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Keywords:

  • aciclovir resistant;
  • foscarnet;
  • herpes simplex virus;
  • keratitis

Abstract

  1. Top of page
  2. A
  3. Introduction
  4. Discussion
  5. Conclusion
  6. References

Herpes simplex virus (HSV) keratitis is a common cause of ocular morbidity. Resistance to aciclovir is probably under recognized. We describe three cases of aciclovir-resistant herpes simplex virus keratitis treated with systemic foscarnet and present a review of the pharmacological options available to manage this condition.


Introduction

  1. Top of page
  2. A
  3. Introduction
  4. Discussion
  5. Conclusion
  6. References

Herpes simplex virus (HSV) keratitis remains a common cause of ocular morbidity.1 Although the natural history of the disease usually results in eventual healing of the corneal ulceration and inflammation, resultant scarring and a tendency for recurrence can lead to blindness. Standard treatment for epithelial disease (classically dendritic/geographic ulceration) consists of topical aciclovir 3% ophthalmic ointment applied five times a day for about 14 days. Stromal disease (both ‘non-necrotizing’, and the much less common ‘necrotizing’ forms) is treated with topical aciclovir in combination with a slowly tapering course of topical steroid, based on the findings of the landmark Herpetic Eye Disease Study (HEDS).2,3 With the advent of new therapies in the last 15 years, many clinicians manage refractory disease with oral aciclovir or valaciclovir.4 Prophylaxis against recurrent disease has been proven with oral aciclovir 400 mg twice a day,5 but oral valaciclovir 500 mg daily is now commonly used instead.6,7

Resistance to aciclovir is probably under-recognized and should be kept in mind (along with poor compliance) when lesions fail to respond to standard therapy, as the following case reports illustrate.

Case 1

An 87-year-old man presented with a right dendritic corneal ulcer in his functionally only eye. His left eye was nearly blind (‘perception of light’) following a long history of recurrent herpes simplex stromal keratitis. He had initially undergone left penetrating keratoplasty for corneal scarring 18 years earlier, and required three subsequent transplants on that eye (the first for corneal perforation secondary to herpetic stromal keratitis, the next for graft rejection, and the last for crystalline keratopathy due to Streptococcus mitis infection). A poor clinical response to topical aciclovir ophthalmic ointment five times a day had been noted over the years. Topical trifluridine 1% four times a day had also been trialled; however, local toxicity was intolerable and the medication ceased. Subsequent recurrences had been treated with appropriate and escalating doses of oral aciclovir or valaciclovir, again with poor clinical response. There were no identifiable compliance issues (as with cases 2 and 3). Corneal swabs from the left eye previously cultured HSV-1 resistant to aciclovir (90% inhibitory concentration [IC90] = 100 µg/mL), but sensitive to foscarnet (IC90 = 200 µg/mL), showed via plaque reduction assay. In view of the viral resistance and well-established high risk of postoperative disease recurrence, one week of intravenous foscarnet had been given as a perioperative prophylactic measure for the second and third corneal grafts without complication. However, the most recent transplant proceeded without foscarnet cover and the disease recurred in the operative eye in addition to development of a new dendritic ulcer in the contralateral (right) eye. Intravenous foscarnet was administered at a dose of 19 mg/kg three times a day (reduced for his creatinine clearance of 0.63 mL/kg/min). After 14 days of therapy all lesions had healed bilaterally leaving mild anterior stromal scarring.

Case 2

A 65-year-old man presented with right HSV-1 keratitis and a 20-year history of recurrent disease in the same eye. Although initially susceptible to topical aciclovir 3% ophthalmic ointment, a recurrence developed which failed to respond to 4 months of oral valaciclovir as well as topical therapy. He underwent a corneal scraping which was polymerase chain reaction and culture positive for HSV-1. Sensitivity testing showed aciclovir resistance (IC90 = 100 µg/mL) but sensitive to foscarnet (IC90 = 100 µg/mL). He was treated systemically with intravenous foscarnet at a dose of 30 mg/kg three times a day for 10 days. His corneal ulcer that had progressed before foscarnet therapy healed after initiation of therapy. He was left with vision of ‘hand movements’ in the affected eye. The patient experienced two further recurrences in the same eye, both of which were treated and responded to courses of intravenous foscarnet.

