Imiquimod 5-percent cream does not alter the natural history of recurrent herpes genitalis: a phase II,randomized, double-blind,placebo-controlled study

Present strategies for control of herpes genitalis recurrences require multiple daily doses of antiviral medication. Imiquimod, an immune response modifier, induces alpha interferon and interleukin-12; application in the presence of local herpes antigens during a recurrence may augment herpes simplex virus (HSV)-specific cell-mediated immunity. To test this theory, we performed a randomized, double-blind, placebo-controlled study of imiquimod 5% cream to assess safety and efficacy for decreasing recurrences. Patients with six or more recurrences of herpes genitalis per year applied study cream (imiquimod or placebo) to lesions one, two, or three times per week for 3 weeks for each recurrence during a 16-week treatment period. This was followed by a 16-week observation period. Of 124 patients randomized to the study, 103 completed the treatment period and 93 completed the observation period. The median times to first genital herpes recurrence were 53 days for those receiving placebo (n = 30) and 54, 60, and 64 days for those receiving imiquimod one time per week (n = 34), two times per week (n = 32), and three times per week (n = 28), respectively. The median annualized recurrence rates during the treatment period were 3.8, 4.9, 3.2, and 3.1, respectively. There were no statistically significant differences in the time to first recurrence or in the annualized recurrence rate between the imiquimod and placebo groups in either the treatment or the observation period. A trend in increased rates of local adverse events at the application site and a delay in lesion healing with more frequent dosing suggested a pharmacologic effect. Although clinical efficacy has been observed for imiquimod in other conditions in which a TH1-type immune response may be beneficial, including other viral infections such as those caused by human papillomavirus, no apparent effect on the short-term natural history of herpes genitalis recurrences was observed.     

Comparison of intramuscular recombinant alpha interferon (rIFN-2A) with topical acyclovir for the treatment of first-episode herpes genitalis and prevention of recurrences.

Intramuscular recombinant alpha interferon (rIFN-2A; 9 million IU given for 5 days during a 9-day treatment period) was compared with topical acyclovir in a double-blind, placebo-controlled trial for the treatment of first-episode genital herpes simplex virus (HSV) infection and for subsequent alteration of the frequency of recurrences. rIFN-2A (within 96 h of onset of the first episode) was not superior to topical acyclovir in a well-matched group of 105 patients. The early use of rIFN-2A also did not alter the frequency or severity of genital HSV recurrences within either the first or second 6 months following therapy. Separate analyses by HSV type and by type of infection (primary versus nonprimary) did not change this conclusion. Furthermore, there was significant toxicity associated with rIFN-2A therapy. rIFN-2A is not indicated for the treatment of genital HSV infections.     

Recurrent genital herpes simplex virus infection in guinea pigs

After recovery from initial genital herpes simplex virus (HSV) infections, female guinea pigs developed spontaneous recurrent infections characterized by discrete erythematous or vesicular herpetic lesions on the external genital skin. HSV type 2 (HSV2) caused significantly more recurrent infections in guinea pigs than did HSV type 1 (HSV1). HSV2-infected animals demonstrated a significant decline in frequency of recurrences over time. The viral nature of the recurrent lesions was confirmed by recovery of infectious HSV, detection of HSV antigen, and histologic examination. Latent HSV2 could be demonstrated in dorsal root ganglia and external genital skin after recovery from the primary infection. Recurrent genital HSV infection in the guinea pig shares many features with recurrent genital herpes in humans and provides a model for studying the relationship between latency and recurrences and for exploring methods for control of recurrent disease.     

Effects of the immunomodulating agent R837 on acute and latent herpes simplex virus type 2 infections.

R837 is an immune modulator with no in vitro activity against herpes simplex virus (HSV). We evaluated topical R837 as therapy for genital HSV type 2 infection using the guinea pig model of this disease. Furthermore, we investigated the effect of R837 therapy on acute and latent neural HSV infections. Therapy initiated 12 h after viral inoculation and given twice a day significantly reduced the acute neural infection so that HSV was recovered from only 1 of 64 neural tissue specimens obtained from R837 recipients compared with 43 of 56 specimens obtained from placebo recipients (P less than 0.0001). R837 initiated 36 h after HSV inoculation and given once a day also significantly reduced the total mean lesion score of the acute disease from 14.1 +/- 4.3 to 2.6 +/- 5.3 (P less than 0.0001) and shortened the period of vaginal HSV shedding from 6.9 +/- 1.7 to 3.2 +/- 1.4 days (P less than 0.001). R837-treated animals also developed fewer HSV recurrences than did controls (2.0 +/- 1.7 versus 5.1 +/- 1.7; P less than 0.0002). Latent HSV was detected in 23 of 24 dorsal root ganglia explant cultures from placebo recipients but in only 2 of 30 cultures from R837-treated animals, and HSV in these 2 cultures was detectable only with the addition of a demethylating agent. Topical R837 exhibited in vivo anti-HSV activity, reducing both acute and latent neural infections as well as acute and recurrent genital disease.     

