Herpesvirus resistance to antiviral drugs: a review of the mechanisms, clinical importance and therapeutic options

REVIEW

Herpesvirus resistance to antiviral drugs: of the mechanisms, clinical importance therapeutic options

a review and

P. Reusser Departmetzts

of Medicine

Rrceksed IO Jawary

attd Research, Uttiaevsit~~ Hospital, CH-JO.71 Basel, Switzerland 195%; recised matmscvipt accepted 13 Febmaty 1996

Summary:

During the past decade, potent agents against herpes simplex L irus (IIS\‘) types 1 and 2, \xricella-zoster virus (VZV), and cytomegalovirus (CiXIY) have become available. The increasing clinical use of ac>;clovir, ganciclovir, and foscarnet has been associated \vith the emergence ot drugresistant herpes\~irus strains. Resistance to acyclovir or ganciclovir most frequently results from deficient intracellular phosphor!-lation of these agents \vhich is required for drug activation. Resistance to foscarnet is due to viral IIS. polymerase mutants that permit viral replication despite the presence of the drug. In immunocompetent patients, herpes\,irus resistance is rare and generally does not correlate with clinical outcome. In contrast, in of FISV, \‘%\‘, and CRlL’ is inimmunocompromised hosts, resistance creasingly detected, and may be associated with disease refractor! to antiviral therapy. 1;oscarnet treatment has been used with some clinical benefit in patients \vith acyclo~ir-resistatit IISV or YZ\‘, or ganciclo\-ir-resistant For therapy of resistant mucocutaneous HSV disease, topical triRuoroth>midinc, and topical or intra\-cnous cidofovir (I-IPILIPC) have y~clclcd encouraging results that warrant further in\,estigation. Improved methods for detection of herpesvirus resistance, and \-alidation of alternati\.c therap> for patients LXith documented resistance are required to reduce the clinical impact of drug-resistant herpesCruses.

cnlv.

Kr~~zcorct.s: Resistance; megalo\-irus; ac)-clo\.ir; t

herpes simplex \.irus; \~aricclln-zoster pcnciclovir; ganciclor-ir; foscarnet;

virus; cidofovir;

cytotri-

Introduction

Human herpesviruses are distributed \\-orld\vide and are among the most frequent causes of viral infections in both immunocompetent and immunocompromised patients. FolloLving primary infection, herpesviruses establish long-term latency and reactivate intermittently, particularly during periods of profound immunosuppression.‘,’ Among immunocompetent

235

236

P. Reusser

patients, herpesvirus infection is in most cases self-limited and usually does not require antiviral therapy. In contrast, immunocompromised hosts may develop severe viral disease which can be life-threatening and needs prompt treatment with antiviral agents.3’4 Of the eight members of the human herpesvirus group, infections due to herpes simplex virus (HSV) types 1 and 2, varicella-zoster virus (VZV), h ave been particularly well-studied, in part and cytomegalovirus (CMV) because potent antiviral drugs against these viruses have been introduced into clinical use in recent years.4-” Following the widespread use of antiviral agents against herpesviruses, the isolation of resistant virus strains has been reported with increasing frequency.12 This review will focus on resistance of HSV, VZV, and CMV to currently available antiviral drugs. In the first part of the article, the mechanisms of action of these drugs and the mechanisms of viral resistance will be discussed; the second part will review data on the incidence and clinical importance of herpesvirus resistance, and on the therapeutic options when the presence of resistant virus is documented. Mechanisms

of antiviral

drug action

and of virus

resistance

Acyclovir and valaciclovir Acyclovir is a synthetic analogue of the nucleoside guanosine with marked inhibitory activity against HSV types 1 and 2, and VZV.6 More recently, valaciclovir has been introduced, which is the L-valyl ester of acyclovir. It is rapidly and almost completely converted to acyclovir after oral administration.8”3 Following oral administration of valaciclovir, the bioavailability of acyclovir is three to five times greater than that observed with oral acyclovir.‘3 In order to inhibit viral DNA synthesis, acyclovir must be activated by intracellular phosphorylation to acyclovir-triphosphate (Figure 1).6 The conversion to acyclovir-monophosphate is catalysed by a viral thymidine kinase (TK) encoded by HSV and VZV. As a consequence, acyclovir is concentrated 40-100 times and preferentially activated in cells infected by these viruses. Further phosphorylations are mediated by cellular enzymes. Acyclovir-triphosphate functions as a substrate for the viral DNA polymerase, and is incorporated into the viral DNA where it acts as a chain terminator. Moreover, the viral DNA polymerase is inactivated by irreversible binding to the acyclovir-terminated DNA chain. Three different mechanisms of HSV and VZV resistance to acyclovir have been identified. The most frequent cause of resistance in clinical isolates is mutations in the gene of the viral TK which result in reduced or abrogated production of this enzyme (TK-deficient mutant) and in subsequent decrease or lack of acyclovir phosphorylation (Figure l).14-23 Less commonly, resistance results from the generation of mutants with altered TK substrate specificity (TK-altered mutants) that allows for