Case 3

A 76-year-old woman presented with a non-healing left corneal ulcer 6 weeks following pterygium surgery. She recalled one previous episode of HSV keratitis in the same eye that had been treated successfully with oral aciclovir 20 years earlier. A corneal polymerase chain reaction swab was positive for HSV-1; however, examination for mutations in viral TK, DNA polymerase and anti-viral susceptibility was unable to be performed. The ulcer progressed despite 26 days of oral valaciclovir with dose escalation, so aciclovir-resistant HSV was clinically suspected. Unaided vision was right 6/9, left ‘hand movements’ on presentation to our service. Right eye examination was unremarkable; however, a 3.7 × 3.0 mm geographic corneal ulcer with 50% stromal thinning and moderate infiltrate was noted in the mid-periphery of the left cornea adjacent to the site of recent pterygium excision with autoconjunctival graft. Foscarnet was administered intravenously at a reduced dose of 24 mg/kg three times a day (for a creatinine clearance of 0.85 mL/kg/min) for 7 days. The ulcer healed within a few days of starting foscarnet, leaving residual stromal scarring and peripheral corneal neovascularization with vision of ‘count fingers’.

Discussion

  1. Top of page
  2. A
  3. Introduction
  4. Discussion
  5. Conclusion
  6. References

Ocular HSV has been reported to occur at an incidence of 8.4 new cases per 100 000 people per year with keratitis occurring in 69% of cases.8 Most episodes occurring for the first time are unilateral; however, bilateral involvement occurs in 10–12%.1

Recurrent disease is common. The HEDS group followed 346 patients for 18 months after a single episode of ocular HSV and found that keratitis recurred in 34%.9 Commonly, the same virus is associated with the recurrent episodes. Multiple factors have been associated with recurrent disease including ocular trauma and surgery, ultraviolet light exposure, fever and hormonal changes.1

HSV-1 and 2 are members of the Herpesviridae family, which are enveloped, DNA viruses. HSV-1 is responsible for the bulk of ocular disease. Replication is a highly regulated process. Viral DNA polymerase, as well as viral thymidine kinase (TK), is one of the early proteins produced in infection and is responsible for chain elongation. It is the target for antiviral drugs such as aciclovir, ganciclovir, famciclovir, valaciclovir, foscarnet and cidofovir, which all have activity against HSV.

Aciclovir, a deoxyguanosine analogue, and the valyl ester prodrug, valaciclovir, are widely used in the treatment of a broad range of HSV infections. These as well as the acyclic guanosine analogues, penciclovir and famciclovir, require viral TK to undergo phosphorylation to their active forms. It is via mutations affecting the production (complete deficiency or decreased production) or specificity of viral TK that allows HSV to become resistant to those antiviral agents that rely on the activity of viral TK. The active forms of these drugs, as well as foscarnet and cidofovir (which do not require viral TK), prevent viral DNA synthesis by inhibition of DNA polymerase. In 5% of aciclovir-resistant isolates, a lack of any mutations in viral TK suggests mutations in the DNA polymerase gene and thus resistance to a wider range of antivirals (such as foscarnet and cidofovir).10 The first two cases had proven resistance to aciclovir but remained susceptible to foscarnet. This suggests a viral TK mutation. Whereas resistance was not proven in Case 3, it was however, suspected on clinical grounds.