Civamide (cis-Capsaicin) for Treatment of Primary or Recurrent Experimental Genital Herpes

Neuropharmacologic agents able to disrupt normal virus-neuron interactions may provide an alternative strategy for the treatment of herpes simplex virus (HSV) infections. We have previously shown that prophylactic treatment with capsaicin, a natural compound that alters function in sensory neurons, can protect guinea pigs against cutaneous HSV disease, even though the compound has no direct antiviral activity. Here we have examined the ability of civamide, the cis isomer of capsaicin, to interfere with HSV disease. We show that, even when the onset of treatment was delayed until after intravaginal virus challenge, primary genital skin disease severity was significantly reduced. In addition, animals treated during primary infection subsequently experienced a long-lasting reduction in recurrent disease. Civamide treatment during latent infection also significantly reduced recurrent disease, although for a shorter period. Further a single weekly treatment with civamide during latent infection was sufficient to reduce recurrent disease, indicating that an infrequent suppressive maintenance therapy might be possible.     

Current and potential uses of imiquimod

Imiquimod, an imidazoquinoline amine, is an immune response modifier first FDA-approved for the treatment of external genital and perianal warts in 1997. Since its appearance on the market, its antiviral and antitumor properties have been used in the treatment of a variety of dermatologic conditions. In this review article, the basic mechanism of action of imiquimod, current FDA-approved and non-FDA-approved uses of imiquimod, and key points of medication application frequency, possible adverse effects, and use in combination therapy are discussed. Common skin conditions that may be eradicated with imiquimod are emphasized.     

Assessment of a selective inhibitor of herpes simplex virus thymidine kinase (L-653,180) as therapy for experimental recurrent genital herpes.

Herpes simplex virus (HSV)-coded thymidine kinase (TK) is important in efficient reactivation of latent infection. These studies were designed to investigate whether treatment of latently infected animals with a TK inhibitor altered the natural history of recurrent HSV disease. 9-([(Z)-2-(hydroxymethyl)cyclohexyl]methyl) guanine (L-653,180) is a potent and selective nonsubstrate inhibitor of HSV TK which can suppress or delay reactivation of HSV-1 from latently infected cells in vitro without affecting viral replication. In an initial study, six female Hartley guinea pigs were treated with L-653,180 in their diet (25 mg/30 g of food) and water (300 mg/liter) for 7 days. Blood, urine, kidney, liver, spinal cord, and cerebral cortex specimens were collected. L-653,180 was detected in all specimens at concentrations which, although low, were higher than the in vitro 50% inhibitory concentration of the drug against HSV TK. In the second study, 20 female Hartley guinea pigs were randomized into two groups following recovery from primary genital HSV-2 infection. One group received L-653,180 in diet and water for 4 weeks beginning 21 days postinoculation. Animals were examined daily for recurrent lesions for 10 weeks. Treated animals experienced fewer recurrences during the treatment period but the results were not significantly different from results with controls. During the first 2-week posttreatment period, L-653,180-treated animals had significantly fewer recurrences than control animals (P = 0.02). Over the entire 10-week observation period, treated animals experienced fewer recurrences (P = 0.06). These results suggest that inhibitors of viral TK may be useful in limiting reactivation of latent virus and thus recurrent infections. In these experiments, the amount of drug that could be administered to the animals was limited by its poor solubility. Further studies with more potent and soluble inhibitors of HSV TK appear to be warranted.     