Herpesvirus HSV vzv

resistance

to drugs Ganciclovir

Acyclovir

-+I-

%

--t------~

i Thymidine kinase

------~.

237

/-~

f!--~ I

/

\

CMV ~-.\

; i +--,;’ /’

“\ \\ \

/ r, NA-monophosphate -... ; &/‘::::-

i

VL 97.encoded phosphotransfer-use

y&r-

~

, NA-triphosphate

Termination of DNA chain

Inhibition of viral DNA polymer-ax

Permissive

cell

of activation of the nucleoside analogues (X.4) acyclovir and ganFigure 1. 3Iechanisms ciclovir in cells infected with either herpes simplex virus (HSV), varicella-zostcr \.irus to NA-monophosphate is catalysed by a c\:zv1. I or cvtomegalovirus (CnlV). C onversion ;.iral thymidine ltinasc encoded by HSV and VZV for acyclorir, and is mediated by a phosphotransferase encoded by the UL97-gene of Cnl\T for ganciclovir. The triphosphate form is the active metabolite of both drugs which inhibits viral DD;A synthesis, and thereb! viral replication.

phosphorylation of thymidine but not of acyclovir. I’,I9,23~?;l’he third mechanism of resistance involves mutations in the viral DI%A polymerase gene that permit viral DNA replication in the presence of acyclovir-triphosphate. 14.15.2(>,27 Pencicloair and famciclocir Penciclovir is a new nucleoside analogue with similar antiviral spectrum to acyclovir.2x,“’ Famciclovir is an oral prodrug of penciclovir with bioavailability of up to 77’%.“~“” Like acyclovir, penciclovir is activated via phosphorylation to penciclovir-triphosphate, and the first step to penciclovir-monophosphate is catalysed by a virus-encoded TK.“,” In contrast to acyclovir, penciclovir-triphosphate does not act as an immediate DNA chain terminator, but selectively suppresses \-iral replication through competitive inhibition of the viral DNA polymerase.“2 The mechanisms of herpesvirus resistance to penciclovir remain to be elucidated, but are likely to be similar to those described for acyclovir. In a series of five clinical HSV isolates that xvere resistant to acyclovir but not

238

P. Reusser

to foscarnet, suggesting a mutation within the viral TK gene, each isolate was found to be highly resistant to penciclovir. 33However, cross-resistance between TK-dependent antiviral drugs is not always present, as demonstrated in an acyclovir-resistant VZV strain with TK-altered phenotype which was susceptible to penciclovir. 34 Ganciclovir The nucleoside analogue ganciclovir has antiviral activity against all members of the human herpesvirus group, but is considerably more potent than acyclovir against CMV.’ Ganciclovir is phosphorylated intracellularly to its active form, ganciclovir-triphosphate (Figure 1). However, in contrast to TK-dependent antiviral agents, conversion to ganciclovir-monophosphate is catalysed by a phosphotransferase encoded by the UL-97 gene of CMV.35a36 Ganciclovir-triphosphate competitively inhibits the association of deoxyguanosine-triphosphate with viral DNA polymerase, and also reduces viral DNA synthesis by being incorporated into the DNA chain, thereby decreasing the rate of DNA chain elongation.” Two mechanisms of CMV resistance to ganciclovir have been identified. Resistance in nine CMV strains from patients who failed long-term gangiclovir therapy was due to deficient phosphorylation of ganciclovir, suggesting underlying mutations in the gene of the UL-97-encoded in this gene that confer ganphosphotransferase (Figure 1).37 Mutations resistance can ciclovir resistance were recently identified. 3840 Ganciclovir also be caused by alterations of the viral DNA polymerase, as documented in a CMV isolate from a heart transplant recipient.” Cidofovir (HPMPC) Cidofovir ((S)-1-[3-hydroxy-2-(phosphonylmethoxy) propyl] cytosine; HPMPC) is a novel nucleotide analogue (nucleoside-monophosphate) with potent in-vitro and in-vivo activity against CMV and other herpesis of particular interest because it contains a phosviruses. ‘0,4245 Cidofovir phonate group, and therefore does not require initial phosphorylation by a virus-encoded enzyme for activation. Cellular enzymes mediate phosphorylation of cidofovir to its active metabolite that selectively inhibits viral DNA polymerase.46 Cidofovir might prove to be an important treatment alternative when herpesvirus resistance to nucleoside analogues is associated with deficient production or altered substrate specificity of the enzymes responsible for conversion to the monophosphate form during drug activation. Foscarnet Foscarnet is a pyrophosphate analogue and thus belongs to a different class of antiviral agents than the nucleoside and nucleotide analogues discussed above. The drug inhibits viral DNA polymerase of herpesviruses, including CMV, without requiring prior phosphorylation.7 Foscarnet binds close to

