Therapy, and Immunoprophylaxis. Cambridge: Cambridge University Press; 2007.

Cover of Human Herpesviruses

Human Herpesviruses: Biology, Therapy, and Immunoprophylaxis.

Show details

Chapter 64Antiviral therapy of HSV-1 and -2

and .

Author Information

Introduction

The discovery of effective antiviral agents has been facilitated by advances in the fields of molecular biology and virology. In the pre-antiviral era, the widely held belief was that any therapeutically meaningful interference with viral replication would destroy the host cell upon which viral replication was dependent. A growing understanding of host cell–virus interactions and viral replication, however, has led to the development of safe and effective antivirals. These agents act by impeding entry of viruses into host cells; interfering with viral assembly, release, or de-aggregation; inhibiting transcription or replication of the viral genome; or interrupting viral protein synthesis.

Antiviral agents can be used to treat disease (a therapeutic strategy), to prevent infection (a prophylactic strategy), or to prevent disease (a preemptive strategy). Prophylaxis refers to the administration of an agent to patients at risk of contracting infection (e.g., acyclovir given to HSV-seropositive renal transplant recipients). Pre-emptive treatment refers to the administration of a drug after there is evidence of infection, but before there is evidence of disease (e.g., ganciclovir given to bone marrow transplant recipients with positive CMV culture, but no symptoms of infection).

The effectiveness of antiviral therapy sometimes is limited by the development of antiviral resistance. Antiviral drug resistance has increased in parallel with the expanded use of, and indications for, antiviral therapy. Resistance most commonly occurs in patients with chronic and/or progressive infections who have been exposed to prolonged or repeated courses of therapy. An impaired host immune system which cannot fully contribute to suppressing viral replication, thus leaving to antiviral agent(s) as the sole defense against ongoing viral disease, also predisposes to the development of antiviral resistance, as does administration of the antiviral agent at doses which produce subtherapeutic drug concentrations relative to that needed for virocidal or virostatic activity. In general, antiviral resistance should be suspected if the clinical response to therapy is less than that anticipated on the basis of prior experience (Kimberlin et al., 1995b).

There are a number of antiviral medications with activity against HSV-1 and HSV-2. With the exception of foscarnet and cidofovir, all are nucleoside analogues. While three of these medications (acyclovir, famciclovir, and valaciclovir) are used to treat the overwhelming majority of cases of HSV-1 and HSV-2, the other medications reviewed in this chapter (cidofovir, foscarnet, ganciclovir, and valganciclovir) also have activity against the alpha herpesviruses and are indicated in certain circumstances, such as the treatment of some acyclovir-resistant HSV isolates. Discussion in this chapter of the efficacies of these first-line and second-line drugs will be limited to their use as second-line agents for HSV-1 and HSV-2 infections. Antiviral treatment of VZV and CMV can be found in Chapters 70 and 71, respectively.

First-line antiviral agents for HSV-1 and HSV-2 infections

Acyclovir

Acyclovir is in many regards the prototypic antiviral agent. The notable safety profile of acyclovir relates to its initial activation by the viral-induced enzyme thymidine kinase. Acyclovir is most active against HSV; activity against VZV also is substantial but approximately ten-fold less. Epstein Barr virus (EBV) is only moderately susceptible to acyclovir because EBV has minimal thymidine kinase activity. Activity against CMV is poor because CMV does not have a unique thymidine kinase, and CMV DNA polymerase is poorly inhibited by acyclovir triphosphate. Acyclovir is the most frequently prescribed antiviral agent. It has been available for clinical use for over two decades and has demonstrated remarkable safety and efficacy against mild to severe infections caused by HSV and VZV in both normal and immunocompromised patients.

Mechanism of action and pharmacokinetics

Acyclovir is a deoxyguanosine analogue with an acyclic side chain that lacks the 3′-hydoxyl group of natural nucleosides (Wagstaff et al., 1994). Following preferential uptake by infected cells, acyclovir is monophosphorylated by virus-encoded thymidine kinase; host cell thymidine kinase is approximately 1 millionfold less capable of converting acyclovir to its monophosphate derivative. Subsequent diphosphorylation and triphosphorylation are catalyzed by host cell enzymes, resulting in acyclovir triphosphate concentrations that are 40 to 100 times higher in HSV-infected cells than in uninfected cells (Elion, 1982). Acyclovir triphosphate prevents viral DNA synthesis by inhibiting the viral DNA polymerase. In vitro, acyclovir triphosphate competes with deoxyguanosine triphosphate as a substrate for viral DNA polymerase. Because acyclovir triphosphate lacks the 3’-hydroxyl group required to elongate the DNA chain, the growing chain of DNA is terminated. In the presence of the deoxynucleoside triphosphate complementary to the next template position, the viral DNA polymerase is functionally inactivated (Reardon and Spector, 1989). In addition, acyclovir triphosphate is a much better substrate for the viral polymerase than for cellular DNA polymerase α, resulting in little incorporation of acyclovir into cellular DNA.

The oral bioavailability of acyclovir is poor, with only 15%–30% of the oral formulations being absorbed. Following a 200 mg dose, a peak concentration of about 0.5 μg/ml is attained at approximately 1.5 to 2.5 hours (Wagstaff et al., 1994). Higher doses of acyclovir result in higher serum concentrations. Food does not substantially alter extent of absorption. After intravenous doses of 2.5 to 15 mg/kg, steady-state concentrations of acyclovir range from 6.7 to 20.6 μg/ml. Acyclovir is widely distributed; high concentrations are attained in kidneys, lung, liver, heart, and skin vesicles; concentrations in the cerebrospinal fluid (CSF) are about 50% of those in the plasma (Wagstaff et al., 1994). Acyclovir crosses the placenta and accumulates in breast milk. Protein binding ranges from 9% to 33% and less than 20% of drug is metabolized to biologically inactive metabolites.

In the absence of compromised renal function, the half-life of acyclovir is 2 to 3 hours in older children and adults and 2.5 to 5 hours in neonates with normal creatinine clearance. More than 60% of administered drug is excreted in the urine (Wagstaff et al., 1994). Elimination is prolonged in patients with renal dysfunction; the half-life is approximately 20 hours in persons with end-stage renal disease, necessitating dose modifications for those with creatinine clearance less than 50 ml/min per 1.73 m2 (Laskin et al., 1982). Acyclovir is effectively removed by hemodialysis but not by continuous ambulatory peritoneal dialysis (Krasny et al., 1982).

Antiviral therapy

Clinical efficacy in HSV-1 and HSV-2 infections

Genital herpes

For the treatment of first episode genital herpes, the dose of oral acyclovir is 200 mg orally five times per day, or 400 mg orally three times per day (Table 64.1). Neither higher doses of oral acyclovir nor the addition of topical acyclovir provide added benefit (Wald et al., 1994). Duration of therapy in first episode disease is 7–10 days (Anonymous, 2002). Acyclovir therapy for the treatment of first episode genital herpes reduces the duration of viral shedding by about a week, time to healing of lesions by approximately four days, and time to complete resolution of signs and symptoms by approximately two days (Bryson et al., 1983; Mertz et al., 1984) (Table 64.2).

Table 64.1. Therapeutic management of genital herpes.

Table 64.1

Therapeutic management of genital herpes.

Table 64.2. Efficacies of acyclovir, valaciclovir, and famciclovir in the treatment of genital HSV disease.

Table 64.2

Efficacies of acyclovir, valaciclovir, and famciclovir in the treatment of genital HSV disease.

For the episodic treatment of recurrent genital herpes, dosing options for acyclovir include 200 mg orally five times per day, or 800 mg orally two times per day, administered for 5 days (Anonymous, 2002) (Table 64.1). Topical acyclovir provides no clinical benefit in the episodic management of recurrences and is not recommended (Corey et al., 1982; Luby et al., 1984). A recent study indicates that 2 days of oral acyclovir therapy (800 mg three times per day) is also efficacious in the episodic treatment of genital HSV recurrences (Wald et al., 2002). When started within 24 hours of the onset of a genital herpes recurrence, oral acyclovir reduces the duration of viral shedding by approximately two days, time to healing by just over a day, and time to complete resolution of signs and symptoms by approximately a day (Tyring et al., 1998) (Table 64.2). Episodic treatment does not reduce the length of time to subsequent recurrence (Nilsen et al., 1982; Reichman et al., 1984; Ruhnek-Forsbeck et al., 1985).

In addition to the treatment of an active genital herpes infection, acyclovir has been effectively used to prevent recurrences of genital herpes. The most frequent indication for suppressive acyclovir therapy is in patients with frequently recurrent genital infections, in whom chronic suppressive acyclovir therapy reduces the frequency of recurrences by approximately 75% (Douglas et al., 1984; Mertz et al., 1988a; Mertz et al., 1988b; Mindel et al., 1988; Straus et al., 1984) (Table 64.2). One quarter to one-third of patients on suppressive therapy experience no further recurrences while taking acyclovir. Daily administration of acyclovir maintains a high degree of efficacy and little toxicity, even after more than 5 years of continuous suppressive therapy (Goldberg et al., 1993). Suppressive therapy reduces the frequency of asymptomatic shedding of HSV in the genital tract by more than 80% (Wald et al., 1997; Wald et al., 1996) (Table 64.2). The acyclovir dose when used as suppressive therapy is 400 mg administered twice daily (Table 64.1).

The historic rationale for episodic treatment of genital herpes was that, in many patients, the frequency and/or severity of clinical recurrences made treatment of the recurrences desirable, but they were not sufficiently frequent or annoying to warrant daily suppressive therapy. Advances in recent years in our understanding of asymptomatic viral shedding have begun to shift our therapeutic management away from episodic treatment and toward suppressive therapy (Kimberlin and Rouse, 2004). The current rationale for suppressive treatment is as follows: (1) most persons with first episode genital herpes are at risk of frequent recurrences over the next few years (Benedetti et al., 1994); (2) 70%–80% of patients receiving suppressive therapy remain recurrence-free at 4 months (Table 64.2), vs. 5%–10% of persons receiving placebo (Douglas et al., 1984; Mertz et al., 1988b; Mertz et al., 1997b; Patel et al., 1997; Reitano et al., 1998); (3) days with subclinical (asymptomatic) shedding are reduced by 80%–95% compared with placebo (Table 64.2) (Sacks et al., 1997; Wald et al., 1997; Wald et al., 1998; Wald et al., 1996); (4) suppressive therapy reduces the risk of HSV transmission to uninfected partners (Corey et al., 2004); (5) quality of life often is improved in patients with frequent recurrences who receive suppressive compared with episodic treatment (Alexander and Naisbett, 2002); and (6) suppressive therapy is safe (Douglas et al., 1984; Mertz et al., 1997b; Patel et al., 1997; Reitano et al., 1998).

HSV gingivostomatitis and recurrent herpes labialis

Treatment of primary gingivostomatitis in pediatric patients using oral acyclovir decreases time to cessation of symptoms by 30%–50%, and time to lesion healing by 20%–25% (Aoki et al., 1993). Compared with patients receiving placebo, subjects treated with oral acyclovir at 600 mg/m2 per dose administered four times per day for 10 days experienced cessation of drooling in 4 days (vs. 8 days in placebo recipients) and resolution of gum swelling in 5 days (vs. 7 days in placebo recipients). Intraoral lesions in acyclovir recipients healed at 6 days (vs. 8 days in placebo recipients), and extraoral lesions healed in 7 days (vs. 9 days in placebo recipients) (Aoki et al., 1993).

Oral acyclovir has a more modest effect in the treatment of recurrent herpes labialis (Raborn et al., 1988; Raborn et al., 1987), and treatment of these patients should be individualized (Kimberlin and Prober, 2003). In general, therapeutic benefit is enhanced if treatment is initiated as soon as possible after onset of symptoms, preferably within 24 to 48 hours of onset of the recurrence. Among patients who start treatment in the prodrome or erythema lesion stage, acyclovir therapy (400 mg five times a day for 5 days) reduces the duration of pain by approximately one-third, and the healing time to loss of crust by approximately one-fourth (Spruance et al., 1990). Topical acyclovir cream may also modestly decrease the duration of a clinical recurrence of herpes labialis by approximately half a day (approximately 4½ days for topical acyclovir recipients, compared with approximately 5 days for placebo recipients) (Spruance et al., 2002), although benefit of topical acyclovir is not conferred by acyclovir ointment, which has a polyethylene glycol base (Shaw et al., 1985; Spruance et al., 1984).

