Treatment of Herpes Simplex Virus Infections CME
Robert Snoeck, MD, PhD, Erik De Clercq, MD, PhD, Rega Institute for Medical Research, Leuven, Belgium
Abstract
Herpes simplex viral infections are common in both immunocompetent and immunocompromised patients. While nucleoside analogues such as acyclovir remain the mainstay of HSV treatment and prophylaxis, the emergence of drug-resistant strains has stimulated the search for new antiviral drugs. Effective control of HSV infections is now possible with such potent antiviral agents as nucleoside analogues (famciclovir), pyrophosphate analogues (foscarnet), and phosphonate analogues (cidofovir). [Infect Med 16(4):249-250, 256-257, 261-265, 1999. Вc 1999 SCP Communications, Inc.]
Introduction
Herpes simplex virus (HSV) is a frequently occurring pathogen in both immunocompromised patients, in whom it can cause severe disease, and immunocompetent patients. It was not until 1968 that well-defined antigenic and biologic differences were demonstrated between HSV-1 and HSV-2[1]: HSV-1 was shown to be more frequently associated with nongenital infections and HSV-2 with genital infections. Other major steps that have contributed to a better understanding of the natural history of the HSVs and their treatment include the utilization of viral antigens to understand clinical epidemiology and to improve diagnosis; the use of restriction endonuclease analysis as an epidemiologic tool; and the progress achieved in the treatment of HSV encephalitis, genital HSV infections, and mucocutaneous HSV infections in the immunocompromised host.
In the immunocompetent host, HSV is responsible for both primary and recurrent mucocutaneous infections, including orolabial and genital infections and keratoconjunctivitis. Both serotypes have been shown to establish latency in the neurosensory ganglia after the primary infection. Reactivation may occur with both; conditions such as fever or ultraviolet irradiation favor the reactivation process.
HSV is the most commonly identified cause of sporadic encephalitis. The virus may spread to the brain during primary or, possibly, recurrent infections, but vesicles are not usually present on the skin or mucosa.[2]
HSV infections in immunocompromised patients are characterized by severe, chronic, and often extensive lesions of the mucous membranes. HSV infections of the lip, mouth, skin, perianal area, or genital region may be more severe in immunocompromised patients than in normal subjects. The lesions tend to be more invasive, heal more slowly, and lead to prolonged viral shedding. HSV is often reactivated at multiple sites in immunocompromised patients. HSV hepatitis has been observed in the immunocompetent as well as in recipients of solid organ transplants; liver transplant patients account for two thirds of these cases.[3-6]
In patients with hematologic malignancies, viral cultures from saliva have revealed an association between the presence of HSV and oral ulcers, especially those located on the alveolar process. HSV infection represents one of the major opportunistic infections in AIDS patients, who often manifest HSV in association with other (viral or nonviral) opportunistic infections.
HSV Drug Resistance
With the development of potent antiviral agents such as acyclovir (ACV), effective control of HSV infections is now possible. However, viral drug resistance has emerged, particularly in immunocompromised patients, and this has stimulated the search for new antiviral drugs active against HSV.
Drug-resistant HSV strains have been studied extensively in cell culture. While drug-resistant strains can be readily elicited in vitro, they occur infrequently in patients with normal immune function. However, the emergence of drug-resistant viruses is a common problem in immunocompromised patients, particularly in those with AIDS or in organ transplant recipients.
Most of the available clinical data on HSV drug resistance concern ACV, because it is the most commonly used drug for the treatment of HSV infections. Approximately 5% of immunosuppressed patients will develop an ACV-resistant HSV infection, generally following prolonged exposure to the drug. ACV-resistant HSV in ACV-naive patients has occasionally been reported, although it is not known whether the drug-resistant virus arose out of spontaneous mutations in the viral DNA or through the acquisition of resistant virus from another individual. For a more detailed discussion, see recent comprehensive reviews and references cited herein.[7,8]
Mechanisms of Action
All the antiviral agents directed against HSV infections are
targeted at the viral DNA polymerase, blocking viral DNA replication. Although
these agents share a common target, there are 2 distinct mechanisms by which
they achieve their goal: competitive and noncompetitive inhibition (Table I, Fig. 1).
