Resistance of Herpes Simplex Virus Infections to Nucleoside Analogues in HIV-Infected Patients
- 1Pediatric Infectious Diseases, University of Colorado Health Sciences Center, Denver
- 2Consumer Healthcare, GlaxoSmithKline, Weybridge, United Kingdom
- 3Department of Virology, GlaxoSmithKline, Research Triangle Park, North Carolina
- Reprints or correspondence: Dr. Jeffry J. Leary, GlaxoSmithKline, 5 Moore Dr., P.O. Box 13398, Research Triangle Park, NC 27709 (jeffry.j.leary{at}gsk.com).
Abstract
Antiviral treatment of herpes simplex virus (HSV) infections with nucleoside analogues has been well established for >2 decades, but isolation of drug-resistant HSV from immunocompetent patients has remained infrequent (0.1%–0.7% of isolates) during this period. Even when drug-resistant HSV is isolated from an immunocompetent patient, this virus, with rare exceptions, is cleared normally without adverse clinical outcome. Although drug-resistant HSV is more commonly isolated from immunocompromised patients (4%–7% of isolates) and is more likely to be clinically significant, the prevalence of drug-resistant HSV even among these patients, has been stable over the past 2 decades. Despite this stable prevalence, disease due to drug-resistant HSV remains an important problem for many immunocompromised patients, including those with HIV infection. This article reviews the prevalence, pathogenesis, and implications of drug-resistant HSV infections in HIV-infected patients.
Characteristics of Herpes Simplex Virus (HSV) Infections in Immunocompromised Patients
The clinical manifestations of HSV infections in immunocompromised HIV-infected patients are similar to those observed in other disease states characterized by inadequate HSV-specific cell-mediated immunity [1–8]. In these patients, local mucocutaneous oral or genital disease may become chronic and more severe than typical disease in immunocompetent persons, depending on the level of residual or reconstituted immune function. Lesions are not strictly limited to oral or genital areas and may occur on digits or the face. Severe manifestations are more likely to be apparent with first-episode infection than with recurrences. Moreover, although the likelihood of dissemination is very low, this is most likely to occur with a first-episode infection, especially if it is the primary HSV infection [9]. A much more common problem is that of recurrences of HSV at oral or genital sites. These outbreaks are often more frequent, more extensive and necrotic, of longer duration, atypical in appearance, and complicated by oral mucositis or esophagitis [2, 5, 7, 10–13]. The more severe the immunosuppression, the more likely the episode is to be clinically complex.
Numerous immunologic and clinical factors, in combination, provide an opportunity for HSV to become resistant to antiviral therapy. Two factors are the major determinants of resistance. First, a deficit in HSV-specific cell-mediated immunity results in delay (weeks rather than days) in the normal rapid clearing of HSV from mucocutaneous lesions, leading to large areas of involved tissue (cm2 as opposed to mm2) containing persistently replicating HSV. The extent to which viral replication continues unimpeded reflects the level of immunosuppression, as has been demonstrated for viral shedding and culture positivity, which, in turn, should be related to replication level [14–17]. The second factor is the prolonged use of antiviral therapy: large numbers of HSV replicating in the presence of an inhibitor selects for naturally occurring resistant variants [18]. Over time, these 2 factors would be expected to result in acyclovir-resistant HSV becoming the predominant virus in the lesion. An exacerbating third factor can be suboptimal adherence to therapy by some HIV-infected patients because of debility, depression, and/or a large pill burden.
Mode of Action of Nucleoside Analogues Commonly Used for the Treatment of HSV Infections
Acyclovir, the first effective anti-HSV drug, is the prototype for treatment of HSV infections. Valacyclovir is an aminoacyl prodrug of acyclovir that is rapidly converted to acyclovir by host acetylases in the intestinal wall and the liver. Bioavailability of acyclovir administered as the prodrug is 2–3-fold greater than when it is administered as the free drug. Acyclovir that enters HSV-infected cells is phosphorylated specifically by the HSV thymidine kinase (TK [gi:3915741]) and cellular kinases to acyclovir triphosphate. Acyclovir triphosphate, the active metabolite of acyclovir and valacyclovir, inhibits HSV replication by selective inhibition of viral DNA polymerase (Pol [gi:118881]) and by termination of growing viral DNA strands [19]. The activation and mechanism of action of penciclovir (active ingredient of famciclovir) is similar to that of acyclovir [20, 21].