Prophylactic acyclovir also has been used to prevent reactivation of herpes labialis following exposure to ultraviolet radiation, facial surgery, or exposure to sun and wind while skiing (Gold and Corey, 1987; Spruance et al., 1991; Spruance et al., 1988). Topical acyclovir cream also is effective in preventing recurrent herpes labialis in skiers (Raborn et al., 1997) and in persons with a history of frequent recurrences of herpes labialis (Gibson et al., 1986). Long-term suppressive therapy reduces the number of recurrences of oral infection in those with histories of frequent recurrences (Rooney et al., 1993). In one study of 400 mg of oral acyclovir administered twice daily for 4 months, clinical recurrences were reduced by more than half, and culture-confirmed recurrences were reduced by more than two-thirds (Rooney et al., 1993).

Herpes simplex encephalitis (HSE)

For herpes simplex encephalitis, intravenous acyclovir should be administered at 30 mg/kg per day for 14–21 days for the treatment of HSE (Whitley et al., 1986). Some experts recommend higher dosages of intravenous acyclovir be considered (45–60 mg/kg per day), although neurotoxicity can be a limiting factor in increasing the dose in larger children and adults. In untreated patients, mortality from HSE exceeds 70%, and only 2.5% of survivors return to normal neurologic function. Even with appropriate administration of antiviral therapy, substantial mortality and morbidity from HSE remain (Skoldenberg et al., 1984), with 19% of patients dying and 62% of survivors having residual neurologic sequelae (Whitley et al., 1986). Patients with a Glasgow coma score of less than 6, those older than 30 years, and those with encephalitis for longer than 4 days have a poorer outcome (Whitley et al., 1986).

Neonatal HSV

For neonatal HSV disease, intravenous acyclovir at 60 mg/kg per day delivered in three divided daily doses is currently recommended (American Academy of Pediatrics, 2003; Kimberlin et al., 2001a). The dosing interval of intravenous acyclovir may need to be increased in premature infants, based upon their creatinine clearance (Englund et al., 1991). Duration of therapy is 21 days for patients with disseminated or CNS neonatal HSV disease, and 14 days for patients with HSV infection limited to the SEM (American Academy of Pediatrics, 2003). The primary apparent toxicity associated with the use of this dose of intravenous acyclovir is neutropenia, with approximately one-fifth of patients with localized HSV disease (CNS or SEM) developing an absolute neutrophil count (ANC) of ≤1000/µl (Kimberlin et al., 2001a). Although the neutropenia resolves either during continuation of intravenous acyclovir or following its cessation, it is prudent to monitor neutrophil counts at least twice weekly throughout the course of intravenous acyclovir therapy, with consideration being given to decreasing the dose of acyclovir or administering granulocyte colony stimulating factor (GCSF) if the ANC remains below 500/µL for a prolonged period of time (Kimberlin et al., 2001a). All patients with CNS HSV involvement should have a repeat lumbar puncture at the end of intravenous acyclovir therapy to determine that the specimen is PCR-negative in a reliable laboratory, and to document the end-of-therapy CSF indices (Kimberlin et al., 2001b). Those persons who remain PCR-positive should continue to receive intravenous antiviral therapy until PCR-negativity is achieved (Kimberlin et al., 1996b; Kimberlin et al., 2001b).

In the pre-antiviral era, 85% of patients with disseminated neonatal HSV disease died by one year of age, as did 50% of patients with CNS neonatal HSV disease (Whitley et al., 1980a) (Table 64.3). Evaluations of two different doses of vidarabine and of a lower dose of acyclovir (30 mg/kg/day for 10 days) documented that both of these antiviral drugs reduce mortality to comparable degrees (Whitley et al., 1991a; Whitley et al., 1980a; Whitley et al., 1983), with mortality rates at 1 year from disseminated disease decreasing to 54% and from CNS disease decreasing to 14% (Whitley et al., 1991a) (Table 64.3). Despite its lack of therapeutic superiority, the lower dose of acyclovir quickly supplanted vidarabine as the treatment of choice for neonatal HSV disease due to its favorable safety profile and its ease of administration. Unlike acyclovir, vidarabine had to be administered over prolonged infusion times and in large volumes of fluid.

Table 64.3. Mortality and morbidity outcomes among 295 infants with neonatal HSV infection, evaluated by the National Institutes of Allergy and Infectious Diseases’ Collaborative Antiviral Study Group between 1974 and 1997.

Table 64.3

Mortality and morbidity outcomes among 295 infants with neonatal HSV infection, evaluated by the National Institutes of Allergy and Infectious Diseases’ Collaborative Antiviral Study Group between 1974 and 1997.

With utilization of a higher dose of acyclovir (60 mg/kg per day for 21 days), 12 month mortality is further reduced to 29% for disseminated neonatal HSV disease and to 4% for CNS HSV disease (Kimberlin et al., 2001a) (Figs. 64.1 and 64.2). Differences in mortality at 24 months among patients treated with the higher dose of acyclovir and the lower dose of acyclovir are statistically significant after stratification for disease category (CNS vs. disseminated) (Kimberlin et al., 2001a). Lethargy and severe hepatitis are associated with mortality among patients with disseminated disease, as are prematurity and seizures in patients with CNS disease (Kimberlin et al., 2001b).

Fig. 64.1. Mortality in patients with disseminated neonatal HSV disease.

Fig. 64.1

Mortality in patients with disseminated neonatal HSV disease. (From Kimberlin et al., 2001a.)

Fig. 64.2. Mortality in patients with CNS neonatal HSV disease.

Fig. 64.2

Mortality in patients with CNS neonatal HSV disease. (From Kimberlin et al., 2001a.)

Improvements in morbidity rates with antiviral therapies have not been as dramatic as with mortality. In the pre-antiviral era, 50% of survivors of disseminated neonatal HSV infections were developing normally at 12 months of age (Whitley et al., 1980a) (Table 64.3). With utilization of the higher dose of acyclovir for 21 days, this percentage has increased to 83% (Kimberlin et al., 2001a) (Fig. 64.3). In the case of CNS neonatal HSV disease, 33% of patients in the pre-antiviral era were developing normally at 12 months of age (Whitley et al., 1980a) (Table 64.3), while 31% of higher dose acyclovir recipients develop normally at 12 months today (Kimberlin et al., 2001a) (Fig. 64.3). While these differences are not dramatic, it is important to note that as more neonates survive neonatal HSV disease based upon the mortality data presented above, the total numbers of patients who subsequently develop normally is higher today even while the percentages of survivors with normal development are not dramatically different. Seizures at or before the time of initiation of antiviral therapy are associated with increased risk of morbidity both in patients with CNS disease and in patients with disseminated infection (Kimberlin et al., 2001b).

Fig. 64.3. Morbidity among patients with known outcomes after 12 months of life.

Fig. 64.3

Morbidity among patients with known outcomes after 12 months of life. (From Kimberlin et al., 2001a.)

Unlike disseminated or CNS neonatal HSV disease, morbidity following SEM disease has dramatically improved during the antiviral era. Prior to utilization of antiviral therapies, 38% of SEM patients experienced developmental difficulties at 12 months of age (Whitley et al., 1980a) (Table 64.3). With vidarabine and lower dose acyclovir, these percentages were reduced to 12% and 2%, respectively (Whitley et al., 1991a). In the high-dose acyclovir study, no SEM patients developed neurologic sequelae at 12 months of life (Kimberlin et al., 2001a) (Fig. 64.3).

In the pre-antiviral era, 70% of neonates with disease initially limited to skin vesicles experienced progression of disease to involvement of the CNS or visceral organs (Whitley et al., 1980b). It is likely that the initial reduction in morbidity among patients with SEM disease from 38% (Whitley et al., 1980a) to 2–12% (Whitley et al., 1991a) resulted from antiviral therapy impeding this progression to CNS or disseminated disease categories, each of which carries a higher risk of neurologic sequelae (Whitley et al., 1988). The continued reduction in morbidity among patients with SEM disease seen in the recently completed high-dose acyclovir study might relate to a redefinition of what constitutes SEM vs. CNS involvement. Prior to the application of PCR technology to neonatal HSV disease, patients were classified as having SEM disease if they had no overt laboratory or clinical evidence of viral dissemination to the viscera and/or CNS. The lack of CNS involvement was manifest by no CNS symptomatology (seizures, abnormal neuroimaging studies, abnormal electroencephalograms, etc.) and normal CSF indices. As discussed above, however, PCR analysis of CSF specimens from neonates classified by these criteria as having SEM disease revealed that approximately one-quarter (7 of 29, or 24%) of these infants actually had HSV DNA present in their CSF during the acute disease course (Kimberlin et al., 1996b). One of these seven patients subsequently developed significant neurologic impairment by age 12 months. Thus, it is possible that at least some of the SEM patients in the earlier studies who subsequently developed neurologic impairment actually had subclinical CNS disease, which could only be detected by means of the powerful investigative tool provided by PCR beginning in the 1990s. These data have resulted in a revised classification of CNS disease, such that a positive CSF PCR result is now sufficient to classify a patient as having CNS HSV infection.

Another possible explanation for the neurologic impairment previously experienced by some infants with SEM disease could be that, while low level viremia from the cutaneous lesions results in seeding of the CNS, initial damage to brain tissue during the acute illness does not occur either due to a host response to infection or due to antiviral therapy. Subclinical reactivation of virus within the CNS, with or without a clinical cutaneous recurrence, might then produce neurologic impairment, as has been suggested (Kimberlin, 2001; Whitley et al., 1991b). Supporting this hypothesis, HSV DNA has been detected in the CSF of an SEM infant at the time of a cutaneous recurrence (Kimberlin et al., 1996a). Randomized, controlled studies of long-term suppressive oral acyclovir therapy following the acute neonatal disease are currently being conducted by the NIAID Collaborative Antiviral Study Group to evaluate this hypothesis. At the current time, however, no evidence exists to suggest that suppressive oral acyclovir therapy is beneficial in preventing neurologic complications. Furthermore, almost half of infants receiving oral acyclovir in an open-label phase I/Ⅱ investigation developed neutropenia while on therapy (Kimberlin et al., 1996a), raising substantial questions about the safety of such a therapeutic approach outside of the strictly monitored confines of a clinical investigation.

HSV disease in the immunocompromised host

Acyclovir also is indicated for the treatment of disseminated HSV infections in otherwise normal hosts, including pregnant women, and mucocutaneous HSV infections in immunocompromised hosts (Kimberlin and Prober, 2003). Similarly, HSV infections of the lip, mouth, skin, perianal area, or genitals may be much more severe in immunocompromised patients than in normal hosts, with HSV lesions tending to be more invasive, slower to heal, and associated with prolonged viral shedding. Intravenous acyclovir therapy is very beneficial in such patients (Wade et al., 1982). Immunocompromised patients receiving acyclovir have a shorter duration of viral shedding and more rapid healing of lesions than patients receiving placebo (Meyers et al., 1982). Oral acyclovir therapy is also very effective in immunocompromised patients (Shepp et al., 1985).

Acyclovir prophylaxis of HSV infections is of clinical value in severely immunocompromised patients, especially those undergoing induction chemotherapy or transplantation. Intravenous or oral administration of acyclovir reduces the incidence of symptomatic HSV infection from about 70% to 5%–20% (Saral et al., 1981). A sequential regimen of intravenous acyclovir followed by oral acyclovir for 3 to 6 months can virtually eliminate symptomatic HSV infections in organ transplant recipients. A variety of oral dosing regimens, ranging from 200 mg 3 times daily to 800 mg twice daily, have been used successfully. Among bone marrow transplant recipients and patients with AIDS, acyclovir-resistant HSV isolates have been identified more frequently after therapeutic acyclovir administration than during prophylaxis (Wade et al., 1983).