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Figure 1. (click image to zoom) Chemical structures of drugs used to treat HSV infections. |
Nucleoside and nucleotide analogues, including ACV, are compounds that must be phosphorylated intracellularly to deoxynucleoside triphosphate (dNTP) analogues to be antivirally active. The active metabolite of the compound then serves as a competitive inhibitor of the viral DNA polymerase. In general, these inhibitors are recognized by the viral DNA polymerase as alternative substrates and are incorporated into the growing viral DNA chain, slowing down or blocking replication.
In contrast, foscarnet (phosphonoformatic acid [PFA]), a pyrophosphate analogue, directly inhibits viral DNA polymerase and thus does not need to be activated intracellularly. PFA competes with pyrophosphate, a product of the DNA polymerization step, for the pyrophosphate binding site of the DNA polymerase. In contrast to the nucleoside analogues, PFA is a noncompetitive inhibitor of the DNA polymerase.[9]
The active forms of these antiviral agents are able to selectively block viral replication because they inhibit viral DNA polymerase at concentrations lower than those required to inhibit cellular DNA polymerases. Several of the nucleoside analogues, including ACV, penciclovir (PCV), and ganciclovir (GCV), gain additional selectivity because their activation depends on the initial phosphorylation by HSV-specific thymidine kinase (TK), rather than by cellular kinases. Thus, these compounds are activated preferentially in virus-infected cells. Although this preferential phosphorylation provides an additional level of selectivity, thereby reducing their cytotoxic potential for uninfected cells, it also provides a second site in the viral DNA where mutations lead to resistance.
HSV has become resistant to currently used antiviral agents because of mutations within 2 viral proteins: Mutations in the DNA polymerase (pol) gene have been described for ACV- and PFA-resistant viruses, and mutations in the viral TK gene have been described for ACV-resistant mutants.[10]
Brivudin and Sorivudine
Among the nucleoside analogues that have been pursued in the clinic (albeit in a limited manner) for the treatment of varicella zoster virus (VZV) infections are brivudin [BVDU, or (E)-5-(2-bromovinyl)-2'-deoxyuridine] and sorivudine [BVaraU, or 1-beta-D-arabinofuranosyl-(E)-5-(2-bromovinyl)uracil], the most potent inhibitors of VZV in vitro replication ever described. However, their antiviral activity is not restricted to VZV. BVDU and BVaraU are also active against HSV-1, and BVDU is active against other herpesviruses as well.[11]
These analogues are exquisitely potent and selective in their anti-VZV activity. They inhibit VZV replication in cell cultures at a concentration of 1ng/mL and do not affect normal cell metabolism when they are used at concentrations of 50 to 100mcg/mL, which is 50,000- or 100,000-fold higher than the minimum antiviral concentration. BVDU was first described as a potent inhibitor of HSV-1 replication with minimal toxicity to uninfected cells.[12] The high selectivity resulted from the much greater affinity of BVDU for viral TK than for cellular TK.[13]
In contrast to ACV, both BVDU and BVaraU have good oral bioavailability. The pharmacokinetic analysis for BVaraU revealed that the elimination of half-life ranges from 5 to about 8 hours, with a statistically significant greater half-life in the elderly compared with young volunteers.
Both BVDU and BVaraU have been the subject of limited clinical trials. BVDU given orally (7.5mg/kg/day for 5 days) to patients with underlying malignancy and severe herpes zoster could stop progression of the disease within 1 day after initiation of the treatment.[14,15] BVaraU was found to be clinically efficacious in both immunocompetent and immunocompromised patients.[16,17] Neither BVDU nor BVaraU has been approved for use in the US.
