Treatment of recalcitrant herpes simplex virus with topical imiquimod

Herpes simplex virus (HSV) is a common, easily transmissible virus. There is growing awareness of acyclovir-resistant HSV particularly among immunocompromised patients, which may be due to protracted treatments with guanosine analogues. Given the considerable morbidity associated with other classes of antiherpetic medications such as foscarnet (renal impairment, seizures) and cidofovir (renal impairment, neutropenia), imiquimod, a toll-like receptor agonist that enhances the innate immunologic responses against the virus, has been utilized in treating acyclovir-resistant HSV. We present a case of a human immunodeficiency virus (HIV)-positive patient who was successfully treated with topical imiquimod after treatment failures with other oral antivirals.     

Treatment of mucocutaneous presentations of herpes simplex virus infections

Infections by herpes simplex virus (HSV) types I and II are diverse and quite frequent. After primary infection, the virus establishes a life-long latency in the sensory ganglia and recrudescences may occur at an unpredictable rate. Recurrent labial and genital herpes infections represent the majority of clinical manifestations of HSV infections. Their management is currently well established using evidence-based medicine data. Primary labial herpes is generally not treated with antivirals in otherwise healthy children, although intravenous aciclovir may be offered in severe primary infections, particularly in the immunocompromised patient. The decision whether or not to treat recurrent labial herpes should be evaluated individually and depends on the frequency and severity of relapses, the impairment of the quality of life, and the cost of therapy. Patients with mild disease may benefit from topical therapy, and those with severe and frequent recurrences may be considered for intermittent or long-term oral antiviral therapy. Primary genital herpes is treated with oral or intravenous antivirals, depending on the severity of the infection and associated symptoms. Recurrent genital herpes can be managed with episodic short courses of oral antivirals in patients whose recurrences are moderate to severe and rare, and have a clear prodrome. Patients with >5 episodes/year, severe recurrences or unrecognisable prodromes may be best managed with long-term suppressive antiviral prophylaxis. HSV is also responsible for a variety of other clinical manifestations, including herpetic whitlow, neonatal infection, disseminated and atypical cutaneous infections, traumatic herpes, eczema herpeticum, and HSV-associated erythema multiforme. HSV infection may also represent a complication following cosmetic procedures of the oro-facial region, surgical and dental interventions, sun exposure and burns. Precise treatment guidelines for these HSV infections are not firmly established.     

Antigen presentation in patients with recrudescent orofacial herpes simplex virus infections

Recovery from epidermal herpes simplex virus (HSV) infection depends primarily on development of an effective cell-mediated immune response, possibly generated following antigen (Ag) presentation by epidermal cells (EC). The ability of EC to present HSV Ag was investigated in 12 subjects with occasional recrudescent facial HSV infections. All had circulating HSV specific antibodies and cell-mediated immunity to the virus. Peripheral blood mononuclear cell suspensions, depleted of antigen presenting cells (APC) by glass adherence and then enriched for T cells by adsorption on nylon wool columns, did not proliferate in response to HSV Ag. Both EC suspensions, prepared from suction blister roofs, and glass-adherent peripheral blood mononuclear cells (AC) preincubated with ultraviolet-inactivated HSV, reconstituted the T-cell proliferative response to HSV. EC were more efficient than AC at presenting HSV Ag to T cells. Depletion of CD1+ cells from EC suspensions by cell sorting reduced their ability to present HSV Ag and augmentation of CD1+ cell numbers supplemented it. Preincubation of EC or AC with monoclonal antibodies to major histocompatibility complex class II antigens DP, DQ or DR, blocked the lymphoproliferative response to HSV Ag. Evidence was obtained that cells co-ordinately expressing products of the DP, DQ and DR loci are involved in presentation of HSV Ag by both EC and AC.     

