Atypical presentations of genital herpes simplex virus in HIV-1 and HIV-2 effectively treated by imiquimod

Introduction

Genital herpes simplex virus type 2 (HSV-2) ulcers occur frequently in HIV-positive patients and may have atypical manifestations. Atypical HSV presenting as extensive, hypertrophic or vegetating ulcers have been described either in the context of severe immunosuppression, as part of an immune reconstitution syndrome (IRIS) or in patients stable on combination antiretroviral therapy (cART) with good CD4 counts.^1–3 We describe two HIV-positive patients (one with HIV-2) presenting with hypertrophic genital ulcers which resolved completely with topical imiquimod therapy after failure of multiple anti-viral treatments.

Case 1

A 44-year-old man of West African origin presented with genital ulceration. All cultures (including HSV) and syphilis serology were negative. The ulcers resolved after empirical aciclovir treatment. He was also diagnosed with HIV-2 and hepatitis B co-infection (CD4 60 cells/mm³) but then defaulted care prior to starting cART. Three years later he re-presented with a six-month history of intermittently recurring genital ulceration with a CD4 of 20 cells/mm³, HIV-VL 5200 copies/ml. He had three painless hypertrophic ulcers on his scrotum and one on his penile shaft (Figure 1(a)). He was commenced on aciclovir 800 mg TDS, PCP and MAI prophylaxis and cART (Truvada, darunavir and ritonavir). The ulcers were HSV-2-positive on PCR testing. After four weeks, the ulcers had fully healed and the aciclovir dose was reduced to 400 mg BD. OPEN IN VIEWER

Seven months later the genital ulceration recurred and aciclovir was increased (400 mg TDS). He was on cART with good adherence, CD4 200 cells/mm³ and HIV-VL < 50 copies/ml. The ulcers were again HSV-2 positive on PCR testing and showed no improvement after four weeks of aciclovir. Tests for other STIs including syphilis were negative. Treatment was switched to valaciclovir for two weeks, followed by topical foscarnet cream for three months. However, there was no improvement and the ulcer remained positive for HSV-2 on a PCR swab. A biopsy showed a non-specific inflammatory infiltrate with no viral inclusions seen and no pathogens identified on staining. Further courses of valganciclovir and then topical foscarnet cream were given with minimal improvement. Topical imiquimod therapy was commenced (three times weekly) and the ulcers healed completely after eight weeks of treatment (Figure 1(b)). He suffered a recurrence several months later which also fully responded to a two-week course of imiquimod.

Case 2

A 38-year-old HIV-1-positive African woman established on cART (Atripla): CD4 460 cells/mm³ and VL < 50 copies/ml, presented with a three-week history of a large, tender hypertrophic ulcer on the left labium majus (Figure 1(c)). She was commenced on aciclovir (400 mg TDS for two weeks), and a PCR swab of the ulcer was positive for HSV-2; other STI tests including syphilis were negative. There was minimal response, and treatment was switched to valaciclovir, initially 500 mg BD (for three weeks) and then 1 g BD (for four weeks). The ulcer persisted (still PCR positive for HSV-2) and a biopsy taken at this point showed extensive ulceration with non-specific inflammatory changes; staining for micro-organisms was negative. Further treatment courses of valganciclovir and then topical foscarnet led to minimal improvement over the next 12 months. She was commenced on topical imiquimod (three times a week) and within two months the ulcer had completely resolved (Figure 1(d)).

Discussion

Hypertrophic HSV can give rise to both diagnostic and management conundrums. The differential diagnosis includes malignancy and a variety of infectious causes, with management often complicated by a poor response to first-line anti-viral agents. Descriptions of such cases can be found in the literature but this is the first reported case of hypertrophic genital HSV in a patient with HIV-2. The natural history of HIV-2 disease progression is usually more indolent compared to that of HIV-1. Case 1 was significantly immunosuppressed at presentation and therefore at risk of such florid symptoms. IRIS is an unlikely underlying cause in either of our cases; the ulceration in case 1 appeared prior to the commencement of cART and case 2 was well established on cART with good immune reconstitution.

Resistance of HSV to aciclovir, valaciclovir and famciclovir occurs through thymidine kinase (TK) deficiency. ² TK is needed to convert aciclovir to its active form through phosphorylation. Less commonly, resistance to foscarnet and cidofovir occurs through alteration of the viral DNA polymerase. Clinically, our patients did not respond to aciclovir, valaciclovir, foscarnet or valganciclovir. We were unable to demonstrate resistance as we did not have access to testing for inhibition of HSV replication in vitro in the presence of aciclovir (although consistently PCR positive, attempts to culture the virus were unsuccessful in both cases) or for mutations of the TK or DNA polymerase genes. ³ Cidofovir, intra-venous foscarnet and thalidomide have been shown to be effective in case reports but side effects may limit their clinical usefulness.^4,5

Imiquimod is an agonist for toll-like receptor 7 and triggers an immune response leading to activation of inflammatory cells: monocytes, macrophages and dendritic cells and secretion of pro-inflammatory cytokines. It also stimulates the production of IFNγ, TNFα and IL-12. ⁶ This local immune activation results in resolution of viral lesions such as warts and HSV.^3–11 Reported histology findings have been varied but mainly included epidermal hyperplasia and a dense inflammatory infiltrate consisting of lymphocytes, plasma cells and eosinophils. ³

Our cases support the use of imiquimod for refractory hypertrophic HSV, including treatment of recurrences, as well as being effective in HIV-2 co-infected patients. In both of our cases the ulcers were painless before using imiquimod and the only adverse effect seen was itching over the ulcer on application of imiquimod in the male patient. In most case reports, imiquimod was used three times a week and time to healing ranged from one week to 14 weeks with minimal adverse effects. Recurrences also responded well to topical imiquimod as we observed. As imiquimod acts by stimulating the immune system rather than by a direct anti-viral response, resistance is unlikely to occur. Imiquimod in this setting may be an easy-to-use, fast-acting, effective and relatively cheaper treatment option after failure of first-line aciclovir therapy.