Acyclovir
The compound of choice for the prophylaxis and treatment of HSV infections for many years, ACV selectively inhibits HSV DNA replication with low host-cell toxicity. Following uptake of ACV by virus-infected cells, phosphorylation of the drug to ACV-monophosphate (ACV-MP) occurs via HSV-encoded TK. Subsequent conversion to ACV-triphosphate (ACV-TP) is catalyzed by host cell enzymes. ACV-TP preferentially inhibits viral DNA polymerase over cellular DNA polymerases. Of all the human herpesviruses (HHV), HSV-2 and HSV-1 are the most susceptible to ACV, followed (in order of decreasing susceptibility) by VZV, Epstein-Barr virus (EBV), HHV-6, and human cytomegalovirus (CMV). ACV does not exhibit in vitro activity against viruses outside the herpesvirus family.[18-21]
Genital Infection
In immunologically competent patients, ACV has been shown to be active against genital HSV infections. The efficacy of ACV treatment in initial genital herpes infection is well demonstrated. Double-blind, placebo-controlled studies have shown that ACV given IV (5mg/kg 3 times daily), orally (200mg 5 times daily), and to a lesser extent, topically (5% in polyethylene glycol ointment or propylene glycol cream, applied 4 to 6 times daily), initiated within 4 days of the first appearance of signs or symptoms, produces significant reduction in the duration of viral shedding and time to complete healing of lesions (Table II).
ACV treatment of first-episode genital herpes infection does not alter the rate of recurrence of the infection after drug withdrawal. New lesion formation and the duration of episodes is reduced by 1 to 2 days following early oral treatment of recurrent infections, the beneficial effects being less dramatic than those seen in the longer initial episodes. Prophylactic oral administration of ACV at dosages of 800mg to 1000mg/day for up to 1 year suppresses recurrence of genital herpes in 71% to 88% of patients, as shown in several placebo-controlled trials.[19] Recurrence rates returned to pretreatment frequencies after discontinuation of ACV administration. Continuous prophylactic ACV treatment for patients with recurrent attacks of HSV infection is effective, but the costs involved are high. Dosage reduction and episodic treatment have been investigated as possible means of reducing costs and increasing patient adherence, with some success.
Mucocutaneous Infections
For orofacial and cutaneous infections, a randomized trial in patients with herpes labialis has shown a decrease in the mean duration of pain by 36%, and in mean healing time (loss of crusts) by 27% with oral ACV (400mg 5 times daily for 5 days) versus placebo, if administered in the prodromal or the erythema lesion stage.[22] Systemic ACV is also effective in the therapy of mucocutaneous HSV infections. Prophylaxis with oral ACV (800mg/day) reduces the severity and frequency of orofacial and cutaneous HSV recurrence during treatment. However, it does not affect the rate of recurrence after discontinuation of treatment.
Ocular Infections
Several studies have shown that 95% to 100% of herpetic dendritic corneal ulcers are resolved within 5 to 9 days following the application of ACV 3% ophthalmic ointment 5 times daily.[19] In a study comparing oral ACV (400mg 5 times daily) and topical ACV (3% ophthalmic ointment 5 times daily) administered until healing occurred in patients with active herpetic keratitis, oral therapy was equivalent or superior to topical therapy.[23] There was significantly greater improvement in lacrimation and visual acuity scores with oral versus topical therapy. The combination of ACV 3% ophthalmic ointment with topical corticosteroids proved effective in the treatment of herpetic disciform keratitis and necrotizing stromal keratitis, whereas ACV alone was ineffective. No recurrences of herpes simplex keratitis developed during prophylaxis with oral ACV (800mg or 1000mg/day in 4 or 5 doses per day) for 12 to 15 months.[24]
Other Infections
It has been established that ACV 10mg/kg IV every 8 hours administered for at least 10 days is the treatment of choice for biopsy-proven HSV encephalitis. ACV improves overall survival rates and reduces the incidence of serious sequelae. HSV encephalitis, HSV hepatitis, and disseminated HSV infections during pregnancy have been successfully treated with IV ACV.[21]
Infections in Immunosuppressed Patients
In immunocompromised patients, ACV given either IV or orally significantly accelerates the resolution of viral shedding and pain and reduces time to healing of HSV mucocutaneous lesions. ACV given orally or intravenously also proved active when used as prophylaxis for HSV and VZV infections in patients with hematologic disorders. Protection was confined to the period of drug administration.[19] Extension of the period of prophylaxis may offer protection against HSV infections until immunocompetence is achieved in patients completing chemotherapy or radiotherapy. In renal transplant recipients, low-dose oral ACV (600mg to 800mg/day for 4 to 6 weeks) completely suppressed clinical symptoms, although virus breakthrough occurred. In a similar group of patients, high-dose oral ACV (800mg 4 times daily for 12 weeks) completely suppressed HSV shedding in the majority of patients, whereas patients receiving placebo had no suppression of shedding.[19] It was also shown that grafts tended to survive longer in ACV-treated patients than in the placebo group.