HSV keratitis or keratoconjunctivitis

Topical therapy with acyclovir for HSV ocular infections is effective, but probably not superior to trifluridine (Hovding, 1989). Long-term suppressive therapy reduces the number of recurrences of ocular infection in those with histories of frequent recurrences (Herpetic Eye Disease Study Group, 1998, 2000).

Challenges for achieving clinical benefit, including adverse drug effects

Perhaps the most prominent challenge impacting clinical benefit of acyclovir therapy relates to the timing of drug initiation following onset of disease symptoms. In the case of life-threatening HSV disease, consideration of HSV as a possible cause of the illness is needed in order to then initiate acyclovir therapy. In the case of less severe but still consequential infections, such as primary genital herpes, the patient must present to medical attention, be correctly diagnosed, and then started on antiviral therapy as quickly as possible to achieve maximal benefit.

Acyclovir is a safe drug which is generally very well tolerated. Oral acyclovir sometimes causes mild gastrointestinal upset, rash, and headache. If it extravasates, intravenous acyclovir can cause severe inflammation, phlebitis, and sometimes a vesicular eruption leading to cutaneous necrosis at the injection site. If given by rapid intravenous infusion or to poorly hydrated patients or those with pre-existing renal compromise, intravenous acyclovir can cause reversible nephrotoxicity due to the formation of acyclovir crystals precipitating in renal tubules and causing an obstructive nephropathy. Administration of acyclovir by the intravenous route occasionally is associated with rash, sweating, nausea, headache, hematuria, and hypotension. High doses of intravenous acyclovir (60 mg/kg per day) in neonates and prolonged use of oral acyclovir following neonatal disease have been associated with neutropenia (Kimberlin et al., 1996a,2001b).

The most serious side effect of acyclovir is neurotoxicity, which usually occurs in subjects with compromised renal function who attain high serum concentrations of drug (Revankar et al., 1995). Neurotoxicity is manifest as lethargy, confusion, hallucinations, tremors, myoclonus, seizures, extrapyramidal signs, and changes in state of consciousness, developing within the first few days of initiating therapy. These signs and symptoms usually resolve spontaneously within several days of discontinuing acyclovir.

Although acyclovir is mutagenic at high concentrations in some in vitro assays, it is not teratogenic in animals. Limited human data suggest that acyclovir use in pregnant women is not associated with congenital defects or other adverse pregnancy outcomes (Reiff-Eldridge et al., 2000).

The likelihood of renal toxicity of acyclovir is increased when administered with nephrotoxic drugs such as cyclosporine or amphotericin B. Somnolence and lethargy may occur in subjects being treated with both zidovudine and acyclovir. Concomitant administration of probenicid prolongs acyclovir’s half-life, whereas acyclovir can decrease the clearance and prolong the half-life of drugs such as methotrexate that are eliminated by active renal secretion.

Clinical indications

Acyclovir is licensed in the United States for the treatment of initial episodes and management of recurrent episodes of genital herpes, for the treatment of chickenpox, and for the treatment of acute herpes zoster infections. It is also indicated for the treatment of neonatal HSV disease, herpes simplex encephalitis, mucocutaneous and viscerally disseminated herpes infections in immunocompromised hosts, and the treatment of chickenpox in the normal host.

Antiviral resistance

Resistance of HSV to acyclovir has become an important clinical problem, especially among immunocompromised patients exposed to long-term therapy (Englund et al., 1990). Viral resistance to acyclovir usually results from mutations in the viral TK gene although mutations in the viral DNA polymerase gene also occur rarely. Resistant isolates can cause severe, progressive, debilitating mucosal disease and, rarely, visceral dissemination (Field and Biron, 1994; Lyall et al., 1994). Isolates of HSV resistant to acyclovir also have been reported in normal hosts, most commonly in patients with frequently recurrent genital infection who have been treated with chronic acyclovir (Morfin and Thouvenot, 2003).

Famciclovir/penciclovir

Famciclovir is the inactive diacetyl ester prodrug of penciclovir, an acyclic nucleoside analogue. Following oral ingestion and systemic absorption, famciclovir is rapidly deacetylated and oxidized to form the active parent drug penciclovir.

Mechanism of action and pharmacokinetics

In cells which are infected with HSV, the viral thymidine kinase (TK) phosphorylates penciclovir to its monophosphate derivative, which in turn is converted to the active penciclovir triphosphate by cellular kinases. Penciclovir triphosphate inhibits viral DNA polymerase by competing with deoxyguanosine triphosphate for incorporation into the growing DNA strand. While penciclovir triphosphate is neither an obligate DNA chain terminator nor an inactivator of the DNA polymerase, once incorporated penciclovir triphosphate does retard the rate of subsequent nucleotide incorporation. Penciclovir is approximately 100-fold less potent than acyclovir in inhibiting herpesvirus DNA polymerase activity. By virtue of its high intracellular concentrations and long intracellular half-life (7 to 20 hours), though, it remains an effective antiviral agent.

The bioavailability of penciclovir following oral administration of famciclovir is about 70%. Peak concentrations of drug after intravenous administration of 10 mg/kg are approximately six-fold higher than those attained after oral doses of 250 mg. Food delays absorption but does not affect the final plasma drug concentration. Following oral administration, little or no famciclovir is detected in plasma or urine. The plasma half-life of penciclovir is about 2.5 hours, and almost three-quarters is recovered unchanged in the urine. Measurable penciclovir concentrations are not detectable in plasma or urine following topical administration of penciclovir cream. A 12-hour dosing interval is recommended for those with creatinine clearances between 30 and 50 ml/min per 1.73 m2, and a 24-hour interval for those with creatinine clearances less than 30 ml/min per 1.73 m2 (Boike et al., 1994).

Antiviral therapy

Penciclovir’s (and thus famciclovir’s) spectrum of activity against herpesviruses is similar to that of acyclovir. In addition to HSV, penciclovir has demonstrable in vitro activity against VZV, EBV, and hepatitis B virus (HBV).

Clinical efficacy in HSV-1 and HSV-2 infections

Genital herpes

In the episodic treatment of genital herpes, famciclovir reduces time to healing, time to cessation of viral shedding, and durations of lesion edema, vesicles, ulcers, and crusts when compared with placebo (Sacks et al., 1996b). Times to cessation of all symptoms and of moderate to severe lesion tenderness, pain, and burning are also reduced (Sacks et al., 1996b). For suppression of genital HSV recurrences, famciclovir delays the time to the first recurrence of genital herpes when compared with placebo (Diaz-Mitoma et al., 1998; Mertz et al., 1997a). Dosing and anticipated benefits of treatment of primary and recurrent genital herpes, and of suppressive therapy, are shown in Tables 64.1 and 64.2, respectively.

Recurrent herpes labialis

Topical penciclovir (Denavir) for the treatment of recurrent herpes labialis reduces time to healing and duration of pain by about half a day (Boon et al., 2000). Topical penciclovir cream decreases the time to lesion healing by approximately 1 to 2 days when compared with placebo (Boon et al., 2000; Spruance et al., 1997), and is equally effective as topical acyclovir cream (Lin et al., 2002). Additional benefit is noted in a reduction in lesion area; faster loss of lesion-associated symptoms; and reductions in daily assessments of pain, itching, burning, and tenderness (Boon et al., 2000). Faster healing and pain resolution occurs both among patients who first apply penciclovir cream in the prodrome and erythema stages and among those who start treatment in the papule and vesicle lesion stages (Spruance et al., 1997). Application of medicine should begin as early as possible, preferably during the prodromal phase, and should be continued every 2 hours during waking hours for 4 days. (Diaz-Mitoma et al., 1998; Mertz et al., 1997a)

Challenges for achieving clinical benefit, including adverse drug effects

Famciclovir is as well tolerated as acyclovir. Complaints of nausea, diarrhea, and headache occurred in clinical trials, but at frequencies similar to those reported by placebo recipients. No clinically significant drug interactions have been reported to date, although concentrations of famciclovir among volunteers increase by about 20% in patients receiving concomitant cimetidine or theophylline administration.

Clinical indications

Famciclovir was approved by the FDA for the treatment of acute herpes zoster in 1994, and subsequently was approved for the treatment and suppression of genital HSV disease in immunocompetent patients. Famciclovir is also approved for the treatment of recurrent mucocutaneous HSV disease in HIV-infected patients. Topical penciclovir is approved for the treatment of recurrent herpes labialis in adults.

Dosage regimens

For the episodic treatment of recurrent genital HSV disease, the dosage of famciclovir is 125 mg twice daily, administered for 5 days (Table 64.1). The recommended dose for suppression of genital HSV is 250 mg twice daily for up to 1 year (Table 64.1). Note that the lack of harmonization of treatment regimens resulted from different doses of famciclovir being studied in the clinical trials; this produced the unusual dosage recommendation of decreasing the suppression dose to treat a genital HSV recurrence. The safety and efficacy of famciclovir therapy beyond 1 year of treatment have not been established. For recurrent orolabial or genital HSV infection in HIV-infected patients, the recommended dose is 500 mg twice daily for 7 days.

Application of topical penciclovir to recurrent herpes labialis lesions should begin as early as possible, preferably during the prodromal phase, and should be continued every 2 hours during waking hours for 4 days.

Dose reduction of famciclovir is recommended for patients with compromised renal function. A 12-hour dosing interval is recommended for persons with creatinine clearances between 30 and 50 ml/min per 1.73 m2, and a 24-hour interval for those with creatinine clearances less than 30 ml/min per 1.73 m2 (Boike et al., 1994).

The safety and efficacy of famciclovir and topical penciclovir in children have not been established. No liquid or suspension formulation exists currently.

Antiviral resistance

Because penciclovir, like acyclovir, must be activated by the viral encoded TK enzyme, TK-deficient viral strains are resistant to both acyclovir and penciclovir. Strains of HSV whose resistance to acyclovir is conferred by alteration of the TK enzyme or by DNA polymerase mutations may remain sensitive to penciclovir (Kimberlin et al., 1995a).

Valaciclovir

Valaciclovir is the L-valyl ester of acyclovir that is rapidly converted to acyclovir after oral administration by first-pass metabolism in the liver (Jacobson, 1993). Licensed in 1995, it has a safety and efficacy profile similar to which of acyclovir but offers potential pharmacokinetic advantages.

Mechanism of action and pharmacokinetics

As a prodrug of acyclovir, valaciclovir has the same mechanism of action, antiviral spectrum, and resistance profiles as those of its parent drug, acyclovir. Following oral administration of valaciclovir, rapid and complete conversion to acyclovir occurs with first-pass intestinal and hepatic metabolism. The bioavailability of valaciclovir exceeds 50%, which is three to five times greater than that of acyclovir (Soul-Lawton et al., 1995). Peak serum concentrations, attained about 1.5 hours after a dose, are proportional to the amount of drug administered; they range from 0.8 to 8.5 μg/ml for doses of 100 to 2000 mg (Weller et al., 1993). The area under the drug concentration time curve approximates that seen after intravenous acyclovir. All other pharmacokinetic characteristics are similar to those of acyclovir (Nadal et al., 2002).

Antiviral therapy

Acyclovir is most active in vitro against HSV, with activity against VZV being about tenfold less. Although EBV has only minimal thymidine kinase activity, EBV DNA polymerase is susceptible to inhibition by acyclovir triphosphate and thus EBV is moderately susceptible to acyclovir in vitro. Activity against CMV is limited by CMV’s lack of a gene for thymidine kinase; furthermore, CMV DNA polymerase is poorly inhibited by acyclovir triphosphate.

Clinical efficacy in HSV-1 and HSV-2 infections

Genital herpes

Valaciclovir treatment of first-episode genital HSV is as effective as acyclovir therapy, while at the same time providing a more favorable dosing schedule compared with acyclovir (Fife et al., 1997) (Tables 64.1 and 64.2). In the treatment of recurrent genital HSV, valaciclovir decreases the duration of lesions, the duration of pain, and the duration of viral shedding when compared to placebo (Spruance et al., 1996). Valaciclovir also is as effective as acyclovir for the episodic treatment of recurrent genital HSV, again providing a more favorable dosing schedule compared with acyclovir (Tyring et al., 1998) (Tables 64.1 and 64.2). It should be administered for 3 to 5 days when administered as episodic treatment (Anonymous, 2002; Leone et al., 2002). Valaciclovir is also effective in suppressing recurrences of genital HSV when administered as once-daily suppressive therapy (Reitano et al., 1998). Valaciclovir has recently demonstrated efficacy in the suppression of recurrent herpes labialis with 500 mg once-daily (Baker et al., 2000).

