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

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 64.2

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.

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. (From Kimberlin et al., 2001a.)

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. (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.

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.

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.

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.

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.

Ganciclovir

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

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.

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]