ACV Resistance
The vast majority of ACV-resistant HSV mutants (both those generated in vitro and those isolated from patients) contain mutations within the TK gene. Most mutations within this gene cause a substantial decrease (TK-decreased mutants) or deficiency (TK-deficient mutants) of viral TK activity expressed in virus-infected cells. Less commonly, mutations within the TK gene lead to the expression of TK activity with altered substrate specificity (TK-altered mutants). These mutants produce an enzyme that phosphorylates thymidine, the natural substrate, but does not efficiently phosphorylate ACV. With all 3 types of TK mutants, there is a reduction in the extent of ACV phosphorylation in virus-infected cells, resulting in low levels of ACV-TP and poor antiviral activity.
Other nucleoside analogues that rely on viral TK for initial phosphorylation, most notably GCV and PCV, are generally not active against ACV-resistant TK mutants. The one exception is that TK-altered mutants might still recognize GCV or PCV as substrates, depending on the nature of the mutation. However, TK-altered mutants are rare, and there is no way to predict whether a particular mutant will be sensitive to ACV, GCV, or PCV.[9]
ACV has remained the standard compound for treatment and prophylaxis of HSV infections in immunocompetent and immunocompromised patients. Nevertheless, the emergence of resistant viruses, particularly in the immunocompromised host, has stimulated the development of new molecules, some with a spectrum of activity quite similar to that of ACV and with activity against ACV-resistant strains.
Valacyclovir
Closely related to ACV, the L-valyl ester of ACV is an oral prodrug that is rapidly and extensively metabolized to ACV and L-valine. The antiviral activity spectrum and potency of valacyclovir (VACV) are essentially the same as for ACV, but the prodrug was developed to overcome the poor oral bioavailability of ACV. Pharmacokinetic parameters for ACV following VACV administration are similar in healthy volunteers, patients with advanced AIDS, and patients with bone marrow transplantation and normal renal function.[25-27]
The bioavailability of ACV following oral administration of VACV is greater than that achieved after oral ACV administration (54% vs 15% to 30%). VACV is better absorbed through the gut wall than orally administered ACV because of more rapid uptake into the intestinal brush border membranes by an active, saturable transport.
After absorption by the GI tract, VACV undergoes rapid presystemic first-pass intestinal and/or hepatic hydrolysis by an enzyme that is present in the liver and intestinal wall. The kidneys are the main route of elimination for VACV, ACV, and their metabolites.
VACV has been evaluated in the treatment of immunocompetent patients with herpes zoster or genital herpes. In immunocompetent patients with a history of recurrent genital herpes, VACV (1000mg twice daily) compared with ACV (200mg 5 times daily), both given for 10 days, gave similar results for all efficacy parameters, including the time for lesions to heal, time for termination of viral shedding, and time to resolution of pain.[25] The therapeutic efficacy of VACV was also evaluated in several studies in patients with recurrent episodes of genital herpes. Compared with placebo, VACV reduced the duration of viral shedding and accelerated lesion healing. VACV had comparable activity to ACV in patients with recurrent genital infections. VACV given at 500mg daily for 12 months effectively prevents recurrent episodes of genital herpes.