Accordingly, in vitro resistance of HSV-1 and HSV-2 to acyclovir results from mutations in the viral genes encoding TK or DNA polymerase [19, 22, 23]. Such mutations occur naturally in the absence of acyclovir.
Determination of Resistant HSV
A variety of phenotypic methods have been used to determine the susceptibility of HSV isolates to antivirals, including dye-uptake assays, viral DNA–inhibition assays, EIAs, and the plaque-reduction assay. Efforts have been made to standardize these assays, because many variables can influence the final result [24–26]. The plaque-reduction assay [27] is used most widely for susceptibility testing, in part because a correlation has been established between in vitro susceptibility to acyclovir, measured by this assay, and clinical response, based on data from 243 HSV isolates from 115 HIV-infected patients [28]. In this study, the predictive value of an IC50 of <2 µg/mL, measured by the plaque-reduction assay in Vero cells, for complete healing of lesions was 62%. Accordingly, an IC50 of ⩾2 µg/mL is often used as a break point for in vitro assays. HSV resistance to acyclovir and related drugs has been reviewed elsewhere, most recently by Field [29] and Bacon et al. [30].
Characteristics of Resistant HSV
Three distinct classes of acyclovir-resistant TK mutants have been identified (table 1); TK-negative (TKN) mutants lack TK activity, TK-partial (TKP) mutants express reduced levels of TK activity, and TK-altered (TKA) substrate specificity mutants phosphorylate thymidine but not acyclovir. Because it is often difficult to distinguish low TKP from TKN mutants, they are sometimes jointly referred to as TK-deficient (TKD) mutants.
Table 1
Characterization of acyclovir-resistant herpes simplex virus mutants.
About 95% of acyclovir-resistant HSV isolates are TKD, and the remaining isolates are usually TKA [32]. Although mutants with altered DNA polymerase have also been identified, these are infrequently reported either clinically or among laboratory-selected mutants [13, 22]. Viruses with TK mutations are normally cross-resistant to other drugs dependent on the viral TK for activation, such as penciclovir, but generally remain susceptible to antiviral agents that act directly on DNA polymerase, such as foscarnet and cidofovir [32]. The less common or rare viruses with TKA mutations or DNA polymerase mutations may display more complex in vitro cross-resistance patterns [32, 33].
The pathogenicity of acyclovir-resistant HSV mutants has been evaluated in animal models, which have been used to evaluate cutaneous (or other peripheral site) infections, neurovirulence, and reactivation from latency. Typically, TKN mutants reveal the greatest reduction in virulence, compared with wild-type viruses (table 1) [34]. TKN strains, with rare exception, are unable to reactivate from latency in the ganglia after infection in mice and are much less neurovirulent. Although it is difficult to identify TKP mutants by biochemical assays alone, evaluation of pathogenicity in animal models can be helpful. TKP strains show some reduction in pathogenicity in mice compared with wild-type virus, but are generally more capable of reactivation from latency [34]. Rare, atypical TKN mutants have been shown to reactivate from latency in mice or to cause recurrent human disease and are thus potentially important [35–39]. These isolates “recover” the ability to reactivate through various mechanisms: genetic reversion of the original TK mutation, resulting in acyclovir-susceptible virus; a TK protein expression anomaly, such as frame-shifting; or complementation by another viral kinase activity or wild-type virus [35, 39, 40]. Although such atypical strains are theoretically more transmissible, at least one such strain was isolated a decade ago without evidence of subsequent spread [35, 36]. One recent report suggests that the guinea pig model, rather than the mouse model, accurately evaluates viral pathogenicity, and TKD HSV may be more pathogenic in this model [41].