Herpesvirus

resistance

239

to drugs

the pyrophosphate binding site on the viral DNA polymerase, and thereb) from the deoxynucleoside triprevents cleavage of pyrophosphate phosphates, which terminates elongation of the viral DNA chain.’ Enlike in nucleoside analogues, herpesvirus resistance to foscarnet results exclusively from mutations in the viral DNA polymerase gene.“,” Clinical

importance

and

therapy of infections herpesviruses

due to resistant

Immunocompetent patients Recovery of resistant herpesvirus strains from immunocompetent patients is rare and does not appear to correlate with clinical outcome. The isolation of resistant VZ\’ or ClL’IV strains from this group of patients has not been reported to date. HSV resistance to acyclovir \vas detected in t\vo (0.3%) of 601 immunocompetent hosts in a HSV sensitivity screening survey,” but \vas not found in any isolate from 59 immunologically normal patients in a retrospecti\-e incidence cohort study.” The effect of long-term antiviral treatment on the emergence of resistance in immunocompetent hosts is well-studied among patients with frequentI!. recurring genital herpes (Table I).47~50In the study of Straus et a/.” resistant HSV strains were isolated from 8.6% of patients during acyclovir treatment, but later recurrences of genital herpes responded to acyclovir therapy in these patients. Fife et al.‘” evaluated HSV resistance following continuous acyclovir treatment for six years, and found a 3.5% rate of acyclovir-resistant isolates which \vas similar to the rate observed prior to therapy. Three of the four patients Lvith resistant HS1’ isolates in that study had no recurrences of genital herpes during the last t\vo years of suppressive treatment, Lvhereas the remaining patient had four recurrences in year five of suppression but only one episode in year six.‘” Thus, in immunocompetent patients, longterm acyclovir treatment for genital herpes does not increase the risk for HSV resistance, and recovery of resistant virus strains is not associated with clinical treatment failure. To date, there is only one report of an immunocompetent host in whom the presence of resistant HSV correlated with clinical outcome.” This patient might have acquired the resistant virus strain from a sexual contact infected with the human immunodeficiency virus (HI\‘) who recei\.ed longterm acyclovir for recurring genital herpes, but \vho declined further investigations. HSL’ disease in the immunocompetent patient was unresponsive to oral acyclovir therapy, even when the drug ~vas gi\.en at a dose of 6 x X00 mg per day.” ImmunorompPomised patients In contrast to immunocompetent patients, the emergence of herpesvirus resistance in immunocompromised hosts has been reported with increasing frequency in recent years.” The different rates of resistance between the t\vo

Duration Number of patients receiving acyclovir Rate of HSV resistance during or after acyclovir treatment

treatment:

I. Herpes simplex

Oral acyclovir Regimen

Table

virus

0

et a1.‘8

with frequently

8.6%

Lehrman

patients

77

Nusinoff

in immunocompetent

35

et al.“?

to acyclovir

5 x 200 mg per day or 2 x 200 mg per day Four months

Straus

resistance

5 x 200 mg per day for one week, then 3 x 200 mg per day Four months

(HSV)

herpes Fife et al.“”

genital

3.5%

239

Six years

2 x 400 mg per day

recurring

Herpesvirus Table

Patient

I I. Herpes

group

Organ transplant: Bone marrollHeart Kidney Pancreas Liver Rlalignanq AIDS or ARC 1\Iiscellaneous Neonates ‘Total

simplex

resistance

z,i~us (HSV] resistance to acvcloeir compromised patient? Number of patients

29 21 21 13 3 39 14 6

241

to drugs ill 7’arious gwups

Patients with isolation of HSV during or after acyclovir treatment s (%I) 19 (66) 5 24) 10 (48) 8 (621 1 (33) 6 (15) 9 (64) II i (50) 59 (40)

of immurm-

Patients with resistant HS\ nT (‘Xl)