Imiquimod, a Patient-Applied Immune-Response Modifier for Treatment of External Genital Warts

Genital human papillomavirus infection is one of the most common sexually transmitted diseases. Imiquimod is a new agent, an immune-response modifier, that has been demonstrated to have potent in vivo antiviral and antitumor effects in animal models. The present prospective, multicenter, double-blind, randomized, vehicle-controlled trial evaluated the efficacy and safety of daily patient-applied imiquimod for up to 16 weeks for the treatment of external genital warts. Wart recurrence was investigated during a 12-week treatment-free follow-up period. In the intent-to-treat analysis, baseline warts cleared from 49 of 94 (52%) patients treated with 5% imiquimod cream, 13 of 90 (14%) patients treated with 1% imiquimod cream, and 3 of 95 (4%) vehicle-treated patients; the differences between the groups treated with vehicle and imiquimod were significant (P < 0.0001). For subjects who completed the follow-up period, recurrence rates after a complete response were 19% (9 of 48 patients) in the 5% imiquimod cream group, 17% (2 of 12) in the 1% imiquimod cream group, and 0% (0 of 3) in the vehicle-treated group. There were no systemic reactions, although local skin reactions (generally of mild or moderate severity) were common, particularly in the 5% imiquimod cream group. Local reactions caused two patients to discontinue treatment. The most frequently reported local skin reactions were erythema, excoriation or flaking, and erosion. Patient-applied 5% imiquimod cream is effective for the treatment of external genital warts and has a favorable safety profile.     

Valacyclovir for the treatment of genital herpes

Genital herpes is the most prevalent sexually transmitted infection in the USA. While sometimes mild in severity, it can be a distressing and painful chronic condition. Likewise, herpes labialis and herpes zoster can be both physically and psychologically painful. While there is no cure for these conditions, treatment to alleviate symptoms, suppress recurrences and reduce transmission has been drastically improved over the past 20 years with the use of guanine nucleoside antivirals, such as valacyclovir hydrochloride (Valtrex), GlaxoSmithKline) the highly bioavailable prodrug of acyclovir (Zovirax((R)), GlaxoSmithKline), and famciclovir (Famvir, Novartis), a highly bioavailable prodrug of penciclovir (Denavir, Novartis). Clinical trials involving approximately 10,000 patients (including patients from nongenital herpes studies, such as herpes zoster) have assessed the safety and efficacy of valacyclovir in the treatment of initial genital herpes outbreaks, episodic treatment of recurrent episodes and daily suppressive therapy. It was shown that valacyclovir has similar efficacy to acyclovir in the episodic and suppressive treatment of genital herpes. Valacyclovir is the only antiviral drug approved for a once-daily dose of suppressive therapy for genital herpes, as well as the only antiviral drug US FDA approved for a 3-day regimen of episodic treatment of recurrent genital herpes. In addition, valacyclovir is also indicated in the reduction of the sexual transmission of herpes simplex virus infection and for the treatment of herpes labialis. In herpes zoster, valacyclovir is more effective than acyclovir or placebo (and as equally effective as famciclovir) in shortening the length and severity of herpes zoster-associated pain and postherpetic neuralgia. Valacyclovir has an acceptable safety profile in patients with herpes simplex and herpes zoster. The less frequent dosing regimen makes it an attractive option in the treatment of genital herpes and other viral infections, and may contribute to increased patient adherence to therapy.     

Herpes simplex and varicella zoster virus infections

Herpes simplex virus (HSV) and varicella-zoster virus (VZV) are both human alpha-herpes viruses. They are capable of establishing latent infections in neural tissues and to reactive from these sites, determining the clinical features of the disease (primary infection versus recurrences). Infections with these viruses are common; an increased number of elderly and immunocompromised individuals will likely lead to an even higher prevalence. HSV infection--in its typical form characterized by grouped vesicles--is frequently inapparent or atypical in both primary and recurrent disease. The clinical spectrum is wide, ranging from trivial labial blisters to the most severe fatal sporadic encephalitis and neonatal infection. Seroprevalence studies in the Western world demonstrate a much higher percentage of people infected with HSV-2 than are currently identified by clinical studies. Since undiagnosed genital herpes infections are the major factor in fueling the genital herpes epidemic, awareness and more accurate diagnosis followed by therapy and counseling are mandatory. Primary VZV infection and herpes zoster are usually diagnosed clinically, but can be confirmed by virus detection methods from swabs of lesions or antibody tests. Antiviral therapy should be considered in varicella if the disease is complicated. In herpes zoster antiviral therapy should be given within 72 hours in immunocompromised patients and those at risk of postherpetic neuralgia. The availability of effective antiviral therapy makes early diagnosis most important.     

Frequent genital herpes simplex virus 2 shedding in immunocompetent women. Effect of acyclovir treatment.