Recurrent herpes labialis

Valaciclovir administered at high doses for short periods of time (2 grams orally twice a day for 1 day) reduces the time to lesion healing and time to cessation of pain and/or discomfort compared to placebo, with the overall duration of the episode being decreased by approximately one day (Spruance et al., 2003). However, early valaciclovir treatment does not appear to increase the likelihood that a clinical recurrence will be aborted prior to cold sore lesion development (Chosidow et al., 2003; Spruance et al., 2003).

Valaciclovir administered as a 500 mg dose once daily is effective in suppressing recurrences of herpes labialis, with almost two-thirds of treated patients remaining recurrence-free during four months of suppressive therapy compared with approximately one-third of placebo recipients (Baker and Eisen, 2003; Baker et al., 2000).

Herpes simplex encephalitis

Herpes simplex encephalitis is managed acutely with intravenous acyclovir, as discussed above. A randomized, controlled trial of long-term suppressive oral valaciclovir therapy following the treatment of the acute HSE disease is currently being conducted by the NIAID Collaborative Antiviral Study Group. This study will determine whether subclinical reactivation of HSV within the brain contributes to the neurologic impairment experienced by many HSE survivors. At the current time, however, no evidence exists to suggest that suppressive oral valaciclovir therapy is beneficial in preventing neurologic complications.

Challenges for achieving clinical benefit, including adverse drug effects

The profiles of adverse effects and potential drug interactions observed with valaciclovir therapy are the same as those observed with acyclovir treatment. Neurotoxicity has not been reported in humans to date, although it has been observed in animal models (Jacobson, 1993). Manifestations resembling thrombotic microangiopathy have been described in patients with advanced HIV disease receiving very high doses of valaciclovir (8 grams per day), but the multitude of other medications being administered to such patients makes the establishment of a causal relationship to valaciclovir difficult (Bell et al., 1997). Although causation has not been established, use of valaciclovir at such high doses should involve evaluation of potential risks and benefits.

A limited number of adverse drug interactions with acyclovir have been reported. Subjects being treated with both zidovudine and acyclovir can develop severe somnolence and lethargy. The likelihood of renal toxicity is increased when acyclovir is administered with nephrotoxic drugs such as cyclosporine and amphotericin B. Concomitant administration of probenicid decreases renal clearance of acyclovir and prolongs its half-life; conversely, acyclovir can decrease the clearance of drugs such as methotrexate that are eliminated by active renal secretion.

Clinical indications

Valaciclovir is indicated for the treatment of herpes zoster, and for the treatment or suppression of genital herpes. Although data from controlled clinical trials are limited, because of greater bioavailability, valaciclovir may be advantageous in treating infections caused by viruses relatively less sensitive to acyclovir than HSV (e.g., VZV and CMV).

Dosage regimens

Adult treatment doses for HSV-1 and HSV-2 infections are: 1) 1 gram orally twice daily for 7–10 days for first episode genital herpes (Table 64.164.2) 500 mg orally twice daily for 3–5 days for episodic treatment of recurrent genital HSV disease (Table 64.1); and 64.3) 1 gram orally once daily for suppression of recurrent genital HSV (Table 64.1). Suppression of recurrent oral herpes infections has been accomplished with single daily doses of 500 mg.

Valaciclovir dosages in children are not yet established. A valaciclovir oral suspension has recently been formulated and is undergoing Phase I evaluation in infants and children.

With decreasing creatinine clearance, the dosing interval should be spread. With significant renal impairment, the dose should also be reduced in half. Acyclovir is removed during hemodialysis, and therefore an extra dose of valaciclovir should be administered following completion of hemodialysis. Supplemental doses of valaciclovir are not required following chronic ambulatory peritoneal dialysis (CAPD) and continuous arteriovenous hemofiltration/dialysis (CAVHD).

Antiviral resistance

HSV resistance to acyclovir can result from mutations in either the viral TK gene or the viral DNA polymerase gene. Although these acyclovir-resistant isolates exhibit diminished virulence in animal models, among HIV-infected patients they can cause severe, progressive, debilitating mucosal disease and (rarely) visceral dissemination (Gateley et al., 1990). Acyclovir-resistant strains of HSV also have been recovered from cancer chemotherapy patients, bone marrow and solid organ transplant recipients, children with congenital immunodeficiency syndromes, and neonates (Kimberlin et al., 1996a). Although it is uncommon, genital herpes caused by acyclovir-resistant isolates has also been reported in immunocompetent hosts who usually have received chronic acyclovir therapy (Kost et al., 1993).

Second-line antiviral agents for HSV-1 and HSV-2 infections cidofovir

Cidofovir was first approved for use in the United States for the therapy of AIDS-associated retinitis caused by CMV, and this remains the main indication for this antiviral agent. With a mechanism of action independent of viral TK activity, however, cidofovir can have a role in the management of HSV-1 and HSV-2 infections which are acyclovir resistant, as described below.

Mechanism of action and pharmacokinetics

Cidofovir is a novel acyclic phosphonate nucleotide analogue. In its native form, cidofovir already has a single phosphate group attached, and thus viral enzymes are not required for initial phosphorylation of drug. In this regard, it is dissimilar to the nucleoside analogues such as acyclovir and ganciclovir. Cellular kinases sequentially attach two additional phosphate groups, converting cidofovir to its active diphosphate form.

Cidofovir has a mechanism of action which is similar to other nucleoside analogues. The active cidofovir diphosphate serves as a competitive inhibitor of DNA polymerase (Ho et al., 1992). While cidofovir is taken up by both virally infected and uninfected cells, the active form of the drug exhibits a 25- to 50-fold greater affinity for the viral DNA polymerase as compared to the cellular DNA polymerase, thereby selectively inhibiting viral replication (Ho et al., 1992). Incorporation of cidofovir into the growing viral DNA chain results in reductions in the rate of viral DNA synthesis.

Only 2%–26% of cidofovir is absorbed after oral administration, requiring that cidofovir be administered intravenously in the clinical management of patients. The plasma half-life of cidofovir is 2.6 hours, but active intracellular metabolites of cidofovir have half-lives of 17 to 48 hours (Cundy et al., 1995). Ninety percent of the drug is excreted in the urine, primarily by renal tubular secretion (Lalezari et al., 1995).

Antiviral therapy

While primarily a CMV drug, cidofovir has demonstrable activity against HSV as well. Due to its unique phosphorylation requirements for activation, the drug usually maintains activity against acyclovir- and foscarnet-resistant HSV isolates (Safrin et al., 1999). Although cidofovir is less potent in vitro against HSV than is acyclovir, its favorable pharmacokinetic profile increases its anti-HSV activity. Cidofovir also has demonstrated in vitro activity against varicella-zoster virus, Epstein–Barr virus, human herpesvirus-6, human herpesvirus-8, polyomaviruses, adenovirus, and human papillomavirus (HPV).

Clinical efficacy in HSV-1 and HSV-2 infections

The primary use for cidofovir at the current time is for the management of CMV retinitis in patients with acquired immunodeficiency syndrome (AIDS) (Lalezari et al., 1997; Studies of Ocular Complications of AIDS Research Group in collaboration with the AIDS Clinical Trials Group, 1997). However, cidofovir has been utilized successfully in the management of disease caused by acyclovir-resistant HSV isolates (Lalezari et al., 1994). Due in part to its toxicity profile (described below), cidofovir does not have a role in antiviral prophylaxis of herpesvirus infections.

The safety and efficacy of cidofovir in children have not been studied. Due to the risk of long-term carcinogenicity and reproductive toxicity, the use of cidofovir in children warrants caution.

Challenges for achieving clinical benefit, including adverse drug effects

The principle adverse event associated with systemic administration of cidofovir is nephrotoxicity. Cidofovir concentrates in renal cells in amounts 100 times greater than is seen in other tissues, producing severe proximal convoluted tubule nephrotoxicity when concomitant hydration and administration of probenicid are not employed (Cundy et al., 1995; Lalezari et al., 1995). When present, renal toxicity manifests as proteinuria and glycosuria. In order to decrease the potential for nephrotoxicity, aggressive intravenous prehydration and coadministration of probenecid are required with each cidofovir dose. Within 48 hours prior to delivery of each dose of cidofovir, serum creatinine and urine protein must be determined, with adjustment in dose as indicated. Due to its potential for nephrotoxicity, cidofovir should not be administered concomitantly with other potentially nephrotoxic agents (e.g., intravenous aminoglycosides (e.g., tobramycin, gentamicin, and amikacin), amphotericin B, foscarnet, intravenous pentamidine, vancomycin, and non-steroidal anti-inflammatory agents).

Cidofovir’s potential for nephrotoxicity, neutropenia, ocular hypotony, and metabolic acidosis are judged significant enough to warrant warning statements from the FDA in the package insert. Cidofovir is carcinogenic, teratogenic, and causes hypospermia in animal studies.

Clinical indications

Cidofovir is licensed for the treatment of CMV retinitis in AIDS patients. The safety and efficacy of cidofovir for the treatment of other CMV infections, including those in non-HIV-infected individuals, or of resistant HSV infections has not been established.

Dosage regimens

Due to poor oral bioavailability (2%–26%), cidofovir can only be administered intravenously or topically. The recommended induction dose of cidofovir for patients with a serum creatinine of ≤1.5 mg/dl, a calculated creatinine clearance >55 ml/min, and a urine protein <100 mg/dl (equivalent to <2 + proteinuria) is 5 mg/kg body weight administered once weekly for two consecutive weeks. The recommended maintenance dose of cidofovir is 5 mg/kg body weight administered once every 2 weeks. Aggressive intravenous prehydration and coadministration of probenecid are required with each cidofovir dose. Cidofovir must not be administered intraocularly due to the potential for ocular hypotony.

Cidofovir is contraindicated in patients with serum creatinine >1.5 mg/dL, calculated creatinine clearance ≤55 ml/min, or urine protein ≥100 mg/dl (equivalent to ≥2+ proteinuria). The maintenance dose of cidofovir must be reduced from 5 mg/kg to 3 mg/kg for an increase in serum creatinine of 0.3–0.4 mg/dl above baseline. Cidofovir therapy must be discontinued if serum creatinine increases ≥0.5 mg/dl above baseline.

Foscarnet

Foscarnet is an organic analogue of inorganic pyrophosphate, with the chemical name of phosphonoformic acid (PFA). As such, it is the only antiherpes drug that is not a nucleoside or nucleotide analogue. It has the potential to chelate divalent metal ions, such as calcium and magnesium, to form stable coordination compounds. It is not a first-line drug but is useful for the treatment of infections caused by resistant herpes viruses.

Mechanism of action and pharmacokinetics

Foscarnet directly inhibits DNA polymerase by blocking the pyrophosphate binding site and preventing cleavage of pyrophosphate from deoxynucleotide triphosphates (Wagstaff and Bryson, 1994). It is a non-competitive inhibitor of viral DNA polymerases or HIV reverse transcriptase, and is not incorporated into the growing viral DNA chain. It is approximately 100-fold more active against viral enzymes than host cellular enzymes.

Foscarnet is poorly absorbed after oral administration, with a bioavailability of only about 20%, thereby limiting foscarnet’s delivery to the intravenous route. Maximum serum concentration attained after a dose of 60 mg/kg is approximately 500 μmol/l (Wagstaff and Bryson, 1994). Data are limited regarding tissue distribution, but CSF concentrations are about two-thirds of those in serum. Eighty percent of an administered dose of foscarnet is eliminated unchanged in the urine; half-life is 48 hours, and dosage adjustments are necessary even in the presence of minimal degrees of renal dysfunction. Hemodialysis efficiently eliminates foscarnet and therefore an extra dose of drug is recommended after a 3-hour dialysis run (MacGregor et al., 1991). There are no pharmacokinetic data for foscarnet in neonates.