Famciclovir
Famciclovir (FCV) is an oral prodrug, the diacetyl ester of 6-deoxy-PCV. PCV, a nucleoside analogue that is closely related to ACV, has an antiviral spectrum similar to that of ACV.[26,28,29]
After oral administration, FCV is rapidly and extensively absorbed in the upper intestine. FCV undergoes substantial first-pass metabolism in the intestinal wall and liver (via deacetylation and oxidation) to yield PCV. The pharmacokinet-ics of PCV do not appear to be altered sufficiently to necessitate FCV dosage adjustment in elderly patients. Urinary excretion of PCV decreases in proportion to the decrease in estimated creatinine clearance. Thus, the interval of FCV dosing should be prolonged from 8 hours to 12 or 24 hours for patients with moderate or severe renal impairment, respectively.
The 50% inhibitory concentration (IC50) of PCV for HSV-1 and HSV-2 clinical strains in vitro is comparable to that of ACV. Intracellular PCV-triphosphate (PCV-TP) persists for a longer time than ACV-TP in HSV-infected cells. The intracellular half-life of PCV-TP in cells infected with HSV-1, HSV-2, or VZV is 10, 20, and 7.2 hours, respectively, while for ACV-TP the half-life is 0.7, 1.0 hour, and below the detection limit in HSV-1-, HSV-2-, and VZV-infected cells, respectively. HSV-1 replication in infected cells is suppressed following exposure to PCV, even when extracellular concentrations of the compound are no longer detectable. This phenomenon has not been observed in virus-infected cells treated with ACV.
Although PCV-TP reaches higher intracellular concentrations than ACV-TP, PCV-TP is a less potent inhibitor of viral HSV-1 and VZV DNA polymerase than ACV-TP (Ki, the inhibitory constant, is 100-fold greater for PCV-TP than for ACV-TP). Thus, the high levels of PCV-TP compensate for its diminished affinity for DNA polymerase, which is why in standard plaque reduction assays ACV and PCV demonstrate similar antiviral activity.
PCV-TP is a competitive inhibitor of HSV-1 and HSV-2 DNA polymerase with respect to the natural substrate dGTP. Under conditions where ACV-TP clearly acts as a chain terminator, PCV-TP allows limited DNA chain elongation.
PCV has been shown to be active against DNA polymerase-based virus mutants that are resistant to ACV. This suggests that PCV and ACV triphosphates must interact in a different fashion with the viral DNA polymerase.
In patients with a history of recurrent episodes of genital herpes, continuous administration of FCV (125mg or 250mg once or twice daily or 500mg once daily for 120 days) effectively prolonged the time to the next episode of genital herpes.[30] FCV administered in doses ranging from 125mg to 500mg twice daily, initiated within 6 hours after the onset of symptoms, was significantly more effective than placebo.[29] There was a reduction in the duration of viral shedding by 50%, and patients treated with FCV had significant reductions in median times to loss of vesicles, crusts, and ulcers and in relief of symptoms.
Several studies comparing FCV and oral ACV showed no differ-ences in times to cessation of viral shedding, complete healing, or loss of all symptoms between groups.[29]
Vidarabine and Trifluorothymidine
Vidarabine (araA), trifluorothymidine (TFT), and foscarnet (PFA) all have activity against TK mutant HSV strains. The first to be used clinically, araA is a nucleoside analogue that is rapidly phosphorylated by cellular enzymes to its triphosphate form, which is re-sponsible for the inhibition of HSV DNA polymerase. In contrast to ACV, araA, which closely resembles a natural nucleoside, is phosphorylated by cellular rather than viral enzymes. Although this compound is active against TK mutants in vitro, it is not effective in patients because of its intrinsi-cally low potency and dose-limiting toxicity.
araA is no longer the drug of choice for the treatment of ACV-resistant HSV infections, mainly because of its relatively low potency, rapid degradation (by deamination), and poor aqueous solubility, necessitating the infusion of large amounts of fluid. In addition, neurologic disorders have been described in association with araA therapy. In fact, patients with HIV infection are particularly prone to the neurologic side effects of araA, for unexplained reasons.
