Genital herpes simplex virus (HSV) may be deceptive in HIV-infected patients . Chronic HSV infection masquerading as carcinoma vegetans was first described in 1983 by Leming et al. . Thirty-three cases in HIV-infected patients [3–22] and seven in immunocompromised patients without HIV infection [2,23–28] have since been published. We report five new HIV-related cases, focusing in treatment options and long-term follow-up.
Between 2007 and 2009, we identified five cases of pseudotumoral herpes in a cohort of more than 500 HIV-infected patients. Tumoral lesions with HSV infection documented by PCR and immunochemistry on a proper excisional biopsy specimen, with histological features excluding invasive carcinoma, were considered to be pseudotumoral herpes. Clinical data were extracted retrospectively.
The patients studied were four women and one man, aged from 39 to 48 years, all originally from Congo. Highly-active antiretroviral therapy had increased their CD4 cell counts to 154–616 cells/μl, and the virus had been undetectable for the last 6 months. All patients reported previous recurrent genital herpes.
The four women had vulval tumors, with three bifocal perineal localizations. The man had a tumor at the base of the penis that recurred in the perianal area and the groin. The location often changed between recurrences in a given patient. The lesions ranged from 1.5 to 7 cm in diameter.
During the median follow-up period of 3.3 years, all patients presented recurrences, despite surgical excision and/or drug treatment. No event was correlated with CD4 cell count. Recurrences and initial lesions often occurred at different sites. Clinical responses differed considerably between patients and recurrences. The size of the lesion was not predictive of the effect of drug treatment.
Recurrences were observed in all four cases treated by complete local excision, with a disease-free period of 1 month to 4 years.
Oral nucleoside analogs (2–3 g/day valacyclovir) were initially administered to all patients, with no improvement. Case 1 received high doses of intravenous acyclovir (15 mg/kg/8 h for 15 days), but two courses of this treatment did not result in complete remission.
Intravenous foscavir treatment was successful in four patients, who received 80 mg/kg/day until complete remission, with a maximum of 4 weeks of treatment. Complete remission was observed after 15 days (cases 2, 3 and 5), 1 (case 3) and 2 months (case 1; Fig. 1a and b). The disease-free period lasted from 0 to 2 years.
Three cases received topical treatment with 1% cidofovir, which was applied to lesions, 5 days per week, until complete remission. This drug was used alone (cases 1 and 2) or in combination with valacyclovir (cases 1 and 4). Complete remission was achieved in three patients, after 1–3 months of treatment. A recurrence occurred in one patient after 7 months (case 1), but the reinitiation of topical cidofovir treatment led to secondary cure.
Thalidomide (100 mg/day for 1.5 months) cured recurrences in two cases (Fig. 1c,d), but with one dissociated response in a bifocal tumor. Imiquimod was used in combination with valacyclovir in one case, with the complete resolution of two of the three lesions.
Foscavir was not given in case 4 because renal failure had occurred during previous treatment with foscavir for chronic genital herpes. No adverse effects of any of the treatments used were reported during this study.
It is difficult to compare the results of different studies because diverse treatments are administered and follow-up times are short . Whatever the treatment, lesions often recur in the longer term.
Surgery provides immediate resolution of the lesion but does not protect against short-term recurrence, with possible problems of surgical closure in cases of large and/or periorificial lesions . In our opinion, drugs should, therefore, be preferred for first-line treatment.
Nucleoside analogs are the approved first-line treatment for HSV infection. Unfortunately, such treatments decrease the size of most pseudotumoral lesions but do not eliminate them completely. This persistence of tumors may be accounted for by the presence of mixed resistant and wild populations of HSV , and may explain why acyclovir continues to be efficient at preventing other forms of herpes.
For patients displaying either resistance or an inadequate response to nucleoside analogs, intravenous foscarnet is recommended. We report the largest ever series of cases of pseudotumoral herpes treated with foscavir. Our experience and published findings suggest that this drug should be offered as a first-line intravenous treatment.
Topical treatments have been developed because relapses are frequent and systemic treatments have potential side effects. Topical applications of 1–2% cidofovir and 2.4% foscarnet have been reported to be effective. We consider such treatments to be of potential value when used in combination and/or in relay with systemic antiviral treatment. Immunomodulation treatments have also recently been tested. Interferon-α is produced principally by plasmacytoid dendritic cells, which are lacking in patients with AIDS; this cytokine plays a critical role in the control of viral infection. Imiquimod has been successfully used in three published cases [16,18] and in case four reported here.
Thalidomide is known to downregulate proinflammatory cytokines and to be antiangiogenic, antiproliferative and proapoptotic. Following the successful treatment of recurrent aphthous ulceration in HIV-infected patients  with thalidomide, this drug was successfully used to treat five HIV-infected individuals with genital hypertrophic herpes , and two further cases treated by us. As thalidomide may exacerbate the immunodeficiency associated with HIV and/or the secondary effects of some antiviral drugs, we restrict its use to cases of resistance to systemic antiviral drugs and multiple recurrences.
Finally, if the lesion does not regress rapidly despite the use of these various drug treatments, surgery should be carried out to prevent the misdiagnosis of carcinoma.
In HIV-infected patients with a good immune status and recurrent genital herpes, pseudotumoral herpes should be considered on the basis of a proper excisional biopsy, in the differential diagnosis of anogenital carcinoma, to prevent unnecessary major surgery. The disparity of the results obtained for treatments that were only temporarily curative and the short follow-up period for this series made it impossible to draw firm conclusions about treatment. However, we suggest that drugs should be favored as a first-line treatment, with surgery limited to small or resistant lesions.
Clinical investigators: D.L.C.J., J.S., G.L., M.J.P., D.A., A.M.F., D.N.
Referent pathologist: P.F.
Referent for viral analysis: L.H., R.F.
Conflict of interest
There are no conflicts of interest.
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