Reactivation of herpes simplex virus type 2 (HSV-2) occurs intermittently as perceived clinically and by viral culture. We performed a series of studies to evaluate the frequency and pattern of HSV-2 reactivation using both viral isolation and HSV PCR assay. Daily samples of genital secretions were obtained from 27 HSV-2 seropositive women; a subset of subjects obtained samples while receiving oral acyclovir 400 mg PO twice a day. HSV DNA was detected in genital swab specimens on 28% of 1,410 d compared with 8.1% of days by viral isolation. 11 of 20 women had HSV DNA detected on > 20% of days, 4 on > 50%, and 2 on > 75% of days; in contrast, none of the women shed on > 21% of days by viral isolation. The daily administration of oral acyclovir promptly reduced the frequency of HSV DNA detection by a median of 80%. Within 3-4 d of discontinuing daily acyclovir, HSV DNA again appeared in the genital area. HSV-2 shedding in the genital mucosa occurs much more frequently than previously appreciated. This frequent reactivation likely plays a role in the epidemic spread of genital herpes worldwide.     

Therapy of genital herpes with topically applied interferon.

Ninety-four patients with recurrences of genital herpes were randomized in a double-blind trial to receive topical therapy for 5 days with either alpha-2a interferon at 30 X 10(6) IU/ml or 10 X 10(6) IU/ml or placebo six times daily. No differences were noted between either interferon dose and placebo with respect to the duration of viral shedding, the time to crusting, or the time to healing of herpetic lesions. Aqueous solutions of alpha-2a interferon applied topically to unroofed vesicles do not appear to be clinically useful in the treatment of recurrences of genital herpes.     

Management of genital warts

Genital warts caused by human papillomavirus infection are encountered commonly in primary care. Evidence guiding treatment selection is limited, but treatment guidelines recently have changed. Biopsy, viral typing, acetowhite staining, and other diagnostic measures are not routinely required. The goal of treatment is clearance of visible warts; some evidence exists that treatment reduces infectivity, but there is no evidence that treatment reduces the incidence of cervical and genital cancer. The choice of therapy is based on the number, size, site, and morphology of lesions, as well as patient preferences, cost, convenience, adverse effects, and clinician experience. Patient-applied therapy such as imiquimod cream or podofilox is increasingly recommended. Podofilox, imiquimod, surgical excision, and cryotherapy are the most convenient and effective options. Fluorouracil and interferon are no longer recommended for routine use. The cost per successful treatment course is approximately dollars 200 to dollars 300 for podofilox, cryotherapy, electrodesiccation, surgical excision, laser treatment, and the loop electrosurgical excision procedure.     

咪喹莫特治疗支气管哮喘的动物实验研究

目的 :研究咪喹莫特治疗支气管哮喘的疗效及可能的机制。方法 :建立豚鼠哮喘模型 ,随机分为 :①对照组 (哮喘组 ) ;②咪喹莫特吸入组 ;③咪喹莫特灌胃组 ;④咪喹莫特外用组 ;⑤安慰剂组。治疗 2周后 ,支气管肺泡灌洗液 (BALF)及肺组织 ,分别测定外周血IgE ,支气管肺泡灌洗液 (BALF)细胞计数、分类 ,计数肺组织切片 0 1～ 0 3mm范围的支气管壁嗜酸性粒细胞 (EOS)、淋巴细胞 (L)数。结果 :咪喹莫特治疗组外周血IgE值 ,BALF细胞计数、EOS分类及 0 1～ 0 3mm支气管周围EOS计数、L计数与对照组间或安慰剂组间有统计学意义 (P <0 0 5 ) ,而BALFL分类百分比 ,治疗组与对照组间或安慰剂组间无统计学意义。咪喹莫特治疗组间IgE值、BALF计数、EOS分类、支气管旁EOS计数、L计数方差分析均有统计学意义。 结论 :咪喹莫特能显著减轻支气管肺周围的炎性细胞的浸润 (主要表现为下调EOS与L数、EOS百分率和IgE)。咪喹莫特吸入可能是治疗支气管哮喘的一种新方法。     

Clearance of HSV-2 from recurrent genital lesions correlates with infiltration of HSV-specific cytotoxic T lymphocytes.