Prevalence of Resistant HSV
The first clinical report of an HSV isolate resistant to acyclovir appeared in 1982, soon after trials of acyclovir had begun [42]. This isolate was obtained from an immunocompromised patient, as were most of the isolates subsequently described. However, acyclovir-resistant isolates have also been recovered, albeit very rarely, from immunocompetent patients and even from subjects who were never treated with acyclovir [30, 43–46]. Isolation of acyclovir-resistant HSV from untreated patients underscores the fact that resistant mutants occur naturally and, by chance, can be the only virus sampled and inoculated into cell culture. No consistent differences have been identified in the resistance mutations of acyclovir-resistant isolates from immunocompetent and immunocompromised patients. In contrast, the prevalence of acyclovir-resistant HSV isolates differs greatly for immunocompetent and immunocompromised patient groups.
Resistance to Antivirals in Immunocompetent Patients
The isolation of HSV resistant to acyclovir or other antiherpetic agents is rare in the immunocompetent population (<1%) [44, 47, 48] (reviewed in [29, 30]). Data from extensive surveys conducted in the United Kingdom and United States provide baseline information on the susceptibility of HSV isolates from immunocompetent persons who have not been exposed to acyclovir (table 2) [44, 47, 49–51]. The prevalence of resistant virus in these surveys was 0.3% and 2.5% (by plaque-reduction and dye-uptake assays, respectively) for untreated subjects. However, the dye-uptake assay is likely to overestimate the number of acyclovir-resistant HSV isolates, as a result of the amplification of minor subpopulations of resistant variants during the assay. In contrast, the plaque-reduction assay provides a more accurate reflection of the virus population replicating in the patient at the time of isolation and therefore gives a more reliable prediction of clinical response to antiviral therapy [52]. For this reason, the plaque-reduction assay (used in references cited in table 2) has supplanted the dye-uptake assay in the United States and has been published as a standard by the National Committee for Clinical Laboratory Standards [24]. Moreover, in the same surveys, the prevalence of resistant virus was similar among isolates from acyclovir-treated subjects (0.5% and 3.2%, by plaque-reduction and dye-uptake assays, respectively) and untreated persons (0.3% and 2.5%) (table 2). In addition, the collaborative Task Force on Herpes Simplex Virus Resistance was established in the United States through the Centers for Disease Control and Prevention (CDC) to estimate the prevalence of acyclovir-resistant genital HSV among immunocompetent patients with sexually transmitted diseases and among patients infected with HIV [17, 47]. The results of task force surveillance of treated immunocompetent patients from 1996 to 1998—acyclovir resistance in 0.18% of 1644 isolates—were comparable to the results of earlier surveys. Similarly, a recent survey for penciclovir resistance reported 2 resistant isolates (0.19%) among 1035 obtained from 585 immunocompetent treated patients [53]. Notably, both resistant isolates in this latter report were transient, and subsequent isolates from the same patients were susceptible to penciclovir and acyclovir. Isolates from this study were also included in a survey of isolates from 11 worldwide clinical trials, in which 2145 isolates from 913 immunocompetent persons and 288 immunocompromised persons were assessed. Resistant HSV was isolated from a similar proportion (0.22%) of immunocompetent patients [48]. In another study, Shin et al. [54] detected no resistant HSV in a study of 360 isolates (prevalence, <0.3%) from persons who used topical penciclovir to treat recurrent herpes labialis. A substantial survey effort in France recently reported susceptibility tests of 3900 isolates, with acyclovir-resistant HSV isolated from 0.32% of immunocompetent and 3.6% of immunocompromised patients [55] (table 2). This latter study used a modified dye-uptake assay, which seems better aligned with the plaque-reduction method than the original dye-uptake assay [52, 56].
Table 2
Surveillance for acyclovir-resistant herpes simplex virus (HSV) in the immunocompetent population.