Aciclovir resistance (and thus cross-resistance to other nucleoside analogues) has been a concern given the widespread use of aciclovir for treatment and long-term prophylaxis. However, some studies have found that previous aciclovir treatment was not associated with an increased risk for the development of resistance. In a study of isolates from 239 patients who had previously been on suppressive aciclovir treatment for 6 years, the median aciclovir sensitivity was not statistically significantly different from that of aciclovir-naïve patients.11 A similar study found no significant difference in the incidence of aciclovir resistance between patients who previously received aciclovir treatment and treatment-naïve immunocompetent patients (0.67% vs. 0.42%, respectively).12

The prevalence of aciclovir-resistant HSV isolates is low in the immunocompetent population (0.1–0.98%).12,13 In comparison, resistant isolates are more common in the diverse immunosuppressed population (3.92–14.3%).10,12–15 The highest rates have been found in stem cell transplant recipients (14.3%). Prevalence is lower in the human immunodeficiency virus (HIV)-positive population (3.92–5.9%) but still higher than in the immunocompetent population.12,14,16

The prevalence of aciclovir-resistant HSV isolates specifically in ocular infections was assessed in two studies. The first analysed 40 HSV-1 isolates from 35 patients using a dye uptake method and found that one isolate was resistant whereas three had reduced sensitivity. Thirteen of the cases had keratitis.17 In a second study of 173 immunocompetent patients with HSV keratitis, 11 (6.4%) had aciclovir-resistant isolates. Ten of the 11 had mutations in the viral TK gene conferring the resistant phenotype. Interestingly, one isolate had cross-resistance to foscarnet as well.18

The current options for pharmacological treatment of aciclovir-resistant HSV include foscarnet, vidarabine, cidofovir, trifluridine and brivudin. Only foscarnet and cidofovir are readily available in Australia.

Foscarnet (trisodium phosphonoformate hexahydrate) is a pyrophosphate analogue, which does not require phosphorylation (by viral TK) to inhibit DNA polymerase. As a result, it is active against aciclovir-resistant HSV with mutations in viral TK. It has been shown to be effective in both HIV patients and bone marrow transplant recipients and is currently the recommended treatment for non-ocular aciclovir-resistant HSV disease.19 Intravenous foscarnet for aciclovir-resistant keratitis has been reported in an HIV-positive patient (CD4 count 120/mm3) with a mutation in the HSV TK gene and also in a patient with Wiskott–Aldrich syndrome.20 As there is an intrinsic rate of aciclovir resistance in immunocompetent patients there are likely to be further cases in this population, and intravenous foscarnet is an important therapy to consider. To our knowledge, its systemic use has not been reported in immunocompetent patients for treatment of keratitis.

In our cases, intravenous foscarnet administration was temporally associated with rapid resolution of keratitis previously unresponsive to standard therapy. There are no clinical trials available assessing the efficacy of intravenous foscarnet in aciclovir-resistant HSV keratitis. Case 1 received intravenous foscarnet prophylactically during the perioperative period for two of his four corneal transplant operations. Interestingly, his only perioperative relapse occurred when he did not receive this prophylaxis. There are no data on the use of foscarnet in this situation but our case suggests that it may have had some efficacy.

The eye has different pharmacokinetics compared with other body sites. There has been some concern regarding the intraocular levels of foscarnet achievable with intravenous administration for treatment of cytomegalovirus retinitis.21 Mean vitreal concentrations have been reported as 23.3 µg/mL in patients receiving an induction dose.22 It is difficult to apply this data with regards to HSV keratitis, as doses used are higher than those recommended for HSV infections. In addition, the cornea does not have a direct blood supply and thus is exposed to antimicrobials via diffusion from the aqueous humour, tear secretions or from topical therapy. The levels attained in the aqueous humour are unknown, and tear secretion of the drug may be a clinically relevant parameter.

