Herpes simplex virus (HSV) is one of the most common viral diseases in humans. HSV exists as two types, Herpes simplex virus 1 (HSV-1) and Herpes simplex virus 2 (HSV-2), both distinguished by clinical manifestations, biological and serological criteria.1 Their characteristic feature is a capacity to establish latency in the host after the initial infection and to reactivate periodically. Major symptoms of active infection include prodromal numbness and tingling around the affected area, induration, erythema, itching, burning, pain in the area, and ulcerated lesions.2,3 In the U.S., over 70-90 percent of adults have the antibody to HSV-1 and approximately 22 percent have the antibody to HSV-2. HSV is the fastest growing infectious disease in the world with 500,000 new cases reported each year. HSV active infections are also associated with enhanced Human Immunodeficiency Virus (HIV) transmission.4-6
Oral and topical Acyclovir preparations are used as the current standard of care for treatment of HSV symptoms, including skin lesions. Acyclovir inhibits the replication of herpes virus via inhibition of the viral DNA polymerase, thus preventing the formation of the DNA replication complex and the elongation of the viral DNA chain. Treatment of recurrent and persistent infections with oral Acyclovir, and with other antivirals including valacyclovir, famciclovir, and penciclovir has resulted in clinical benefit, but also has resulted in the emergence of drug-resistant variants and viruses that are more resistant due to their relative deficiency of viral thymidane kinase or DNA polymerase—especially in immunocompromised individuals.3,7,8 Although resistant strains of HSV do not currently pose a threat, in a number of decades it is likely that resistant strains will replace wild-type strains in treated individuals.9
The primary benefit of topical antiviral treatments thus far has been the reduction in healing time.10 However, topical treatments do not mitigate the immune-mediated response of the host to the virus. In a study done by Shaw et al, little to no clinical benefit was seen when skin infections were treated with topical Acyclo-vir.11 Topical Acyclovir also requires daily application, demands good compliance and is relatively expensive. For these reasons, a novel approach to anti-HSV therapy is desirable. Formulations that enhance natural immune modulation and that cause viral destruction and inactivation would be beneficial. Formulations such as Dynamiclear, which require a single dose application and which do not likely encourage drug-resistant variants or mutation of HSV, may hold promise for this intended effect.7
Natural product formulations may serve as effective antiviral and immune modulating agents.9,12-15 The constituent complexity and diverse mode of action of a natural formulation does not result in the type of mutations seen with single element pharmaceutical formulations.16 A number of natural products have been shown to be antiviral, to promote tissue repair and to decrease pain. Furthermore, many natural substances have been shown to support local innate immune activity.16-18 For these reasons, natural products may hold promise in the management of and alteration of the natural progression of HSV recurrence.
Hypericum perforatum, commonly known as St. John’s Wort, has been extensively investigated for its antiviral activities against enveloped viruses like HSV and HIV. The bioactive constituent, hypericin, displays multiple modes of actions, including inhibition of new virion budding, prevention of viral uncoating, and inhibition of protein kinase activity required for replication of a number of viruses.19 Hypericum perforatum has additionally been investigated with regard to its ability to relieve neuropathic pain. Antihyperalgesic activity is also associated with the major bioactive constituent hypericin. In studies, hypericin inhibits protein kinase C gamma and epsilon, which are proteins associated with the development of neuropathic pain.20
Naturally occurring minerals such as zinc and copper also demonstrate antiviral activity. Research has been conducted on the copper-mediated inactivation of HSV. Copper ions have been shown to inactivate several types of viruses, including members of the Herpesvirus and Arenavirus families, various bacteriophages treated in vitro, and free as well as intracellular HIV.7,21 Mechanisms of action studies suggest that copper-mediated damage occurs via binding with DNA causing DNA strand breaks. HSV has also been shown to exhibit sensitivity to low concentrations of copper. It is hypothesized that a potential advantage of copper-mediated viral killing resides in broad molecular damage, in that the host cell has the ability to repair much faster for itself than the virus. In addition, rather than suppressing viral replication, copper ions render the viral DNA nonviable for further replication. Interestingly, studies have been done with copper bound to Acyclovir. This complex reportedly exhibited a significant anti-HSV effect.22 In an in vitro study conducted by Shishkov, et al., a copper complex was found to inhibit the infectivity of free virions.21 The maximum safe level for topical anhydrous copper sulfate use is 5%, which equates to approximately 2% of copper ions.23 Skin exposure to copper can cause allergic reactions in some individuals.
The Dynamiclear formulation used in this study contains copper sulfate pentahydrate (5.0%) and Hypericum perforatum (0.10%). Unlike the majority of topical treatments marketed for symptomatic relief of HSV lesions, this formulation is recommended as a single application. It has been clinically tested for safety, efficacy, and tolerability by an independent CRO (Apothecaries Ltd, India) using Good Clinical Practice in accordance with the principles that originate in the Declaration of Helsinki. Dynamiclear has been listed on the Australian Register of Therapeutic Goods as a Complementary Medicine since July 2008.
The aim of this clinical study was to investigate the efficacy of a single topical application of the Dynamiclear formulation compared to topical Acyclovir, and to determine Dynamiclear’s tolerability in adult patients with recurrent skin, oral, and genital HSV lesions. The trial was a prospective, randomized, multi-centered, comparative, open-label clinical study in patients aged between 18 and 55 years old. No blinded comparator product, placebo or active formulation was suitable for the study. Blinding was considered not feasible without placebo, as the formulation and dosage forms of the Dynamiclear formulation and Acyclovir were completely different.