Resistance to Antivirals in Immunocompromised Patients
Isolation of HSV resistant to acyclovir occurs more frequently in immunocompromised persons (table 3). Almost 20 years ago, Wade et al. [57] reported a prevalence of acyclovir-resistant HSV ranging from 2% to 9% in bone marrow recipients treated with acyclovir. Similar results were reported in 1990 for a set of patients with a variety of underlying immunodeficiencies [58]. With the increase in immunocompromised populations due to transplantation and HIV infection, reports of resistant isolates and resistant disease have increased, but, in fact, the frequency of resistant isolates in case series has remained stable [2, 30, 60]. A contemporary CDC surveillance study reported a 5.3% incidence of acyclovir-resistant HSV strains in this population [47]. Viral resistance to acyclovir after valacyclovir suppressive therapy in HIV-infected subjects was also evaluated in a multicenter, double-blind, placebo-controlled trial. In that study, a similar incidence of acyclovir resistance was observed (3 [6%] of 50 acyclovir-resistant isolates [61]). In the large French study, 3.6% of HSV isolates from immunocompromised patients were acyclovir-resistant, although the prevalence was much higher (>18%) among bone marrow transplant recipients. Among HIV-infected patients, 4.2% of isolates were acyclovir-resistant [55]. The survey of 11 worldwide clinical trials of penciclovir and famciclovir reported an only slightly lower prevalence of resistant HSV isolates among immunocompromised patients: 2.1% [48]. Results consistent with those mentioned above have been obtained in other studies (table 3) and underscore the fact that the prevalence of resistant HSV in this population is stable.
Table 3
Prevalence of acyclovir-resistant herpes simplex virus (HSV) in immunocompromised patients.
Factors Influencing the Emergence and Spread (or Lack Thereof) of Resistant HSV
To date there has been no unequivocal evidence of transmission of an acyclovir-resistant HSV strain from person to person, although this remains a theoretical possibility. A case suggesting transmission of a resistant HSV strain has been reported [62]; however, paired source and patient isolates required for proof of transmission were not available for analysis. Another report suggested transmission of acyclovir-resistant HSV isolated from a patient with primary HSV, in that a close family member was concurrently undergoing nucleoside therapy for HSV stomatitis [55]. Again, paired patient and source isolates were not analyzed, and thus no proof of transmission is available. The absence of additional instances or any reasonable proof is noteworthy, because acyclovir has been heavily used for >2 decades. Moreover, acyclovir-resistant disease-competent HSV has been in the population since the mid-1990s or longer [35, 36] (M. Sowa, personal communication). Absence of documented transmission of acyclovir-resistant HSV is in stark contrast to other virus and drug combinations, such as HIV and antiretrovirals [63]. The apparent lack of transmission is likely a primary reason for the stable and low prevalence of resistant HSV.
Resistant HSV arises spontaneously from the natural variability of the HSV population, as evidenced by the detection of acyclovir-resistant HSV in patients who had not been treated with acyclovir [43, 64]. Indeed, each clinical HSV isolate has some percentage of resistant mutants, although very low (10-4–10-5) [65–67]. These mutants, amplified in infection sites during treatment, provide the source for virtually all resistant infections, because transmitted infection by acyclovir-resistant HSV is so rare. Nonetheless, these mutants rarely become a significant proportion of HSV in immunocompetent patients, and their presence is transient. Only 3 case reports describe reactivation of resistant virus from immunocompetent persons [55, 62, 68]. In all cases, the viral disease or patient presentation was atypical. In the case reported by Swetter et al. [68], the lesions seemed more typical of those seen in immunocompromised patients, although extensive tests revealed no underlying condition. In the most recent report [55], the patient was given the diagnosis of monoclonal gammapathy yet was not considered immunocompromised.
Cases of persistent infection by resistant HSV occur almost exclusively in severely immunocompromised persons. In AIDS patients with acyclovir-resistant HSV infection that responded to foscarnet therapy, isolates from the first recurrences were often susceptible to acyclovir, but isolates from subsequent recurrences were again resistant [7]. Other reports from immunocompromised patients, including those with HIV infection, indicate that recurrences of HSV after a resolved infection with acyclovir-resistant virus can be with either susceptible or acyclovir-resistant HSV. In severely immunocompromised persons, including those with AIDS, serial recurrence of lesions shedding acyclovir-resistant HSV has been reported. These cases may represent true reactivation of acyclovir-resistant HSV from ganglionic latency, subclinical persistence at the lesion site, complementation, reversion, or “leaky” mutations [16, 37, 55, 69–72].