Antiviral therapy

Foscarnet inhibits all known human herpesviruses, including acyclovir-resistant HSV and VZV strains and most ganciclovir-resistant CMV isolates. It also is active against HIV. While the drug concentrations required for inhibition of viral replication vary markedly, they generally range from 10 to 130 μM for HSV, 100 to 300 μM for CMV, and 10 to 25 μM for HIV.

Clinical efficacy in HSV-1 and HSV-2 infections

While primarily a CMV drug, foscarnet has demonstrable activity against HSV as well, and infections caused by acyclovir-resistant strains of HSV have been successfully controlled with foscarnet (Safrin et al., 1991a; Safrin et al., 1991b).

The safety and efficacy of foscarnet in the pediatric population has not been established. Potential exists for deposition of foscarnet in the developing teeth and bone of children. Therefore, administration of foscarnet to pediatric patients should be undertaken only after careful evaluation and only if the potential benefits for treatment outweigh the potential risks.

Challenges for achieving clinical benefit, including adverse drug effects

The most common adverse effects of foscarnet are nephrotoxicity and metabolic derangements. Evidence of nephrotoxicity includes azotemia, proteinuria, acute tubular necrosis, crystalluria, and interstitial nephritis (Studies of Ocular Complications of AIDS Research Group in collaboration with the AIDS Clinical Trials Group, 1992). Serum creatinine concentrations increase in up to 50% of patients, usually during the second week of therapy. Fortunately, renal function returns to normal within two to four weeks of discontinuing therapy in most affected patients. Pre-existing renal disease, concurrent use of other nephrotoxic drugs, dehydration, rapid injection of large doses, or continuous intravenous infusion of drug are risk factors for developing renal dysfunction (Deray et al., 1989).

Metabolic disturbances associated with foscarnet therapy include symptomatic hypo- and hypercalcemia and hypo- and hyperphosphatemia (Markham and Faulds, 1994). Hypocalcemia is due to direct chelation of ionized calcium by the drug, and patients can have such symptoms as paresthesias, tetany, seizures, and arrythmias. Metabolic disturbances can be minimized if foscarnet is administered by slow infusion, with rates not exceeding 1 mg/kg per min. Common central nervous system (CNS) symptoms associated with foscarnet therapy are headache, tremor, irritability, seizures, and hallucinations. Fever, nausea, vomiting, abnormal serum hepatic enzymes, anemia, granulocytopenia, and genital ulcerations also have been reported. The genital ulcerations appear to be associated with high urinary concentrations of drug.

Concomitant use of amphotericin B, cyclosporine, gentamicin, and other nephrotoxic drugs increases the likelihood of renal dysfunction associated with foscarnet therapy. Co-administration of pentamidine increases the risk of hypocalcemia. Anemia and neutropenia are more common when patients also are receiving zidovudine. No drug–drug interactions are known to exist with the concomitant use of foscarnet and ganciclovir.

Foscarnet’s major toxicity of renal impairment is judged significant enough to warrant warning statements from the FDA in the package insert. Serum creatinine should be monitored frequently, and adequate hydration with foscarnet administration is imperative. Elevations in serum creatinine are usually, but not always, reversible following discontinuation or dose adjustment of foscarnet. Patients receiving foscarnet must also be monitored for development of mineral and electrolyte abnormalities that might result in seizures, including hypocalcemia, hypophosphatemia, hyperphosphatemia, hypomagnesemia, and hypokalemia.

Clinical indications

Foscarnet is indicated for the treatment of acyclovir-resistant mucocutaneous HSV infections in immunocompromised patients, and is the drug of choice for both HSV and VZV infections caused by acyclovir-resistant strains. Foscarnet also is indicated for the treatment of CMV retinitis in patients with AIDS.

Dosage regimens

When used for the treatment of acyclovir-resistant strains of HSV, foscarnet should be administered at 120 mg/kg per day in three divided doses. In patients with AIDS, foscarnet therapy should be initiated within 7 to 10 days of suspicion of infection caused by acyclovir-resistant HSV or VZV. Therapy should be continued until lesions have resolved.

The degree of dose reduction is proportional to reduction in creatinine clearance; when creatinine clearance is 50% of normal, the dose should be reduced by about 50%. Detailed tables of dosage adjustments are available in the foscarnet package insert.

Antiviral resistance

Foscarnet does not require activation by viral kinases, including thymidine kinase, and therefore is active in vitro against HSV TK-deficient mutants. Resistance occurs as a result of DNA polymerase mutations (Kimberlin et al., 1995a). Strains of CMV, HSV, and VZV with three- to fivefold reduced sensitivity to foscarnet have been reported (Kimberlin et al., 1995b; Safrin et al., 1994; Snoeck et al., 1994). These isolates may respond to therapy with acyclovir (Safrin et al., 1994) or cidofovir (Snoeck et al., 1994). Conversely, infections caused by acyclovir-resistant strains of HSV and VZV have been successfully controlled with foscarnet (Safrin et al., 1991a; Safrin et al., 1991b).

Ganciclovir

Ganciclovir is a nucleoside analogue that differs from acyclovir by having an extra hydroxymethyl group on the acyclic side chain.

Mechanism of action and pharmacokinetics

As with acyclovir and penciclovir, the first step in ganciclovir phosphorylation is carried out by a virus-encoded enzyme, and the final steps by cellular enzymes. Ganciclovir triphosphate is a competitive inhibitor of herpesviral DNA polymerases, resulting in cessation of DNA chain elongation (Markham and Faulds, 1994). Ganciclovir triphosphate also has some activity against cellular DNA polymerases, and this potential for incorporation into cellular DNA accounts for ganciclovir’s significant toxicities. Ganciclovir has similar activity to acyclovir against HSV-1, HSV-2, and VZV but, in contrast with acyclovir, its greatest activity is against CMV.

Peak serum concentrations of ganciclovir after 5 mg/kg of intravenously-administered drug range from 8 to 11 μg/ml. Concentrations of ganciclovir in the central nervous system range from 24% to 70% of those in the plasma, with brain concentrations of approximately 38% of plasma levels (Fletcher et al., 1986). Most of an administered dose of ganciclovir is eliminated unchanged in the urine, with an elimination half-life of 2 to 3 hours. Intracellular ganciclovir triphosphate has a half-life of more than 24 hours.

Oral bioavailability of ganciclovir is poor, with less than 10% of drug being absorbed following oral administration (Frenkel et al., 2000; Jacobson et al., 1987; Markham and Faulds, 1994). Despite this, an oral dose of 1000 mg of ganciclovir produces a peak plasma concentration of 1 μg/ml. Intravitreal drug concentrations achieved during intravenous induction therapy also average 1 μg/ml, while subretinal concentrations are comparable to those achieved in plasma (Kuppermann et al., 1993).

The pharmacokinetic of intravenous ganciclovir in the neonatal population are similar to those of adults (Trang et al., 1993). Following intravenous administration of 6 mg/kg of ganciclovir, peak concentrations of 7.0 μg/ml are achieved. The mean elimination half-life is 2.4 hours.

Dose reduction, proportional to the degree of reduction in creatinine clearance, is necessary for persons with impaired renal function. A supplemental dose is recommended after dialysis because it is efficiently removed by hemodialysis (Swan et al., 1991).

Antiviral therapy

Ganciclovir’s greatest in vitro activity is against CMV, although it is also as active as acyclovir against HSV-1 and HSV-2 and almost as active against VZV.

Challenges for achieving clinical benefit, including adverse drug effects

Myelosuppression is the most common adverse effect of ganciclovir; dose-related neutropenia (less than 1000 WBC/μl) is the most consistent hematologic disturbance, with an incidence of about 40% of ganciclovir-treated patients (Markham and Faulds, 1994). Neutropenia is dose limiting in about 15% of subjects, and is reversible upon cessation of drug. Neutropenia is less frequent following oral administration of ganciclovir (Drew et al., 1995). Hematopoietic growth factors may be useful in preventing or managing neutropenia. Thrombocytopenia (less than 50 000 platelets/μl) occurs in approximately 20% of treated patients, while anemia in about 2% of ganciclovir recipients. Due to its marrow suppressive effects, ganciclovir should not be administered if the absolute neutrophil count is less than 500 cells/µl or if the platelet count is less than 25 000 cells/µL.

Two to 5% of ganciclovir recipients experience headache, confusion, altered mental status, hallucinations, nightmares, anxiety, ataxia, tremors, seizures, fever, rash, and abnormal levels of serum hepatic enzymes, either singly or in some combination (Markham and Faulds, 1994). Intraocular injection of ganciclovir can cause transient increases in intraocular pressure with associated intense pain and amaurosis lasting up to 30 minutes.

Since both zidovudine and ganciclovir have the potential to cause neutropenia and anemia, some patients may not tolerate concomitant therapy with these drugs at full dosage. Renal clearance of ganciclovir decreases in the presence of probenicid. Generalized seizures have been reported in patients who received ganciclovir and imipenem-cilastatin, and these drugs should not be used concomitantly unless the potential benefits outweigh the risks.

In preclinical test systems, ganciclovir is mutagenic, carcinogenic, and teratogenic. Additionally, it causes irreversible reproductive toxicity in animal models. The use of ganciclovir in the pediatric population warrants extreme caution due to this potential for long-term carcinogenicity and reproductive toxicity. Administration of ganciclovir to pediatric patients should be undertaken only after careful evaluation and only if the potential benefits of treatment outweigh the potential risks.

Clinical indications

Ganciclovir is indicated for the treatment and prevention of CMV infections in immunocompromised patients. Its role in the treatment of HSV-1 or HSV-2 infections is limited to unique situations in which coverage of these viruses in addition to CMV is desirable.

Dosage regimens

The usual therapeutic and prophylactic dose of ganciclovir is 10 mg/kg per day, given by intravenous infusion twice a day for 2 to 3 weeks. For continued suppressive therapy to prevent relapse of infection or for long-term prophylaxis, either of the following may be used: (1) 5 mg/kg as a single daily dose each day of the week; or (2) 6 mg/kg administered 5 days a week. Despite the absence of data, utilization of intravenous ganciclovir is largely being supplanted by oral valganciclovir in clinical practice.

Dose reduction, roughly proportional to the degree of reduction in creatinine clearance, is necessary in persons with impaired renal function (Spector et al., 1995; Swan et al., 1991). When creatinine clearance is between 50 and 79 ml/min per 1.73 m2, half of the usual dose should be given every 12 hours. This same dose should be given every 24 hours if creatinine clearance is between 25 and 49 ml/min per 1.73 m2. Twenty-five percent of the usual dose should be given every 24 hours if creatinine clearance is less than 25 ml/min per 1.73 m2. Because ganciclovir is efficiently removed by hemodialysis, a supplemental dose is recommended after dialysis (Swan et al., 1991).

Antiviral resistance

Strains of HSV that are resistant to acyclovir because of TK deficiency also are much less sensitive to ganciclovir. DNA polymerase HSV mutants that are ganciclovir-resistant have been generated in vitro but are not yet a clinical problem.

Valganciclovir

Valganciclovir was approved by the FDA in March, 2001. Because it is well absorbed after oral administration, it may represent a favorable option to intravenously-administered ganciclovir for the treatment and suppression of CMV infections in immunocompromised hosts.

Mechanism of action and pharmacokinetics

Valganciclovir is an L-valine ester prodrug of ganciclovir and as such has the same mechanism of action, antiviral spectrum, and potential for development of resistance as ganciclovir (Cocohoba and McNicholl, 2002). Valganciclovir is rapidly converted to ganciclovir, with a mean plasma half-life of about 30 minutes (Jung and Dorr, 1999). The absolute bioavailability of valganciclovir exceeds 60% and actually is enhanced by about 30% with concomitant administration of food (Brown et al., 1999). The area under the curve of ganciclovir after oral administration of valganciclovir is one-third to one-half of that attained after intravenous administration of ganciclovir. Patients with impaired renal function require dosage reduction that is roughly proportional to their reduction in creatinine clearance (Cocohoba and McNicholl, 2002).

