Marvin Berkowitz, M.D.

Case Report

The patient is a 42-year-old HIV infected female. She initially presented five years ago with CD4 count of 11 and a viral load of 400,000. She was treated for several years with antiretroviral drugs including zidovudine, 3TC, lamivudine, and indinavir with a good response with viral load decreasing to 4,000 and CD4 T-cells increasing to 400.

The patient was first hospitalized with resistant vaginal herpes that developed into a large ulcerated lesion. She had not responded to outpatient treatment with oval acyclovir, oral famciclovir and a short trial of valacyclovir.

The patient, however, responded very quickly to intravenous foscarnet and received 10 days of induction therapy in the hospital. She also had maintenance foscarnet for two weeks as an outpatient which was then tapered.

Patient did well for six weeks and was changed to a more aggressive antiviral regimen to try to make her levels undetectable. She was changed to 3TC, D4T and nevirapine to control her underlying viral immunosuppression with good response and undetectable viral levels five months later.

Despite this, however, patient developed recurrent herpes simplex that was more external than her initial vaginal lesion and extended to the perirectal area. Viral cultures showed herpes simplex virus, sensitive to acyclovir, ganciclovir, and foscarnet. She was treated with oral acyclovir and oral ganciclovir with minimal response and was readmitted to the hospital. On admission the lesion was 5 cm in diameter with an inflamed base with a new lesion on the other labia. She was restarted on foscarnet with a good clinical response and was discharged after 14 days of induction. She did well for two weeks before developing recurrent lesions, which were culture positive for HSV. The ulcer had grown and become much deeper and she was again admitted for foscarnet, which was continued as maintenance daily treatment after discharge.

After four weeks of maintenance therapy, the genital lesion had resolved, however after eight weeks, new perirectal lesions appeared, which progressed on treatment.

Because of ongoing growth, the foscarnet treatment was stopped and the patient was started on topical cedofovir. Within five days, the lesion showed dramatic improvement. The size of the lesion decreased from 3 cm to 1.5 cm and the depth also decreased from 1 cm to 0.5 cm and there was no local irritation. The remaining area was no longer raw and had new covering epithelium. The lesion continued to reduce in size for the rest of the month. In fact, four weeks after initial treatment with cedofovir, the lesions were almost gone with scattered areas that were denuded and raw. As new lesions appear, patient was given topical cedofovir with good results.

Discussion

Herpes simplex is a frequent cause of genital and perirectal ulceration in patients with HIV infection. Oral acyclovir is usually effective therapy for herpes simplex virus genital lesions, perirectal lesions, proctitis, oral lesions, digital lesions, and esophagitis. Clinical disease due to acyclovir-resistant HSV occurs primarily in immunocompromised patients and is characterized by a chronic, progressive ulcerative mucocutaneous disease with prolonged shedding of virus.¹

This patient progressed on oral acyclovir and required foscarnet and cidofovir to control her acyclovir-resistant strains of herpes simplex virus.

Foscarnet is a fairly effective treatment for resistant genital herpes. Resistance to acyclovir can disappear several weeks after stopping acyclovir and sensitivity to foscarnet can persist during the several weeks of treatment with significant benefit in lesion healing, viral shedding, and pain reduction.² Clinically significant resistance to foscarnet may occur in immunosuppressed patients with prior foscarnet exposure. Addition or substitution of acyclovir to foscarnet therapy may be a useful strategy for patients in whom foscarnet resistance is suspected. Studies have found acyclovir sensitivity in foscarnat resistent isolates.³

Kessler, et al. reported efficacy of topical trifluridine, which is also known as trifluorothymidine, in an open label study involving 26 patients with severe refractory cutaneous HVS infections. They noted complete healing in 29% of patients, with an additional 29% having greater than 50% reduction in lesion area.⁴

Given the limited options for the treatment of acyclovir resistant herpes simplex disease, cidofovir may be a useful alternative in selected patients. This drug, a nucleotide analogue with in vitro activity against herpes viruses, is approved for intravenous administration for cytomegalovirus retinitis. It has been reported to be effective for severe acyclovir resistant perirectal HSV infections.⁵ Lalexari, et al. reported a case with 95% healing after four weekly infusions. Nephrotoxicity is a potential complication with parenteral use of this potent antiviral drug, and it should be administered with oral probenecid after prehydration to minimize adverse effects.⁶

Topical administration of cidofovir is even more promising. A randomized, double blinded placebo controlled trial found substantial efficacy and minimal toxicity.⁵ Ten of twenty patients treated with topical cidofovir for five days had either complete healing (six) or greater than 50% reduction in lesion area (four) within 21 days, versus 0% of patients receiving placebo. This clinical vignette provides additional supporting evidence for this new treatment.