The mechanisms involved in host clearance of symptomatic mucocutaneous herpes simplex virus (HSV) infection are unclear. We studied the functional properties of bulk cultures of skin-infiltrating lymphocytes from normal skin and serial biopsies of recurrent genital HSV-2 lesions, and compared HSV-specific and NK responses with viral clearance. HSV-specific CD4+ or CD8+ T cells were rarely detected in lymphocytes cultured from normal skin. The total lymphocyte count and HSV-specific and NK-like effector cell activities were markedly higher in cultures derived from lesional skin. HSV-specific CD4+ proliferative responses and NK-like cytotoxic responses were present at all stages of herpetic lesions, including biopsies early in the disease course. In contrast, cytotoxic T lymphocyte activity was generally low among cells derived from early culture-positive lesions, and increased during lesion evolution. Viral clearance from the lesion site was associated with a high level of local cytolytic activity towards HSV-infected cells. The phenotypes of cells with HSV-specific cytotoxic responses varied between patients, having CD4+ and CD8+ components. Immunotherapeutic approaches to HSV should be directed at improving in vivo cytolytic activity to HSV.     

Acyclovir susceptibilities of herpes simplex virus strains isolated from solid organ transplant recipients after acyclovir or ganciclovir prophylaxis.

We determined the acyclovir (ACV) susceptibilities of herpes simplex virus (HSV) isolates (n = 18) recovered from solid organ transplant patients after antiviral prophylaxis with ACV or ganciclovir. All isolates tested were susceptible to ACV (50% inhibitory concentration, < 1 microM). A clinical review of patients with HSV disease showed that all improved with specific anti-HSV therapy, and no recurrences were reported.     

Current therapy for Behçet's disease

Classified among the vasculitides, the clinical spectrum of Beh?et's disease (BD) ranges from a mild mucocutaneous disease to a life-threatening systemic vasculitis, characterized by remissions and recurrences. The major morbidity is recurrent eye inflammation that may lead to blindness, but severe central nervous system, gastrointestinal, or vascular involvement may occur and might be fatal. In contradistinction to most other vasculitides, the venous system is commonly affected in BD. The treatment of BD is usually symptomatic and palliative. This includes topical steroids for orogenital ulcers, nonsteroidal antiinflammatory agents for joint involvement, and colchicine as prophylaxis against disease flares (although evidence that colchicine prevents recurrences of oral and genital ulcers is restricted to female patients). Immunosuppressives and cytotoxic agents are used for more severe involvement, and thalidomide and interferon have attracted attention in recent years.     

Treatment of common cutaneous herpes simplex virus infections

Herpes simplex virus infection is increasingly common in the United States. New antiviral medications have expanded treatment options for the two most common cutaneous manifestations, orolabial and genital herpes. Acyclovir therapy remains an effective and often less expensive option. Famciclovir and valacyclovir offer improved oral bioavailability and convenient oral dosing schedules but are more expensive than acyclovir. Patients who have six or more recurrences of genital herpes per year can be treated with one of the following regimens: acyclovir, 400 mg twice daily; valacyclovir, 1 g daily; or famciclovir, 250 mg twice daily. These regimens are effective in suppressing 70 to 80 percent of symptomatic recurrences. Episodic treatment of recurrent genital herpes is of questionable benefit, but it may be helpful in appropriately selected patients. There is little evidence indicating benefit from treatment of recurrent orolabial herpes, which tends to be mild and infrequent.     

Superior efficacy of helicase-primase inhibitor BAY 57-1293 for herpes infection and latency in the guinea pig model of human genital herpes disease

The efficacy of BAY 57-1293, a novel non-nucleosidic inhibitor of herpes simplex virus 1 and 2 (HSV-1 and HSV-2), bovine herpesvirus and pseudorabies virus, was studied in the guinea pig model of genital herpes in comparison with the licensed drug valaciclovir (Valtrex). Early therapy with BAY 57-1293 almost completely suppressed the symptoms of acute HSV-2 infection, and reduced virus shedding and viral load in the sacral dorsal root ganglia by up to three orders of magnitude, resulting in decreased latency and a greatly diminished frequency of subsequent recurrent episodes. In contrast, valaciclovir showed only moderate effects in this set of experiments. When treatment was initiated late during the course of disease after symptoms were apparent, that is, a setting closer to most clinical situations, the efficacy of therapy with BAY 57-1293 was even more pronounced. Compared with valaciclovir, BAY 57-1293 halved the time necessary for complete healing. Moreover, the onset of action was fast, so that only very few animals developed new lesions after treatment commenced. Finally, in a study addressing the treatment of recurrent disease in animals whose primary infection had remained untreated BAY 57-1293 was efficient in suppressing the episodes. In summary, superior potency and efficacy of BAY 57-1293 over standard treatment with valaciclovir was demonstrated in relevant animal models of human genital herpes disease in terms of abrogating an HSV infection, reducing latency and the frequency of subsequent recurrences. Furthermore, BAY 57-1293 shortens the time to healing even if initiation of therapy is delayed.