Antiviral therapy

Valganciclovir provides a more tolerable means by which ganciclovir can be delivered to the body than does intravenous ganciclovir. Studies of this drug to date have not included investigations of use for HSV infections.

Challenges for achieving clinical benefit, including adverse drug effects

Based upon data from 370 subjects participating in clinical trials, the most common side effects associated with valganciclovir therapy include diarrhea (41%), nausea (30%), neutropenia (27%), anemia (26%), and headache (22%) (Cocohoba and McNicholl, 2002).

Clinical indications

Valganciclovir has similar indications to ganciclovir. However, based upon limited controlled trials published to date, it currently is approved for the induction and maintenance therapy of CMV retinitis (Martin et al., 2002).

Dosage regimens

The recommended dose of valganciclovir for induction therapy is 900 mg twice daily for 2 weeks. The recommended dose for maintenance therapy is 900 mg once daily.

Antiviral resistance

Resistance mechanisms are identical between ganciclovir and valganciclovir. Since selective pressure resulting from exposure to lower concentrations of drug appears to increase the likelihood of resistance developing among CMV isolates (Drew et al., 1999), it is likely that the higher serum and tissue concentrations of ganciclovir achieved with administration of valganciclovir will produce less emergence of resistance when compared to oral ganciclovir. Whether or not this is seen in the clinical setting requires completion of Phase Ⅳ trials.