TFT can be phosphorylated by viral TK, but it is also efficiently phosphorylated by cellular enzymes, resulting in high levels of TFT triphosphate even in cells infected with TK-deficient mutants. TFT owes its antiviral activity mainly to the inhibition of thymidylate synthase. Consequently, it is active against TK mutants in vitro, and is currently in clinical trials as a topical agent for the treatment of HSV infections, including ACV-resistant HSV lesions.
Foscarnet
Clinical trials in which PFA was compared with araA for the treatment of ACV-resistant mucocuta-neous HSV infections in patients with AIDS showed that PFA has better efficacy and lower toxicity. Based on these trials, PFA is now the drug of choice for the treatment of ACV-resistant HSV infec-tions.[7,8,31] The activity of PFA does not depend on conversion to an active form by viral TK or any other viral or cellular enzyme. PFA selectively and reversibly inhibits the activity of herpesviruses. It interferes with the elongation of the viral DNA chain through inhibition of the cleavage of the pyrophosphate groups from the deoxynucleoside triphosphates (dNTPs), a crucial step in DNA chain elongation. When virus-infected cells are no longer exposed to PFA, viral DNA polymerase activity, and therefore virus replication, resumes.
PFA is poorly absorbed after oral administration. The drug is not metabolized after IV administration. Up to 88% of IV administered PFA is recovered unchanged in the urine within a week after terminating infusion. Excretion of PFA is assumed to occur entirely via the kidneys: renal clearance is 78% to 86%. The remaining 14% to 21% of total clearance has been attributed to bone uptake. Renal clearance occurs via glomerular filtration and tubular secretion. No major differences were observed in the pharmacokinetic profile of PFA administered at 90mg/kg twice daily or 60mg/kg 3 times daily. Plasma PFA clearance decreased significantly with decreased renal function.
The major indication for PFA is the treatment of CMV retinitis in patients with AIDS, mostly for patients who are unable to continue GCV therapy or patients who have developed resistance to GCV. PFA has been used for the treatment of gastrointestinal CMV disease in AIDS patients, and also for the treatment of CMV infections in bone marrow transplant recipients.
The major side effect of PFA is renal toxicity. The nephrotoxicity observed with PFA is related to tubulointerstitial lesions. The renal impairment associated with the use of PFA is reversible. Hydration before and during each infusion reduces the severity of renal dys-function in most patients. Hypo- and hypercalcemia have been reported in patients treated with PFA.[31] Transient hyperphosphatemia, hypophosphatemia, hyperkalemia, hypomagnesemia, and anemia have been reported. In addition, consistent with the observation that PFA is excreted un-changed in the urine, penile and vulvar ulcerations have been reported as side effects.
As expected, HSV infections that are resistant to ACV because of TK mutations remain fully susceptible to PFA. This efficacy has been demonstrated in clinical trials in which IV PFA was able to reduce time to complete healing and time of viral shedding in approximately 90% of the ACV-resistant HSV infections.[32] Though effective, PFA therapy is associated with significant adverse events and the inconvenience of IV infusions multiple times per day.
Cidofovir and Other Acyclic Nucleoside Phosphonates
First of a new series of antiviral agents recently approved for the treatment of CMV retinitis, cidofovir [(S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine, HPMPC] is an acyclic phosphonate analogue with potent and selective anti-HSV activity in vitro and in vivo.[33,34] Cidofovir is active against a wide range of DNA viruses, including all HHVs, human adenoviruses, poxviruses, and papovaviruses (polyomaviruses and papil-lomaviruses). The spectrum of cidofovir also covers a number of animal viruses of veterinary im-portance such as African swine fever virus and equine and bovine herpesviruses. Cidofovir has also been shown to inhibit HHVs that are deficient for viral TK as well as herpesviruses with DNA polymerase mutations emerging under PFA pressure.