Efficacy of cidofovir in an HIV infected patient with an acyclovir and foscarnet resistant herpes simplex virus infection]

BACKGROUND: We report the case of an AIDS patient, whose persistant HSV2 ulceration was clinically and phenotypically resistant to acyclovir and foscarnet. Only five clinical isolates of simultaneous acyclovir and foscarnet resistance have been previously described. CASE REPORT: This patient, without history of opportunistic infection, was hospitalized for a recurrent scrotal ulceration resistant to several antiviral treatment such as acyclovir, valacyclovir or foscarnet. The CD4 count was stable at 150/mm(3) and the HIV viral load was below detection level. The last recurrence appeared rapidly under valacyclovir therapy which had been introduced after 65 days of foscarnet therapy. Thus, the patient received a new dose of foscarnet. After initial efficacy, the ulceration increased once again. HSV2 phenotypic determination was done and detected, at that time, a double resistance to acyclovir and foscarnet. Healing was obtained with intravenous cidofovir. DISCUSSION: Foscarnet and acyclovir resistance in an HSV2 isolate is rare. This report presents several particularities. First, whereas the earlier published patients with an acyclovir and foscarnet resistant strain were widely immunocompromised, this was not the case for our patient. Secondly, in contrast with most precedent observations in which acyclovir-resistant strain disappeared after foscarnet therapy, in our case the acyclovir resistant strain remained after foscarnet therapy. Finally, few reports concerned the clinical efficacy of cidofovir in HSV infection. In this case, we proved that intravenously cidofovir was highly and rapidly effective on acyclovir and foscarnet resistant strains.     

Detection of cutaneous herpes simplex virus infections by immunofluorescence vs. PCR

BACKGROUND: Detection of cutaneous infections with herpes simplex virus (HSV) has proven difficult, as serum antibody tests sometimes are not sensitive and specific enough for that purpose. OBJECTIVE: This study was conducted to compare the sensitivity for detection of HSV of an immunofluorescence method (Syva Microtrak) and an internally controlled PCR. METHODS: Cutaneous swabs from skin lesions were analysed by immunofluorescence separately for HSV types 1 and 2 and by competitive PCR. Detection of PCR products was done by ELISA, if positive additionally by agarose gel electrophoresis. RESULTS: Of 79 samples 34 were PCR-positive by ELISA (34 = 100%), of which 23 (68%) were also positive on the agarose gel. Eleven samples (32%) were positive by immunofluorescence. No sample was positive by immunofluorescence and negative by PCR. CONCLUSIONS: These results demonstrate that immunofluorescence using Syva Microtrak is not suitable for exclusion of herpes simplex virus infection as sensitivity was only 32%. However, as immunofluorescence is cheaper and faster than PCR, first screening can be done with immunofluorescence, and negative samples can be investigated by PCR to finally prove or exclude the presence of HSV DNA.     

Cimetidine therapy of herpes simplex virus infections in immunocompromised patients

Five severely immunocompromised patients with progressive mucocutaneous manifestations of culture-proven herpes simplex virus infection were treated with cimetidine—1200 mg per day by mouth (four patients) or by i.v. infusion (one patient). Treatment resulted in rapid improvement as evidenced by decreased local pain and crusting of lesions within 24–48 h. Complete resolution was observed within 3–13 days. These encouraging, albeit preliminary, findings suggest that cimetidine warrants further, large-scale trials in patients with herpes virus infections.     

Relation between herpes simplex viruses and human immunodeficiency virus infections

The rates of herpes simplex virus (HSV) infection are rising, the highest prevalence being in the group infected with the human immunodeficiency virus (HIV). We review the relation between these 2 infections. The presence of genital ulcers increases the transmission of HIV, and the presence of HIV adversely affects the natural history of HSV infection. The detection and treatment of sexually transmitted diseases such as genital herpes actually decrease the rates of HIV infection in groups studied. The treatment of HSV in persons with HIV is challenging because the incidence of immunosuppression increases. Acyclovir resistance is more common in this group, but acyclovir use may prolong survival in some HIV-seropositive patients. Further studies are needed to determine whether persons with HIV disease should routinely be given HSV-specific therapy.     