A combination of viral fitness, aspects of the HSV life cycle, and host immune factors may elucidate the lack of observed transmission and the stable prevalence of acyclovir-resistant HSV.
HSV-Related Factors
Fitness of resistant HSV.The majority of acyclovir-resistant isolates are TKD (88%–96%) [31, 73], and such mutants have reduced pathogenicity in animal models [34]. Therefore, the great majority of resistant strains are likely to be less biologically competent in the normal human infection, reactivation, and transmission cycle. Acyclovir-resistant HSV mutants, other than TKD isolates, may or may not be less fit than wild-type virus, in terms of virulence, and may show lower mouse lethality and less replication at the periphery, either of which suggests reduced likelihood of spread in the population (table 1). Rare strains of acyclovir-resistant HSV TK mutants that retain pathogenicity have been reported, but there is no evidence that they have spread in the population, even though one such virus was isolated more than a decade ago [35–37, 39, 68].
HSV infection and latency.HSV-1 infections, in particular, have a long generation time (time between initiation of infection in one person and subsequent transmission to another person); therefore, phenotypic change for HSV within the population is slower than for viruses that are more readily transmissible, such as influenza virus. HSV infection is lifelong, and infection with multiple strains of either HSV-1 or HSV-2 appears to be unusual [74]. During latency, little, if any, complete viral replication occurs, and thus little, if any, selection for drug resistance occurs, even during suppressive therapy. If resistant virus does emerge during a recurrence, this virus is unlikely to become the source of subsequent reactivations, for the fitness reasons discussed above. Thus, the fit, susceptible, historical virus that caused the first episode of infection at an anatomic site and that established latency is the strain that will typically reactivate to cause a recurrence. Available evidence suggests (see Antiviral Selective Pressure and Emergence of Resistant HSV section) that the latent virus in ganglia of immunocompetent patients is not repeatedly replenished from virus appearing at the periphery during recurrences. Consequently, the nature of latency presents a formidable barrier to the accumulation of resistant HSV in the population.
Host-Related Factors
The integrity of the host immune response has a critical effect on the severity of infection and the risk of clinical resistance.
Primary infection or recurrences of genital herpes or herpes labialis in the immunocompetent host typically last for only a few days and remain localized [75]. Because HSV is cleared rapidly by the immune system, selection of resistant virus can occur in the treated host during a limited time. In patients with recurrent herpes labialis, for example, virus was cleared from the lesions within 4–5 days, although virus is cleared more slowly from first-episode lesions [76, 77]. The immune system clears acyclovir-resistant virus just as efficiently as it clears susceptible virus, ensuring that resistant HSV is typically transient in immunocompetent patients [45, 78].
Loss of HSV-specific immune function in the immunocompromised patient permits replication of both wild-type and less-fit resistant mutants. In the face of antiviral therapy, this will lead to selection of naturally occurring mutations, especially when the duration of therapy is increased for severely immunocompromised patients [29, 30]. Consistent with this, Wright et al. [17] report an inverse correlation between CD4 cell count and the frequency of HSV, isolation in a survey of HIV-seropositive women. Although it seems obvious that isolation of resistant HSV would correlate with drug use, little published evidence actually shows a clear relationship or correlation between isolation of acyclovir-resistant virus and antiviral therapy, except in case studies. The notable exception is the surveillance publication by Reyes et al. [47], in which resistance in the immunocompromised population was correlated with a history of topical acyclovir use but not oral antiviral therapy. Also, it has been found that use of prophylactic antiviral regimens reduces the opportunity for viral replication, which, in turn, decreases the number and likelihood of viral mutations [79]. Therefore, it has been hypothesized that use of suppressive antiherpetic therapy in HIV-infected subjects may actually decrease the probability of resistance [80]. This hypothesis does not have experimental confirmation.
Drug-Related Factors
Mechanism of action.It is precisely the mechanism of acyclovir action through HSV TK that results in most acyclovir-resistant (TKD) viruses being less fit. Viruses resistant to drugs that act through a different mechanism, and thus that select different mutations, may be more or less fit depending on the specific viral gene(s) involved (table 1) [32, 81, 82].