In contrast to cidofovir, which is particularly active against DNA viruses, adefovir [9-(2-phosphonylmethoxyethyl)adenine (PMEA)] and its 2,6-diaminopurine derivative, PMEDAP, exhibit activity against both DNA viruses [herpesviruses (including TK-deficient strains of HSV and VZV) and hepadnaviruses)] and retroviruses [HIV types 1 and 2, simian immunodeficiency virus (SIV), feline immunodeficiency virus (FIV)] as well as visna-maedi virus and murine leukemia and sarcoma viruses. The compounds belonging to the 2-phosphonylmethoxy-propyl (PMP) series (ie, PMPA, PMPDAP) and the 3-fluoro-2-phosphonylmethoxy-propyl (FPMP) series (ie, FPMPA) are in principle active against all retroviruses and hepadnaviruses. For a discussion of the mechanism of action of the phosphonates, see box, "Phosphonate Mechanism of Action."
In animal models, cidofovir was shown to be active in a model of HSV-induced retinitis. Similarly, in mice infected with HSV-2, cidofovir afforded significant protection against mortality. The effi-cacy of an infrequent dosing regimen was demonstrated in mice infected with HSV, as well as in monkeys infected with the simian counterpart of VZV. Prophylaxis with cidofovir has been evaluated in mice given a single dose of drug followed by intraperitoneal infection with HSV-2: 100% of the mice survived when a single dose of 30mg/kg was given up to 4 days prior to virus inoculation.[33,35]
The efficacy of cidofovir against mucocutaneous HSV infections was first reported in a few anecdotal cases showing that topical application (1% in cream) or systemic administration (5mg/kg/week) of cidofovir resulted in complete regression of herpetic lesions due to ACV-resistant virus. There was no evidence of cidofovir resistance.[36,37]
Recently, a double-blind, placebo-randomized study of cidofovir (1% in gel) for the treatment of ACV-unresponsive mucocutaneous HSV infection in AIDS patients showed significant benefit in lesion healing, reduced virus shedding, and pain reduction. Side effects occurred in 25% of patients receiving cidofovir versus 20% in the placebo group. None of the side effects was dose-limiting.[38]
As expected, cidofovir retains full activity against ACV-resistant HSV strains containing TK mutations. In fact, it was recently demonstrated that ACV-resistant HSV strains with the TK-deficient or TK-altered phenotypes are more susceptible to inhibition by cidofovir than are wild-type viruses.[39] The biochemical basis for this increased susceptibility is that HSV TK phosphorylates deoxycytidine in addition to thymidine. Thus, the dCTP pool size in cells infected with TK-deficient or TK-altered HSV mutants does not increase as much as in cells infected with wild-type HSV, or may not increase at all. Since cidofovir diphosphate inhibits HSV DNA polymerase in competition with dCTP, cidofovir is relatively more potent in cells with a smaller dCTP pool size -- that is, in those infected with TK-deficient or TK-altered mutant viruses. Evidence that this hypersensitivity occurs in the clinical setting is provided by the observation that ACV-resistant lesions that do not fully heal following cidofovir treatment (administered for the treatment of CMV retinitis) exhibit a marked shift towards ACV sensitivity and, at least in 1 case, have been successfully treated with ACV following cidofovir treatment.[36,39]
Summary
The limited bioavailability of ACV and the occurrence of ACV-resistant HSV strains, primarily in immunosuppressed patients, has led to the development of newer drugs with better bioavailability and different mechanisms of action. VACV and FCV are better absorbed than ACV, but neither is effective against ACV-resistant strains. In contrast, PFA and cidofovir are both effec-tive against ACV-resistant HSV. Additional studies are needed to determine the role of cidofovir and other phosphonate analogues.
Acknowledgments
The authors thank D. Mendel for constructive comments and C. Callebaut for dedicated editorial assistance.
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Drugs Mentioned
in this Article |
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Acyclovir |
Zovirax, generic |
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Brivudin* |
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Cidofovir |
Vistide, generic |
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Ganciclovir |
Cytovene |
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Famciclovir |
Famvir |
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Penciclovir |
Denavir |
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Sorivudine* |
|
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Trifluorothymidine* |
|
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Valacyclovir |
Valtrex |
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Vidarabine* |
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* Not available for use in the US.