Topical cidofovir for severe cutaneous human papillomavirus and molluscum contagiosum infections in patients with HIV/AIDS. A pilot study

BACKGROUND: Cidofovir is a nucleoside analogue of deoxycytidine with a strong activity against several DNA viruses, including herpes, pox and human papilloma virus (HPV). MATERIAL AND METHODS: Fourteen acquired immunodeficiency syndrome patients, 10 with extensive HPV lesions and four with molluscum contagiosum (MC) infections, unresponsive to conventional therapies, were treated with a cream containing cidofovir 1%. All the subjects had been on treatment with highly active antiretroviral therapy for almost 1 year before starting the cream. Measured end-points of therapy were efficacy, tolerability, side-effects and freedom from recurrence. RESULTS: Thirteen of the 14 patients (92.8%) completed the therapy, one dropped out. These 13 eventually cleared their MC or warts, over varying periods of time. In nine, the lesions regressed 2 weeks from the end of the first cycle of therapy. Three patients needed two cycles and the last three consecutive courses of topical therapy before the cutaneous lesions healed. No recurrence was observed in nine patients over an average follow-up period of 24.1 months (range 12-30 months). Four patients had isolated relapses, which were successfully treated with simple curettage. SIDE-EFFECTS: All the patients experienced side-effects where they applied the cream. Inflammation, erosion and a burning sensation were the most frequent. Postinflammatory hyperpigmentation was observed in six cases, while two developed a transient alopecia on the beard area. No systemic side-effects or alteration of laboratory data were noted. CONCLUSION: Cidofovir appears to offer an effective therapeutic alternative option for lesions that are unresponsive to conventional methods. Appropriate clinical trials are required, however, to confirm the true efficacy and safety of topical cidofovir.     

The difficulty in diagnosis of cutaneous herpes simplex virus infection in patients with AIDS

Three patients with AIDS are described with atypical manifestations of cutaneous herpes simplex virus infection. This infection should be considered in the immuno-suppressed patient with persistent or bizarre cutaneous ulceration despite negative virological cultures, and in the acutely ill patient with a generalized rash.     

Treatment of mucocutaneous herpes simplex infections

Herpes simplex virus (HSV) infections are common, unpleasant, and occasionally dangerous. This has led patients and their doctors to try almost anything to shorten episodes or suppress recurrences. Despite occasionally positive anecdotal experiences, it has been difficult to assess the efficacy of many of these treatments because of the highly variable severity, duration, and frequency of episodes of herpes in individual patients,^1–5 the enormous placebo effect of any new therapy,^6,7 and the unreliability of patient perceptions of drug efficacy. The natural history of genital and orofacial HSV infections has only recently been elucidated and many of the early therapeutic trials failed to take into account such features as the differences in duration and severity of primary, initial, and recurrent infection (Table 1). There has also been considerable variability in the choice of parameters of healing used in the various studies. Some trials relied solely on patient observations of severity or duration of lesions while others, more appropriately, have required frequent examination by physicians and/or frequent viral cultures to document resolution of infection.Many therapeutic modalities have been tried in both oral and genital HSV infections. Most agents have been used in an effort to shorten or ameliorate recurrences, although some trials have focused on prevention of primary infection, treatment of first episodes, or suppression of recurrences. The many attempted approaches to therapy of these infections can be divided into several categories: palliation of symptoms, psychosocial support, enhancement of immunity for suppression of recurrences, specific vaccines to prevent primary or recurrent infection, and antiviral agents to prevent or abbreviate virus replication. In addition to these approaches, a wide variety of surfactants, nutritional therapies, and mechanical devices has been used.     