Selective pressure of antiviral therapy.In the absence of antiviral treatment, selection for resistant virus does not occur. Also, when antiviral activity is completely effective—such that there is no viral replication—there, again, selection for antiviral resistance cannot occur [18]. Selection for resistant virus can therefore occur only when there is sufficient viral replication despite the presence of the antiviral. Thus, the degree of suppression of replication, characteristic of the drug, is an important factor. Episodic or suppressive treatment with acyclovir reduces but does not completely prevent shedding of acyclovir-susceptible virus in patients with acute genital or oral HSV infection [15, 61, 83, 84]. Reasons for this are not clear but may include incomplete absorption or maldistribution of antiviral, sequestration of the source virus from the drug, nonadherence to the prophylaxis, and the occurrence of suboptimal antiviral concentrations between doses. Regardless of the reason, unnecessary or unnecessarily prolonged therapy may contribute to selection of resistance and should be avoided.
Antiviral Selective Pressure and Emergence of Resistant HSV
Selective pressure issues similar to those mentioned above are familiar as the basis for multidrug treatment of tuberculosis and HAART regimens for HIV infection. Two relatively recent publications attempt to address effects of selective pressure on HSV resistance in humans and an animal model [54, 85].
Although the proportion of resistant virus that is detected may vary between clinical isolates and over time as an infection progresses, the clinical implications of such changes are uncertain. A study to investigate the emergence of endogenous resistance from recurrent infections was conducted among immunocompetent patients who were repeatedly treated with topical penciclovir cream for frequent episodes of recurrent herpes labialis. If cases of progressive increase in resistant virus were detected, this would raise the likelihood that resistant virus might be transmitted from patients to susceptible contacts. However, analyses of IC50 data failed to reveal any trend indicating reduced susceptibility to penciclovir after multiple episodes of topical treatment, and no resistant isolates were found in the entire study [54]. In contrast to the IC50 results, the proportion of resistant virus (measured by a plating-efficiency assay) [65, 67, 86] in successive clinical specimens tended to rise during each episode but returned to low levels at the start of each subsequent episode. This suggests that the risk of endogenous resistance, at least in the immunocompetent host treated for HSV infection, is low, for 2 reasons: the latent virus that reactivates remains susceptible, and very little resistant virus accumulates in lesions (and any virus that does accumulate is there for a short time only). Similar results were presented by Hasegawa et al. [87]. Published data about serial isolates from immunocompromised persons undergoing therapy are available but do not have the relevant plating-efficiency data [37, 69, 40]. Regardless of the variability in the proportion of resistant HSV in a specimen, the prevalence of resistant HSV isolates, as measured by the plaque-reduction assay appears to be stable, and this method is correlated with treatment outcome.
The effect of serial passage of HSV in immunocompetent mice treated with suboptimal doses of oral valacyclovir or the similar prodrug famciclovir has been studied by means of plaque-reduction and plating-efficiency assays in parallel to monitor the emergence of resistance [85]. Only 1 of 140 virus isolates from mice treated with the antivirals was drug-resistant, by the plaque-reduction assay, during 7 sequential passages of either HSV-1 or HSV-2. The resistant isolate was obtained after 4 serial passages of HSV-1 in mice treated with valacyclovir. The mean acyclovir and penciclovir IC50s were 9.5 µg/mL and 8.3 µg/mL, respectively, and the specimen contained a relatively large proportion of resistant viruses (47% ACVr and 44% PCVr). Molecular analysis of clones derived from the original isolate revealed a frame-shift mutation in the TK gene, leading to the expression of a truncated TK polypeptide, a typical TKN mutation. Although the preceding isolate in the series was susceptible to acyclovir and penciclovir (IC50s of 0.2 µg/mL and 0.5 µg/mL, respectively), the proportion of resistant virus in the preparation was elevated (∼2% resistant to penciclovir or to acyclovir, compared with <0.007% for virus preparation of the preceding passage ). Curiously, the resistant phenotype was lost on the next passage in mice, despite continued suboptimal treatment with valacyclovir. These results suggest that selection for resistant HSV occurred rapidly under conditions designed to favor the selection of resistance. There was an equally rapid loss of the resistant mutant during the next sequential passage (which simulated transmission), as judged by both in vitro assays, suggesting that a fitness advantage for wild-type virus transmission selects for susceptible virus. This study is in rather good agreement with the study of topical repeat therapy in treatment of cold sores, mentioned above, and with clinical isolation of transient resistant HSV from immunocompetent persons [54]. In contrast, Field [88] demonstrated increasing selection of acyclovir-resistant HSV in very similar animal experiments with mice treated with acyclovir. Why the results of these 2 studies are in disagreement is not clear; however, slight technical differences between the studies (published 20 years apart) seem likely.