References

  • Alexander L., Naisbett B. Patient and physician partnerships in managing genital herpes. J. Infect. Dis. 2002;186:S57–65. [PubMed: 12353188]
  • Pickering L. K.American Academy of Pediatrics (2003). Herpes simplex. In 2003 Red Book: Report of the Committee on Infectious Diseases, ed. American Academy of Pediatrics; Elk Grove Village, IL, pp. 344–353.
  • Anonymous (2002Sexually transmitted diseases treatment guidelines 2002 Morb. Mortal. Wkly Rep. 51, RR-6, 12–17.
  • Aoki, F. Y., Law, B. J., Hammond, G. W. et al. and The Acyclovir-Gingivostomatitis Research Group (1993). Acyclovir (ACV) suspension for treatment of acute herpes simplex virus (HSV) gingivostomatitis in children: a placebo(PL) controlled, double blind trial. 33rd Interscience Conference on Antimicrobial Agents and Chemotherapy. New Orleans, LA, p. 399, Abstract #1530.
  • Baker D., Eisen D. Valacyclovir for prevention of recurrent herpes labialis: 2 double-blind, placebo-controlled studies. Cutis. 2003;71:239–242. [PubMed: 12661753]
  • Baker, D. A., Deeter, R. G., Redder, K., and Phillips, J. A. (2000). Valacyclovir effective for suppression of recurrent HSV-1 herpes labialis. 40th Interscience Conference on Antimicrobial Agents and Chemotherapy. Toronto, Ontario, Canada, p. 263, Abstract #464.
  • Bell W. R., Chulay J. D., Feinberg J. E. Manifestations resembling thrombotic microangiopathy in patients with advanced human immunodeficiency virus (HIV) disease in a cytomegalovirus prophylaxis trial (ACTG 204). Medicine. 1997;76:369–380. [PubMed: 9352739]
  • Benedetti J., Corey L., Ashley R. Recurrence rates in genital herpes after symptomatic first-episode infection. Ann. Intern. Med. 1994;121:847–854. [PubMed: 7978697]
  • Bodsworth N. J., Crooks R. J., Borelli S., et al. and the International Valaciclovir HSV Study Group (1997Valaciclovir versus aciclovir in patient initiated treatment of recurrent genital herpes: a randomised, double blind clinical trial Genitourin. Med. 73110–116. [PMC free article: PMC1195783] [PubMed: 9215092]
  • Boike S. C., Pue M. A., Freed M. I., et al. Pharmacokinetics of famciclovir in subjects with varying degrees of renal impairment. Clin. Pharmacol. Ther. 1994;55:418–426. [PubMed: 8162668]
  • Boon R., Goodman J. J., Martinez J., Marks G. L., Gamble M., Welch C. Penciclovir cream for the treatment of sunlight-induced herpes simplex labialis: a randomized, double-blind, placebo-controlled trial. Penciclovir Cream Herpes Labialis Study Group. Clin. Ther. 2000;22:76–90. [PubMed: 10688392]
  • Brown F., Banken L., Saywell K., Arum I. Pharmacokinetics of valganciclovir and ganciclovir following multiple oral dosages of valganciclovir in HIV- and CMV-seropositive volunteers. Clin. Pharmacokinet. 1999;37:167–176. [PubMed: 10496303]
  • Bryson Y. J., Dillon M., Lovett M., et al. Treatment of first episodes of genital herpes simplex virus infection with oral acyclovir. A randomized double-blind controlled trial in normal subjects. N. Engl. J. Med. 1983;308:916–921. [PubMed: 6339923]
  • Chosidow O., Drouault Y., Leconte-Veyriac F., et al. Famciclovir vs. aciclovir in immunocompetent patients with recurrent genital herpes infections: a parallel-groups, randomized, double-blind clinical trial. Br. J. Dermatol. 2001;144:818–824. [PubMed: 11298543]
  • Chosidow O., Drouault Y., Garraffo R., Veyssier P., and Valaciclovir Herpes Facialis Study, G. (2003Valaciclovir as a single dose during prodrome of herpes facialis: a pilot randomized double-blind clinical trial Br. J. Dermatol. 148142–146. [PubMed: 12534609]
  • Cocohoba J. M., McNicholl I. R. Valganciclovir: an advance in cytomegalovirus therapeutics. Ann. Pharmacother. 2002;36:1075–1079. [PubMed: 12022911]
  • Corey L., Nahmias A. J., Guinan M. E., Benedetti J. K., Critchlow C. W., Holmes K. K. A trial of topical acyclovir in genital herpes simplex virus infections. N. Engl. J. Med. 1982;306:1313–1319. [PubMed: 6280052]
  • Corey L., Wald A., Patel R., et al. and the Valacyclovir HSV Transmission Study Group (2004Once-daily valacyclovir to reduce the risk of transmission of genital herpes N. Engl. J. Med. 35011–20. [PubMed: 14702423]
  • Cundy K. C., Petty B. G., Flaherty J., et al. Clinical pharmacokinetics of cidofovir in human immunodeficiency virus-infected patients. Antimicrob. Agents Chemother. 1995;39:1247–1252. [PMC free article: PMC162721] [PubMed: 7574510]
  • Deray G., Martinez F., Katlama C., et al. Foscarnet nephrotoxicity: mechanism, incidence and prevention. Am. J. Nephrol. 1989;9:316–321. [PubMed: 2554731]
  • Diaz-Mitoma F., Sibbald R. G., Shafran S. D., Boon R., Saltzman R. L., and the Collaborative Famciclovir Genital Herpes Research Group (1998Oral famciclovir for the suppression of recurrent genital herpes: a randomized controlled trial J. Am. Med. Assoc. 280887–892. [PubMed: 9739972]
  • Douglas J. M., Critchlow C., Benedetti J., et al. A double-blind study of oral acyclovir for suppression of recurrences of genital herpes simplex virus infection. N. Engl. J. Med. 1984;310:1551–1556. [PubMed: 6328298]
  • Drew W. L., Ives D., Lalezari J. P., et al. and the Syntex Cooperative Oral Ganciclovir Study Group (1995Oral ganciclovir as maintenance treatment for cytomegalovirus retinitis in patients with AIDS N. Engl. J. Med. 333615–620. [PubMed: 7637721]
  • Drew W. L., Stempien M. J., Andrews J., et al. Cytomegalovirus (CMV) resistance in patients with CMV retinitis and AIDS treated with oral or intravenous ganciclovir. J. Infect. Dis. 1999;179:1352–1355. [PubMed: 10228054]
  • Elion G. B. Mechanism of action and selectivity of acyclovir. Am. J. Med. 1982;73:7–13. [PubMed: 6285736]
  • Englund J. A., Zimmerman M. E., Swierkosz E. M., Goodman J. L., Scholl D. R., Balfour H. H. Jr. Herpes simplex virus resistant to acyclovir. A study in a tertiary care center. Ann. Intern. Med. 1990;112:416–422. [PubMed: 2155570]
  • Englund J. A., Fletcher C. V., Balfour H. H. Jr. Acyclovir therapy in neonates. J. Pediatr. 1991;119:129–135. [PubMed: 2066845]
  • Field A. K., Biron K. K. The end of innocence revisited: resistance of herpesviruses to antiviral drugs. Clin. Microbiol. Rev. 1994;7:1–13. [PMC free article: PMC358302] [PubMed: 8118786]
  • Fife K. H., Barbarash R. A., Rudolph T., Degregorio B., Roth R., and the Valaciclovir International Herpes Simplex Virus Study Group (1997Valaciclovir versus acyclovir in the treatment of first-episode genital herpes infection. Results of an international, multicenter, double-blind, randomized clinical trial Sexually Transm. Dis. 24481–486. [PubMed: 9293612]
  • Fletcher C., Sawchuk R., Chinnock B., Miranda, Balfour H. H. Jr. Human pharmacokinetics of the antiviral drug DHPG. Clin. Pharmacol. Ther. 1986;40:281–286. [PubMed: 3017630]
  • Frenkel L. M., Capparelli E. V., Dankner W. M., et al. and The Pediatric AIDS Clinical Trials Group (2000Oral ganciclovir in children: pharmacokinetics, safety, tolerance, and antiviral effects J. Infect. Dis. 1821616–1624. [PubMed: 11069232]
  • Gateley A., Gander R. M., Johnson P. C., Kit S., Otsuka H., Kohl S. Herpes simplex virus type 2 meningoencephalitis resistant to acyclovir in a patient with AIDS. J. Infect. Dis. 1990;161:711–715. [PubMed: 2156946]
  • Gibson J. R., Klaber M. R., Harvey S. G., Tosti A., Jones D., Yeo J. M. Prophylaxis against herpes labialis with acyclovir cream – a placebo-controlled study. Dermatologica. 1986;172:104–107. [PubMed: 3512326]
  • Gold D., Corey L. Acyclovir prophylaxis for herpes simplex virus infection. Antimicrob. Agents Chemother. 1987;31:361–367. [PMC free article: PMC174733] [PubMed: 3555331]
  • Goldberg L. H., Kaufman R., Kurtz T. O., et al. Long-term suppression of recurrent genital herpes with acyclovir. A 5-year benchmark. Acyclovir Study Group. Arch. Dermatol. 1993;129:582–587. [PubMed: 8481018]
  • Herpetic Eye Disease Study Group (1998Acyclovir for the prevention of recurrent herpes simplex virus eye disease N. Engl. J. Med. 339300–306. [PubMed: 9696640]
  • Herpetic Eye Disease Study Group (2000Oral acyclovir for herpes simplex virus eye disease: effect on prevention of epithelial keratitis and stromal keratitis Arch. Ophthalmol. 1181030–1036. [PubMed: 10922194]
  • Ho H. T., Woods K. L., Bronson J. J., Boeck, Martin J. C., Hitchcock M. J. Intracellular metabolism of the antiherpes agent (S)-1-[3-hydroxy-2-(phosphonylmethoxy)propyl]cytosine. Mol. Pharmacol. 1992;41:197–202. [PubMed: 1310143]
  • Hovding G. A comparison between acyclovir and trifluorothymidine ophthalmic ointment in the treatment of epithelial dendritic keratitis. A double blind, randomized parallel group trial. Acta Ophthalmol. 1989;67:51–54. [PubMed: 2505485]
  • Jacobson M. A. 1993Valaciclovir (BW256U87): the L-valyl ester of acyclovir J. Med. Virol., Suppl, 150–153. [PubMed: 8245883]
  • Jacobson M. A., Miranda, Cederberg D. M., et al. Human pharmacokinetics and tolerance of oral ganciclovir. Antimicrob. Agents Chemother. 1987;31:1251–1254. [PMC free article: PMC174913] [PubMed: 2820301]
  • Jung D., Dorr A. Single-dose pharmacokinetics of valganciclovir in HIV- and CMV-seropositive subjects. J. Clin. Pharmacol. 1999;39:800–804. [PubMed: 10434231]
  • Kimberlin D. W. Advances in the treatment of neonatal herpes simplex infections. Rev. Med. Virol. 2001;11:157–163. [PubMed: 11376479]
  • Long S. S., Pickering L. K., Prober C. G.Kimberlin, D. W. and Prober, C. G. (2003). Antiviral agents. In Principles and Practice of Pediatric Infectious Diseases, ed. Philadelphia: Churchill Livingstone, pp. 1527–1547.
  • Kimberlin D. W., Rouse D. J. Genital herpes. N. Engl. J. Med. 2004;350(19):1970–1977. [PubMed: 15128897]
  • Kimberlin D. W., Coen D. M., Biron K. K., et al. Molecular mechanisms of antiviral resistance. Antiviral Res. 1995a;26:369–401. [PubMed: 7574541]
  • Kimberlin D. W., Crumpacker C. S., Straus S. E., et al. Antiviral resistance in clinical practice. Antiviral Res. 1995b;26:423–438. [PubMed: 7574544]
  • Kimberlin D., Powell D., Gruber W., et al. and The National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group (1996aAdministration of oral acyclovir suppressive therapy after neonatal herpes simplex virus disease limited to the skin, eyes and mouth: results of a phase I/Ⅱ trial Pediatr. Infect. Dis. J. 15247–254. [PubMed: 8852914]
  • Kimberlin D. W., Lakeman F. D., Arvin A. M., et al. and The National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group (1996bApplication of the polymerase chain reaction to the diagnosis and management of neonatal herpes simplex virus disease J. Infect. Dis. 1741162–1167. [PubMed: 8940204]
  • Kimberlin D. W., Lin C. Y., Jacobs R. F., et al. and The National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group (2001aSafety and efficacy of high-dose intravenous acyclovir in the management of neonatal herpes simplex virus infections Pediatrics 108230–238. [PubMed: 11483782]
  • Kimberlin D. W., Lin C. Y., Jacobs R. F., et al. and The National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group (2001bNatural history of neonatal herpes simplex virus infections in the acyclovir era Pediatrics 108223–229. [PubMed: 11483781]
  • Kost R. G., Hill E. L., Tigges M., Straus S. E. Brief report: recurrent acyclovir-resistant genital herpes in an immunocompetent patient. N. Engl. J. Med. 1993;329:1777–1782. [PubMed: 8232486]
  • Krasny H. C., Liao S. H., Miranda, Laskin O. L., Whelton A., Lietman P. S. Influence of hemodialysis on acyclovir pharmacokinetics in patients with chronic renal failure. Am. J. Med. 1982;73:202–204. [PubMed: 7102703]
  • Kuppermann B. D., Quiceno J. I., Flores-Aguilar M., et al. Intravitreal ganciclovir concentration after intravenous administration in AIDS patients with cytomegalovirus retinitis: implications for therapy. J. Infect. Dis. 1993;168:1506–1509. [PubMed: 8245536]
  • Lalezari J. P., Drew W. L., Glutzer E., et al. Treatment with intravenous (S)-1-[3-hydroxy-2-(phosphonylmethoxy)propyl]-cytosine of acyclovir-resistant mucocutaneous infection with herpes simplex virus in a patient with AIDS. J. Infect. Dis. 1994;170:570–572. [PubMed: 8077713]
  • Lalezari J. P., Drew W. L., Glutzer E., et al. (S)-1-[3-hydroxy-2-(phosphonylmethoxy)propyl]cytosine (cidofovir): results of a phase I/Ⅱ study of a novel antiviral nucleotide analogue. J. Infect. Dis. 1995;171:788–796. [PubMed: 7706804]
  • Lalezari J. P., Stagg R. J., Kuppermann B. D., et al. Intravenous cidofovir for peripheral cytomegalovirus retinitis in patients with AIDS. A randomized, controlled trial. Ann. Intern. Med. 1997;126:257–263. [PubMed: 9036797]
  • Laskin O. L., Longstreth J. A., Whelton A., et al. Effect of renal failure on the pharmacokinetics of acyclovir. Am. J. Med. 1982;73:197–201. [PubMed: 7102702]
  • Leone P. A., Trottier S., Miller J. M. Valacyclovir for episodic treatment of genital herpes: a shorter 3-day treatment course compared with 5-day treatment. Clin. Infect. Dis. 2002;34:958–962. [PubMed: 11880962]
  • Lin L., Chen X. S., Cui P. G., Study G., et al. and Topical Penciclovir Clinical 2002Topical application of penciclovir cream for the treatment of herpes simplex facialis/labialis: a randomized, double-blind, multicentre, aciclovir-controlled trial J. Dermatol. Treatm. 1367–72. [PubMed: 12060504]
  • Loveless, M., Harris, W., and Sacks, S. (1995). Treatment of first episode genital herpes with famciclovir. 35th Interscience Conference on Antimicrobial Agents and Chemotherapy. San Francisco, CA; Abstract H12, Abstract H12.
  • Luby J. P., Gnann J. W. Jr, Alexander W. J., et al. A collaborative study of patient-initiated treatment of recurrent genital herpes with topical acyclovir or placebo. J. Infect. Dis. 1984;150:1–6. [PubMed: 6086765]
  • Lyall E. G., Ogilvie M. M., Smith N. M., Burns S. Acyclovir resistant varicella zoster and HIV infection. Arch. Dis. Child. 1994;70:133–135. [PMC free article: PMC1029717] [PubMed: 8129436]
  • Gregor R. R., Graziani A. L., Weiss R., Grunwald J. E., Gambertoglio J. G.Mac1991Successful foscarnet therapy for cytomegalovirus retinitis in an AIDS patient undergoing hemodialysis: rationale for empiric dosing and plasma level monitoring J. Infect. Dis. 164785–787. [PubMed: 1654363]
  • Markham A., Faulds D. Ganciclovir. an update of its therapeutic use in cytomegalovirus infection. Drugs. 1994;48:455–484. [PubMed: 7527763]
  • Martin D. F., Sierra-Madero J., Walmsley S., et al. and the Valganciclovir Study Group (2002A controlled trial of valganciclovir as induction therapy for cytomegalovirus retinitis N. Engl. J. Med. 3461119–1126. [PubMed: 11948271]
  • Mertz G. J., Critchlow C. W., Benedetti J., et al. Double-blind placebo-controlled trial of oral acyclovir in first-episode genital herpes simplex virus infection. J. Am. Med. Assoc. 1984;252:1147–1151. [PubMed: 6088819]
  • Mertz G. J., Eron L., Kaufman R., et al. Prolonged continuous versus intermittent oral acyclovir treatment in normal adults with frequently recurring genital herpes simplex virus infection. Am. J. Med. 1988a;85:14–19. [PubMed: 3044076]
  • Mertz G. J., Jones C. C., Mills J., et al. Long-term acyclovir suppression of frequently recurring genital herpes simplex virus infection. A multicenter double-blind trial. J. Am. Med. Assoc. 1988b;260:201–206. [PubMed: 3290517]