Treatment of recurrent herpes simplex infections with L-lysine monohydrochloride

In a prospective, randomized, double-blind, placebo-controlled, cross-over study of forty-one patients we found that oral ingestion of 1,248 mg a day of L-Lysine monohydrochloride shows evidence of decreasing the recurrence rate of herpes simplex attacks in nonimmunocompromised hosts. A dose of 624 mg a day was not effective. L-Lysine may also be capable of decreasing the severity of symptoms associated with recurrences. Neither dosage showed any evidence of shortening the healing time compared to placebo.     

Chronic mucocutaneous herpes simplex virus and varicella zoster virus infections

Chronic herpes simplex virus (CHSV) and chronic varicella zoster virus (CVZV) are defined as atypical mucocutaneous wart-like and/or ulcerative HSV or VZV infections, persisting for at least 1 month. Both are commonly associated with HIV infection and may occasionally present with other types of immunosuppression. CHSV and CVZV occur despite the immune restoration effect of highly active antiretroviral therapy for HIV. The clinical polymorphism of CHSV and CVZV makes recognition difficult. Histology, immunohistology, PCR and viral culture all help to confirm the diagnosis. Treatment is frequently complicated by resistance to thymidine kinase (TK)-dependent antivirals, including acyclovir, valacyclovir and famciclovir. Viral culture remains an essential tool for antiviral drug susceptibility testing. Therapeutic alternatives include non-TK-dependent antivirals, such as foscarnet or cidofovir, which directly target viral DNA polymerase. With few exceptions, CHSV and CVZV infections do not constitute significant risk factors for disseminated cutaneous or systemic infection. This review compares the similarities of and differences between CHSV and CVZV infections.     

Langerhans cell- and T-lymphocyte functions in patients with atopic dermatitis with disseminated cutaneous herpes simplex virus infection

We studied whether Langerhans cell (LC)- and T-lymphocyte functions of atopic dermatitis (AD) patients are impaired. Our study groups consisted of 6 patients with AD with previous disseminated herpes simplex virus infection (AD + HSV), 8 patients with ordinary AD, and 5 healthy subjects. Suction blisters were performed on abdominal skin and LC isolated on the basis of their attachment to IgG-coated erythrocyte monolayers. Antigen-presenting function of purified LC was studied by measuring the proliferation of HSV-stimulated T cells. Langerhans cells were also used to stimulate T cells in autologous mixed cell reaction (AMCR). In addition, the production of epidermal cell thymocyte-activating factor (ETAF) by crude epidermal cells was measured. The HSV-induced T-cell proliferation in AD + HSV and AD patients was comparable with that of controls. The AMCR responses of patients with AD + HSV and AD were clearly diminished when compared with healthy controls. Patients with AD also produced significantly less ETAF than controls. Our results suggest that HSV antigen-presenting function of LC from patients with AD + HSV seems to be intact. Defective AMCR may reflect an abnormality in autoregulation and generation of effector cells and this together with decreased ETAF production may have pathogenetic significance in AD.     

Immune responses to herpes simplex virus in patients with facial herpes simplex and those with eczema herpeticum

The immune response to herpes simplex virus (HSV) was studied in 59 patients with primary and recrudescent facial HSV infections. The patients included nine with atopic eczema, seven of whom had eczema herpeticum (EH). All patients had antibodies to HSV (measured by ELISA) and all but three had HSV-specific cell mediated immunity (CMI) (measured by in vitro lymphoproliferation). Thirteen control subjects were negative for both tests. All three patients with absent CMI to HSV had suffered from severe EH and had depressed CMI to HSV for several months following an attack. In two of these EH patients, a positive CMI response was produced by in vitro removal of CD8 + ve T lymphocytes from peripheral blood mononuclear cells using a panning technique. Thus the absence of CMI to HSV in these patients was due to suppressor cell function rather than a lack of specifically responsive cells. The other four EH patients with normal CMI to HSV had suffered less severe EH, but no association between the absence of CMI to HSV and serum IgE level or activity of the eczema was apparent in the atopic patients. No specific anti-HSV IgE antibody was detectable.