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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.
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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.