4 0 1 1 0 0 1 0 0 7

(I-+) (5) (‘9 (7 (S)t

patient populations may be related to several factors. In immunodeficient patients, virus load during infection tends to be high, and viral replication may not be completely suppressed by antiviral therapy, which increases the probability of generating drug-resistant mutants.‘7.‘2 Furthermore, mixed populations of sensitive and resistant virus can be present, as documented in HSV infection,“,“,5’ and use of antiviral drugs may then favour selection of resistant strains.‘5 The immune system probably plays a pivotal role in controlling such resistant strains, which could explain the lower rate of virus resistance observed in immunocompetent patients.

HSV resistance to antiviral agents in immunocompromised hosts \vas first described by Crumpacker et al.“’ in 1982, and has since become recognized as a clinically significant problem in patients Lvith the acquired immunodeficiency syndrome (AIDS) and other immunosuppressive conditions.;‘-‘” In a retrospective series of 148 patients with various underlying immunodeficiencies, the incidence of acyclovir-resistant HSV was 5% (Table II).” In a two-year screening survey of HSV susceptibility to acyclovir, resistant clinical HSV isolates were reco\-ered from 10 (5%) of 184 immunocompromised hosts.22 Resistance to acyclovir in the vast majority of clinical HSV’ strains examined to date has been caused by TK-deficient mutants. 1(,,17.1’1.21,22.57 ‘rhe few HSV isolates resistant to both acyclovir and foscarne?‘.“‘.“” suggested alterations of the viral DNA polymerase. Resistance was observed almost exclusively among patients who received therapeutic antiviral regimens,

242

P. Reusser

whereas prophylactic treatment did not appear to be associated with the emergence of resistant strains.‘7’61 Prophylactic antiviral treatment reduces the number of replicating virus, which is thought to decrease the likelihood of viral mutations.s2 Although resistance to acyclovir is not invariably associated with more severe or prolonged HSV infection,62’h3 resistant HSV strains were recovered from immunocompromised hosts who had serious mucocutaneous HSV disease unresponsive to acyclovir, or who had oesophagitis, meningoencephalitis, or pneumonia due to HSV.‘6~19~s4~s9~6~66 Alternative antiviral therapy is warranted in these patients, and in view of the frequency of TKdeficient HSV mutants, antiviral agents that are not TK-dependent for activation, such as foscarnet or cidofovir, should be considered. In uncontrolled trials and case reports, foscarnet treatment of HSV disease due to resistant virus suggested some antiviral efficacy among both AIDS patients55,67,68 and bone marrow transplant recipients.“9,hh A randomized comparison of foscarnet and vidarabine for therapy of acyclovirresistant mucocutaneous HSV disease in patients with AIDS showed superior efficacy and less frequent toxicity in the group of patients who received foscarnet treatment.2’ These and other similar observations led to the recent recommendation at a consensus conference to use foscarnet in patients suspected to have acyclovir-resistant HSV disease.“8 However, renal toxicity associated with foscarnet is a matter of concern among patients, such as bone marrow transplant recipients, who are exposed to other potentially nephrotoxic agents.69 Moreover, foscarnet is not always effective in acyclovir-resistant HSV disease, because additional resistance to foscarnet may develop.70 If the mucocutaneous lesions due to acyclovir-resistant HSV are accessible for topical treatment, the use of a 5% solution of trifluorothymidine (TFT), a nucleoside analogue usually used for ophthalmic herpes infection, or of topical cidofovir may yield good clinical results, as observed in a few Furthermore, intravenous cidofovir was beneficial also in a patients.“,” patient with acyclovir-resistant perineal HSV disease and warrants further investigation.72

vzv Since the first report by Pahwa et al. 73 in 1988, acyclovir-resistant VZV strains have been isolated from more than 30 immunocompromised patients, and resistance in the strains analysed was associated with altered or deficient kinase function,“‘2”.2”‘31’““.7”‘6 Three VZV strains were resistant to both acyclovir and foscarnet,20’7”~77 suggesting mutations in the viral DNA polymerase gene. Most resistant strains were recovered from patients with AIDS who had chronic and disseminated skin lesions that were hyperkeratotic in some cases.18,20,23~73-7s Data on therapy of resistant VZV infection is limited. thymidine