  • Mertz G. J., Loveless M. O., Levin M. J., et al. and the Collaborative Famciclovir Genital Herpes Research Group (1997aOral famciclovir for suppression of recurrent genital herpes simplex virus infection in women. A multicenter, double-blind, placebo-controlled trial Arch. Intern. Med. 157343–349. [PubMed: 9040303]
  • Mertz G. J., Loveless M. O., Levin M. J., et al. and the Collaborative Famciclovir Genital Herpes Research Group (1997bOral famciclovir for suppression of recurrent genital herpes simplex virus infection in women. A multicenter, double-blind, placebo-controlled trial Arch. Intern. Med. 157343–349. [PubMed: 9040303]
  • Meyers J. D., Wade J. C., Mitchell C. D., et al. Multicenter collaborative trial of intravenous acyclovir for treatment of mucocutaneous herpes simplex virus infection in the immunocompromised host. Am. J. Med. 1982;73:229–235. [PubMed: 7048914]
  • Mindel A., Faherty A., Carney O., Patou G., Freris M., Williams P. Dosage and safety of long-term suppressive acyclovir therapy for recurrent genital herpes. Lancet. 1988;1:926–928. [PubMed: 2895840]
  • Morfin F., Thouvenot D. Herpes simplex virus resistance to antiviral drugs. J. Clin. Virol. 2003;26:29–37. [PubMed: 12589832]
  • Nadal D., Leverger G., Sokal E. M., et al. 2002An investigation of the steady-state pharmacokinetics of oral valacyclovir in immunocompromised children J. Infect. Dis. 186S123–S130. [PubMed: 12353197]
  • Nilsen A. E., Aasen T., Halsos A. M., et al. Efficacy of oral acyclovir in the treatment of initial and recurrent genital herpes. Lancet. 1982;2:571–573. [PubMed: 6125728]
  • Patel R., Bodsworth N. J., Woolley P., et al. and the International Valaciclovir HSV Study Group (1997Valaciclovir for the suppression of recurrent genital HSV infection: a placebo controlled study of once daily therapy Genitourin. Med. 73105–109. [PMC free article: PMC1195782] [PubMed: 9215091]
  • Raborn G. W., Gaw W. T., Grace M., Tyrrell L. D., Samuels S. M., Mc1987Oral acyclovir and herpes labialis: a randomized, double-blind, placebo-controlled study J. Am. Dent. Assoc. 11538–42. [PubMed: 3301980]
  • Raborn G. W., McGaw W. T., Grace M., Percy J. Treatment of herpes labialis with acyclovir. Review of three clinical trials. Am. J. Med. 1988;85:39–42. [PubMed: 3044091]
  • Raborn G. W., Martel A. Y., Grace M. G., McGaw W. T. Herpes labialis in skiers: randomized clinical trial of acyclovir cream versus placebo. Oral Surg., Oral Med., Oral Pathol., Oral Radiol. Endodontics. 1997;84:641–645. [PubMed: 9431533]
  • Reardon J. E., Spector T. Herpes simplex virus type 1 DNA polymerase. Mechanism of inhibition by acyclovir triphosphate. J. Biol. Chem. 1989;264:7405–7411. [PubMed: 2540193]
  • Reichman R. C., Badger G. J., Mertz G. J., et al. Treatment of recurrent genital herpes simplex infections with oral acyclovir. A controlled trial. Jama. 1984;251:2103–2107. [PubMed: 6368877]
  • Reiff-Eldridge R., Heffner C. R., Ephross S. A., Tennis P. S., White A. D., Andrews E. B. Monitoring pregnancy outcomes after prenatal drug exposure through prospective pregnancy registries: a pharmaceutical company commitment. Am. J. Obstet. Gyn. 2000;182:159–163. [PubMed: 10649172]
  • Reitano M., Tyring S., Lang W., et al. and the International Valaciclovir HSV Study Group (1998Valaciclovir for the suppression of recurrent genital herpes simplex virus infection: a large-scale dose range-finding study J. Infect. Dis. 178603–610. [PubMed: 9728526]
  • Revankar S. G., Applegate A. L., Markovitz D. M. Delirium associated with acyclovir treatment in a patient with renal failure. Clin. Infect. Dis. 1995;21:435–436. [PubMed: 8562758]
  • Rooney J. F., Straus S. E., Mannix M. L., et al. Oral acyclovir to suppress frequently recurrent herpes labialis. A double-blind, placebo-controlled trial. Ann. Intern. Med. 1993;118:268–272. [PubMed: 8380540]
  • Ruhnek-Forsbeck M., Sandstrom E., Andersson B., et al. Treatment of recurrent genital herpes simplex infections with oral acyclovir. J. Antimicrob. Chemother. 1985;16:621–628. [PubMed: 3908435]
  • Sacks S. L., Aoki F. Y., Diaz-Mitoma F., Sellors J., Shafran S. D. Patient-initiated, twice-daily oral famciclovir for early recurrent genital herpes. A randomized, double-blind multicenter trial. Canadian Famciclovir Study Group. J. Am. Med. Assoc. 1996a;276:44–49. [PubMed: 8667538]
  • Sacks S. L., Aoki F. Y., Diaz-Mitoma F., Sellors J., Shafran S. D., and the Canadian Famciclovir Study Group (1996bPatient-initiated, twice-daily oral famciclovir for early recurrent genital herpes. A randomized, double-blind multicenter trial J. Am. Med. Assoc. 27644–49. [PubMed: 8667538]
  • Sacks, S. L., Hughes, A., Rennie, B., and Boon, R. (1997). Famciclovir for suppression of asymptomatic and symptomatic recurrent genital herpes shedding: a randomized, double-blind, double-dummy, parallel-group, placebo-controlled trial. 37th Interscience Conference on Antimicrobial Agents and Chemotherapy. Toronto, Ontario, Canada; Abstract H-73.
  • Safrin S., Berger T. G., Gilson I., et al. Foscarnet therapy in five patients with AIDS and acyclovir-resistant varicella-zoster virus infection. Ann. of Inter. Medi. 1991a;115:19–21. [PubMed: 1646585]
  • Safrin S., Crumpacker C., Chatis P., et al. and The AIDS Clinical Trials Group (1991bA controlled trial comparing foscarnet with vidarabine for acyclovir-resistant mucocutaneous herpes simplex in the acquired immunodeficiency syndrome N. Engl. J. Med. 325551–555. [PubMed: 1649971]
  • Safrin S., Kemmerly S., Plotkin B., et al. Foscarnet-resistant herpes simplex virus infection in patients with AIDS. J. Infect. Dis. 1994;169:193–196. [PubMed: 8277181]
  • Safrin S., Cherrington J., Jaffe H. S. Cidofovir. Review of current and potential clinical uses. Adv. Expe. Med. Biol. 1999;458:111–120. [PubMed: 10549383]
  • Saral R., Burns W. H., Laskin O. L., Santos G. W., Lietman P. S. Acyclovir prophylaxis of herpes-simplex-virus infections. N. Engl. J. Med. 1981;305:63–67. [PubMed: 6264292]
  • Shaw M., King M., Best J. M., Banatvala J. E., Gibson J. R., Klaber M. R. Failure of acyclovir cream in treatment of recurrent herpes labialis. Bri. Med. J. Clini. Res. 1985;291:7–9. [PMC free article: PMC1416195] [PubMed: 3926067]
  • Shepp D. H., Newton B. A., Dandliker P. S., Flournoy N., Meyers J. D. Oral acyclovir therapy for mucocutaneous herpes simplex virus infections in immunocompromised marrow transplant recipients. Ann. Inter. Med. 1985;102:783–785. [PubMed: 2986508]
  • Skoldenberg B., Forsgren M., Alestig K., et al. Acyclovir versus vidarabine in herpes simplex encephalitis. Randomised multicentre study in consecutive Swedish patients. Lancet. 1984;2:707–711. [PubMed: 6148470]
  • Snoeck R., Andrei G., Gerard M., et al. Successful treatment of progressive mucocutaneous infection due to acyclovir- and foscarnet-resistant herpes simplex virus with (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine (HPMPC). Clin. Infect. Dis. 1994;18:570–578. [PubMed: 8038312]
  • Soul-Lawton J., Seaber E., On N., Wootton R., Rolan P., Posner J. Absolute bioavailability and metabolic disposition of valaciclovir, the L-valyl ester of acyclovir, following oral administration to humans. Antimicrob. Agents Chemother. 1995;39:2759–2764. [PMC free article: PMC163025] [PubMed: 8593015]
  • Spector S. A., Hsia K., Wolf D., Shinkai M., Smith I. 1995Molecular detection of human cytomegalovirus and determination of genotypic ganciclovir resistance in clinical specimens Clin. Infect. Dis. 21S170–S173. [PubMed: 8845447]
  • Spruance S. L., Crumpacker C. S., Schnipper L. E., et al. Early, patient-initiated treatment of herpes labialis with topical 10% acyclovir. Antimicrob. Agents Chemother. 1984;25:553–555. [PMC free article: PMC185583] [PubMed: 6732224]
  • Spruance S. L., Hamill M. L., Hoge W. S., Davis L. G., Mills J. Acyclovir prevents reactivation of herpes simplex labialis in skiers. J. Am. Med. Assoc. 1988;260:1597–1599. [PubMed: 3411740]
  • Spruance S. L., Stewart J. C., Rowe N. H., McKeough M. B., Wenerstrom G., Freeman D. J. Treatment of recurrent herpes simplex labialis with oral acyclovir. J. Infect. Dis. 1990;161:185–190. [PubMed: 2153735]
  • Spruance S. L., Freeman D. J., Stewart J. C., et al. The natural history of ultraviolet radiation-induced herpes simplex labialis and response to therapy with peroral and topical formulations of acyclovir. J. Infect. Dis. 1991;163:728–734. [PubMed: 1849159]
  • Spruance S. L., Tyring S. K., DeGregorio B., Miller C., Beutner K., and the Valaciclovir HSV Study Group (1996A large-scale, placebo-controlled, dose-ranging trial of peroral valaciclovir for episodic treatment of recurrent herpes genitalis Arch. Intern. Med. 1561729–1735. [PubMed: 8694673]
  • Spruance S. L., Rea T. L., 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. J. Am. Med. Assoc. 1997;277:1374–1379. [PubMed: 9134943]
  • Spruance S. L., Nett R., Marbury T., Wolff R., Johnson J., Spaulding T. Acyclovir cream for treatment of herpes simplex labialis: results of two randomized, double-blind, vehicle-controlled, multicenter clinical trials. Antimicrob. Agents Chemother. 2002;46:2238–2243. [PMC free article: PMC127288] [PubMed: 12069980]
  • Spruance S. L., Jones T. M., Blatter M. M., et al. High-dose, short-duration, early valacyclovir therapy for episodic treatment of cold sores: results of two randomized, placebo-controlled, multicenter studies. Antimicrob. Agents Chemother. 2003;47:1072–1080. [PMC free article: PMC149313] [PubMed: 12604544]
  • Straus S. E., Takiff H. E., Seidlin M., et al. Suppression of frequently recurring genital herpes. A placebo-controlled double-blind trial of oral acyclovir. N. Engl. J. Med. 1984;310:1545–1550. [PubMed: 6328297]
  • Studies of Ocular Complications of AIDS Research Group in collaboration with the AIDS Clinical Trials Group (1992Mortality in patients with the acquired immunodeficiency syndrome treated with either foscarnet or ganciclovir for cytomegalovirus retinitis N. Engl. J. Med. 326213–220. [PubMed: 1345799]
  • Studies of Ocular Complications of AIDS Research Group in collaboration with the AIDS Clinical Trials Group (1997Parenteral cidofovir for cytomegalovirus retinitis in patients with AIDS: the HPMPC peripheral cytomegalovirus retinitis trial. A randomized, controlled trial Ann. Intern. Med. 126264–274. [PubMed: 9036798]
  • Swan S. K., Munar M. Y., Wigger M. A., Bennett W. M. Pharmacokinetics of ganciclovir in a patient undergoing hemodialysis. Am. J. Kidney Dis. 1991;17:69–72. [PubMed: 1846060]
  • Trang J. M., Kidd L., Gruber W., et al. and the National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group (1993Linear single-dose pharmacokinetics of ganciclovir in newborns with congenital cytomegalovirus infections Clin. Pharmacol. Ther. 5315–21. [PubMed: 8380762]
  • Tyring S. K., Douglas J. M. Jr, Corey L., Spruance S. L., Esmann J., and the Valaciclovir International Study Group (1998A randomized, placebo-controlled comparison of oral valacyclovir and acyclovir in immunocompetent patients with recurrent genital herpes infections Arch. Dermatol. 134185–191. [PubMed: 9487210]
  • Wade J. C., Newton B., Laren C., Flournoy N., Keeney R. E., Meyers J. D., Mc1982Intravenous acyclovir to treat mucocutaneous herpes simplex virus infection after marrow transplantation: a double-blind trial Ann. Intern. Med. 96265–269. [PubMed: 7036816]
  • Wade J. C., Laren C., Meyers J. D., Mc1983Frequency and significance of acyclovir-resistant herpes simplex virus isolated from marrow transplant patients receiving multiple courses of treatment with acyclovir J. Infect. Dis. 1481077–1082. [PubMed: 6317768]
  • Wagstaff A. J., Bryson H. M. Foscarnet. A reappraisal of its antiviral activity, pharmacokinetic properties and therapeutic use in immunocompromised patients with viral infections. Drugs. 1994;48:199–226. [PubMed: 7527325]
  • Wagstaff A. J., Faulds D., Goa K. L. Aciclovir. A reappraisal of its antiviral activity, pharmacokinetic properties and therapeutic efficacy. Drugs. 1994;47:153–205. [PubMed: 7510619]
  • Wald A., Benedetti J., Davis G., Remington M., Winter C., Corey L. A randomized, double-blind, comparative trial comparing high- and standard-dose oral acyclovir for first-episode genital herpes infections. Antimicrob. Agents Chemother. 1994;38:174–176. [PMC free article: PMC284421] [PubMed: 8192438]
  • Wald A., Zeh J., Barnum G., Davis L. G., Corey L. Suppression of subclinical shedding of herpes simplex virus type 2 with acyclovir. Ann. Intern. Med. 1996;124:8–15. [PubMed: 7503497]
  • Wald A., Corey L., Cone R., Hobson A., Davis G., Zeh J. Frequent genital herpes simplex virus 2 shedding in immunocompetent women. Effect of acyclovir treatment. J. Clin. Investig. 1997;99:1092–1097. [PMC free article: PMC507918] [PubMed: 9062368]
  • Wald, A., Warren, T., Hu, H. et al. (1998). Suppression of subclinical shedding of herpes simplex virus type 2 in the genital tract with valaciclovir. 38th Interscience Conference on Antimicrobial Agents and Chemotherapy. San Diego, California; Abstract H-82.
  • Wald A., Carrell D., Remington M., Kexel E., Zeh J., Corey L. Two-day regimen of acyclovir for treatment of recurrent genital herpes simplex virus type 2 infection. Clin. Infect. Dis. 2002;34:944–948. [PubMed: 11880960]
  • Weller S., Blum M. R., Doucette M., et al. Pharmacokinetics of the acyclovir pro-drug valaciclovir after escalating single- and multiple-dose administration to normal volunteers. Clin. Pharmacol. Ther. 1993;54:595–605. [PubMed: 8275615]
  • Whitley R. J., Nahmias A. J., Soong S. J., Galasso G. G., Fleming C. L., Alford C. A. Vidarabine therapy of neonatal herpes simplex virus infection. Pediatrics. 1980a;66:495–501. [PubMed: 7001331]
  • Whitley R. J., Nahmias A. J., Visintine A. M., Fleming C. L., Alford C. A. The natural history of herpes simplex virus infection of mother and newborn. Pediatrics. 1980b;66:489–494. [PubMed: 6253866]
  • Whitley R. J., Yeager A., Kartus P., et al. Neonatal herpes simplex virus infection: follow-up evaluation of vidarabine therapy. Pediatrics. 1983;72:778–785. [PubMed: 6359047]
  • Whitley R. J., Alford C. A., Hirsch M. S., et al. Vidarabine versus acyclovir therapy in herpes simplex encephalitis. N. Engl. J. Med. 1986;314:144–149. [PubMed: 3001520]
  • Whitley R. J., Corey L., Arvin A., et al. Changing presentation of herpes simplex virus infection in neonates. J. Infect. Dis. 1988;158:109–116. [PubMed: 3392410]
  • Whitley R. J., Arvin A., Prober C., et al. and The National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group (1991aA controlled trial comparing vidarabine with acyclovir in neonatal herpes simplex virus infection N. Engl. J. Med. 324444–449. [PubMed: 1988829]
  • Whitley R. J., Arvin A., Prober C., et al. and The National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group (1991bPredictors of morbidity and mortality in neonates with herpes simplex virus infections N. Engl. J. Med. 324450–454. [PubMed: 1988830]
Copyright © Cambridge University Press 2007.
Bookshelf ID: NBK47444PMID: 21348126

Views

  • PubReader
  • Print View
  • Cite this Page

Related information

  • PMC
    PubMed Central citations
  • PubMed
    Links to PubMed

Similar articles in PubMed

See reviews...See all...

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...