Treatment of Nucleoside-Resistant HSV Infections
Unsuccessful treatment of HSV in HIV-infected patients is suspected when the lesions fail to improve after 4–5 days of therapy. Often, successful therapy produces a diminution of local pain even before the lesions improve in appearance. Increase in the size of lesions and the appearance of satellite lesions are additional indicators of treatment failure. If failure of therapy is suspected, isolates from the lesions should be submitted for susceptibility testing, and a change of therapy should be considered. Because most resistance is the result of mutations in the TK gene, an increased dose of acyclovir (including a switch to iv therapy) is rarely successful and not recommended [2, 10]. Similarly, a switch to a related antiviral that requires activation by TK (such as penciclovir [Famvir]) is not recommended, because there will probably be cross-resistance. Most successful treatment of acyclovir-resistant HSV has been with foscarnet, a drug that acts directly on the HSV DNA polymerase without activation by any viral or host kinase. Acyclovir-resistant HSV almost invariably responds to foscarnet (administered in accordance with the package insert) [7, 10, 59, 89]. Duration of therapy for extensive lesions is at least 10 days, with additional therapy being determined by the clinical response. Subsequent recurrences are often, but not invariably, due to acyclovir-susceptible isolates [7, 55, 59]. Similarly, HSV recurrences are often due to strains susceptible to foscarnet after initial foscarnet therapy [55, 59, 90]. Lesions that fail to respond to foscarnet should be treated with cidofovir, because this analogue is a diphosphonate that is activated by host-specific enzymes [59, 91]. However, cidofovir has more potential toxicity than foscarnet and is therefore used only in cases in which foscarnet resistance has occurred. For local skin lesions, toxicity and resistance may be avoided by use of topical foscarnet [68, 92]. This formulation, which must be compounded locally because only the injectable formulation is commercially available, has the advantages of limiting overall drug exposure and of producing sufficiently high levels of drug locally, such that resistance is unlikely to develop. A topical approach may provide similar advantages for cidofovir [93, 94].
Conclusions
There has been a dramatic increase in the use of antiherpetic nucleosides since their introduction 2 decades ago, but this has not been accompanied by a detectable increase in the prevalence of resistant HSV in immunocompetent or immunocompromised populations. The ability of HSV to establish a lifelong latent infection, together with the finding that the vast majority of acyclovir-resistant HSV isolates studied to date have reduced pathogenicity relative to that of wild-type virus, help to explain this observation of stable prevalence, which is contrary to experience with many other anti-infective agents. These same factors probably also account for the dearth of published examples of transmission of acyclovir-resistant HSV. Although changing prevalence and, thus, population concerns about resistant HSV may not be significant, resistant HSV disease in the individual immunocompromised patient remains important. Persistent or frequently recurring HSV lesions in immunocompromised patients undergoing nucleoside analogue therapy should be managed with resistance in mind and alternative therapy at hand.
Acknowledgments
Financial support.M.J.L. receives funding from the GlaxoSmithKline vaccine division for clinical research.
Potential conflicts of interest.Both T.H.B. and J.J.L. are employees of GlaxoSmithKline, which produces valacyclovir (Valtrex) and acyclovir (Zovirax).
Footnotes
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Portions of this report were published in Clin Microbiol Rev 2003; 16:114–28.
- © 2004 by the Infectious Diseases Society of America
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