Herpesvirus

Foscarnet therapy was resistant herpes zoster, clinical improvement in patient.“’ An additional to foscarnet with healing

resistance

to drugs

243

used in a series of five patients with acyclovirand resulted in complete healing in three and in one, whereas no improvement was observed in one patient xvith acyclovir-resistant zoster responded of the lesions.”

reported by Erice et ~1.” in strains have been recovered, long-term ganciclovir treatof clinical CAIN isolates were strains were resistant either to foscarnet alone, or to both foscarnet and ganciclo\ir.~‘,“‘,“~.~~’ The frequency of CRIV resistance was assessed prospecti\rel\in a group of 72 AIDS patients \vho Lvere treated u-ith intravenous ganciclovir for CM\’ retinitis.?” CLIP strains isolated before or during the first three months of ganciclovir therapy n.ere all susceptible to this drug. Ho\ve\-er, ganciclovir-resistant CM\>- n-as recovered from 38% of patients \\-ho rccei\red treatment for more than three months and \\-ho excreted virus, and the overall prevalence of CAIAr resistance was 8 “’11). “’ Data on CLIV resistance in patients receiving oral ganciclovir are limited so far. In a prospective trial of oral ganciclovir as maintenance treatment for ClLIV retinitis in patients lvith AIDS, in \vhich the retinitis ~vas first stabilized by three lveeks of intravenous ganciclo\-ir, resistant Cn,I\’ \vas not reco\.ered from any patient during oral ganciclovir treatment.” Elowever, the treatment period in this trial \vas shorter than in the aforementioned study of I>rc\\ ct rd.“’ x preliminary report of C:\I\’ resistance rates following therap!. with intravenous or oral ganciclovir indicated that development of rcsistancc ~vas no more frequent \\-ith oral than with intravenous ganciclovir.” The isolation of resistant CJI\’ strains generally has been associated \\,ith the therapeutic use of antiviral agents. Prophylasis, as in HSV infection,” i’,‘i’ does not appear to predispose to C1IV resistance.sx The actual experience kvith therapy of ganciclo\Ar-resistant C1I\- disease is limited to small series and case reports that suggest some clinical benefit from replacement of ganciclovir by foscarnct.“‘,x”,x’,“” In one case of CL11 retinitis associated \\-ith foscarnet-resistant CA,IL’ infection, clinical impro\-emcnt \vas noted after a change to ganciclox-ir therapy.X” Ganciclovir-resistant CnIV disease was first 1989. Since then, additional resistant CMV particularly from patients with AIDS receiving ment for CnI\i retinitis.~l.;“.“‘-“” ’ IYhe majority resistant to ganciclo~ir,~‘~“l~ix~s~~s~~x” but a few

Conclusions

and

future

challenges

In immunocompetent patients, herpesvirus resistance to antiviral drugs is uncommon, and generally does not correlate xvith clinical response. In contrast, immunocompromised hosts may develop severe herpesvirus disease refractory to antiviral drug therapy, and resistant virus isolates are recovered from immunodeficient patients with increasing frequency.

244

P. Reusser

In the presence of herpesvirus disease unresponsive to standard regimens of antiviral agents, a rational selection of alternative therapy should ideally be based on the results of drug susceptibility tests. However, testing for in-vitro susceptibility of herpesviruses is not widely available, and is associated with several problems. The assays are not standardized, are labour-intensive and slow. With the advent of newer, more rapid techniques for detection of antiviral drug resistance,38”0’8y future patients with disease due to resistant herpesvirus strains might benefit from therapeutic decisions based on laboratory results. Broader use of sensitivity testing could furthermore help to better characterize the incidence and clinical significance of herpesvirus resistance in various populations of immunocompromised hosts. To further improve the management of clinically significant herpesvirus resistance, alternative treatment strategies need to be delineated and validated in prospective controlled trials. Issues that should be addressed include pharmacodynamics, the evaluation of newer antivirals that do not require viral enzymes for activation, the use of alternating or combination therapy with drugs known to have distinct mechanisms of resistance, and the assessment of topical antiviral agents. The improvement of methods for detection of herpesvirus resistance, and the validation of new treatment options for patients with documented resistance will be important contributions to reducing the clinical impact of drug-resistant herpesvirus. We thank M. Marti for assistance in manuscript preparation. P.R. was supported of the Swiss *National Research Foundation (no. 32-31314.91).

by a grant

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