Clearly, topical therapy is a potentially effective modality in corneal disease. Topical foscarnet has been shown to be useful in HSV skin lesions.23 The use of foscarnet (6 g/250 mL) has been described in a patient with recurrent aciclovir-resistant HSV keratitis. Mutations were found in both the viral TK and polymerase genes.24 In another study, varying concentrations (1.2%, 1.4%, 1.9%) were used for induction and maintenance therapy in patients with aciclovir-susceptible HSV keratitis. Corneal epithelial toxicity developed in those using 1.9%; however concentrations of 1.2% and 1.4% were well tolerated. The lack of a control group and small numbers make efficacy difficult to ascertain in this series.25 Another small study concluded that topical foscarnet (3%) was as effective as trifluridine in the treatment of HSV keratitis.26

Nephrotoxicity is the major dose-limiting side-effect of systemic foscarnet although this can be limited with pre-hydration with normal saline. Other adverse effects include metabolic abnormalities (foscarnet chelates divalent cations), central nervous system (headache, seizures, hallucinations) and anaemia. Despite this, intravenous and topical foscarnet clearly has potential application in aciclovir-resistant HSV keratitis treatment, but further clinical trials are needed to confirm safety and efficacy.

Trifluridine is a fluorinated pyrimidine nucleoside analogue and an inhibitor of thymidylate synthetase. A 1% solution has been used for the treatment of HSV keratitis (without aciclovir resistance) with similar efficacy to aciclovir and vidarabine.27 Although there are no clinical trials assessing the efficacy of trifluridine in aciclovir-resistant HSV, topical trifluridine has been used to treat aciclovir-resistant mucocutaneous lesions with some success.19 It is not available in a systemic formulation and toxicity is predominantly limited to local complications. Trifluridine is typically well tolerated (although Case 1 developed significant local toxicity) and may be able to be used instead of more toxic therapies. However, as mentioned previously, it is not readily available in Australia, which limits its use in our practice.

Cidofovir is an acyclic phosphonate nucleotide analogue of deoxycytidine monophosphate. It has activity against HSV and other herpesviridae. Like foscarnet, it does not require viral TK for activation and similarly has activity against aciclovir-resistant HSV. As with our use of intravenous foscarnet, intravenous cidofovir has potential application but has greater risk of nephrotoxicity than foscarnet. Additionally, neutropaenia is another significant concern with cidofovir. In experimental aciclovir-resistant keratitis, topical cidofovir is at least as effective as trifluridine.28 A randomized controlled trial of topical cidofovir (1% four times daily and ten times daily) for the treatment of adenovirus keratoconjunctivitis found that a significant proportion of patients experienced dose-dependent toxicity. Some 44.4% and 100% of cases using the lower doses and higher doses, respectively, developed erythema of the lids and conjunctiva and/or inflammatory membranes. These adverse effects will likely limit its use.

Vidarabine, an analogue of adenosine, is active against both HSV-1 and 2 including aciclovir-resistant strains. It does not require viral TK for phosphorylation, rather utilizing cellular enzymes. An ophthalmic preparation is as effective as aciclovir and trifluridine in wild-type HSV keratitis.27 However, like trifluridine, it is not readily available in Australia. Local toxicity is a major complication with topical use. Experimental studies of aciclovir-resistant HSV keratouveitis in rabbits have showed vidarabine to be efficacious.29

Brivudin ([E]-5-[2-bromovinyl-2-deoxyuridine) is a thymidine nucleoside analogue. As an oral formulation it has been used to treat herpes zoster infections.30 Aciclovir-resistant HSV strains have been reported to remain sensitive to Brivudin.29 Hence this may be a possible therapy if required, although there is a lack of clinical trials to support this.

Conclusion

  1. Top of page
  2. A
  3. Introduction
  4. Discussion
  5. Conclusion
  6. References

Although aciclovir-resistant keratitis is considered relatively uncommon, there is an intrinsic level of aciclovir resistance that is not due to prior aciclovir exposure. As a result, intractable keratitis with its significant associated ocular morbidity will undoubtedly remain a challenging clinical management issue. The available treatment options are limited and may be complicated by significant toxicity. As our cases show, intravenous foscarnet is a useful option to consider in an effort to limit permanent visual loss and is potentially the least toxic of the drugs readily accessible in Australia. Topical therapeutic options exist and have the obvious benefit of ease of administration; however access to these medications in Australia is limited. The potential role of topical foscarnet warrants further research.

References

  1. Top of page
  2. A
  3. Introduction
  4. Discussion
  5. Conclusion
  6. References
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