Treatment Of Genital Herpes Research Articles

Efficacy and Safety of Valacyclovir for the Suppression and Episodic Treatment of Herpes Simplex Virus in Patients with HIV

Three randomized controlled trials of valacyclovir for the management of recurrences of genital herpes in HIV-infected persons were conducted between 1991 and 2002. One study evaluated episodic therapy for the treatment of genital herpes, and 2 studies evaluated continuous suppressive therapy. Valacyclovir at 1000 mg twice daily for 5 days was comparable to acyclovir at 200 mg 5 times daily in accelerating healing of a single episode of genital herpes (hazard ratio, 1.0; 95% confidence interval [CI], 0.8-1.2; P=.89). Valacyclovir at 500 mg twice daily was effective in preventing or delaying recurrences of genital herpes compared with placebo (hazard ratio, 0.20; 95% CI, 0.13-0.30; P<.001) and with valacyclovir at 1000 mg once daily (hazard ratio, 0.56; 95% CI, 0.40-0.80; P=.001), in 6-month and 48-week studies, respectively. The safety profile of valacyclovir was similar to that of acyclovir. Valacyclovir is well tolerated, safe, and effective for the treatment and suppression of recurrent genital herpes in human immunodeficiency virus-infected persons.

Antiviral treatment of genital herpes.

A review of the randomized, controlled trials in the literature on the treatment of genital herpes infection with aciclovir, famciclovir and valaciclovir. Common clinical questions encountered by physicians, such as the effect of antivirals on symptoms, healing, aborting attacks and subsequent recurrences, are addressed. There is very little comparative data between the three licensed drugs but the little data that there is shows no difference in efficacy, tolerability and toxicity between aciclovir, valaciclovir or famciclovir when taken orally. Choice of therapy would then depend on convenience of dosing and cost.

Immunomodulation as a treatment strategy for genital herpes: review of the evidence

In this review, we discuss the ongoing development of a new treatment option for genital herpes (GH), the disease caused by herpes simplex virus (HSV) types I and II. Following infection, the virus establishes a latent infection in peripheral neurons, which periodically activates to cause recurrent skin lesions or asymptomatic shedding in the anogenital area. A new class of drugs, the immune response modifiers (IRMs), modulates the immune system against viral infection. This approach is currently being tested as a treatment for GH. We first review the effectiveness of treatment of other viral diseases with imiquimod, the first IRM to be licensed (Aldara™, imiquimod 5% cream), and one used for the treatment of external anogenital warts. We then focus on resiquimod, an analog of imiquimod, which shows early promise as a new treatment option for GH. The evidence from in vitro and in vivo studies, in particular the guinea pig model of GH, describing the effectiveness and mode of action of this novel immunopharmacological agent is presented. Resiquimod stimulates specific cells of the innate immune system (including monocytes/macrophages, dendritic cells (DC) and B lymphocytes) to produce cytokines (in particular IFN-α, IL-12, TNF-α and IFN-γ) that initiate and drive the development of the Th1 acquired immune response against HSV-infected cells. Recent results from clinical trials and in vivo studies in animal models are consistent with the hypothesis that the development of HSV-specific cell-mediated immunity may prove to be the key in providing a long-lasting protection against GH recurrences.

Genital herpes simplex virus infection in the adolescent: special considerations for management.

Genital herpes simplex virus (HSV) infections are increasingly common among adolescents. In developed countries, during the 1990s, adolescent HSV type 2 seroprevalence rates ranged from 4 to 30% depending on the population studied. The clinical diagnosis of genital herpes may be unreliable and laboratory testing is recommended. Aciclovir, valaciclovir, and famciclovir are three antiviral drugs that have proven efficacy in the treatment of genital herpes. These drugs can be used in the treatment of the first episode or for recurrent infections, or can be used long term to suppress recurrent infections. Once or twice daily administration regimens are preferable for adolescents for reasons of adherence, and because it avoids the need to take medication at school. Unproven remedies are used commonly and can be harmful. In addition to antiviral therapy, proper management of the adolescent with genital herpes should also include developmentally appropriate explanations of the diagnosis, treatment and potential complications, recommendations for symptomatic relief, screening for other sexually transmitted infections, and discussion of safer sexual practices. All adolescents should have follow-up visits to complete education and counseling and to assess compliance with antiviral therapy.

Treatment of genital herpes

Treatment of genital herpes

Susceptibility to acyclovir of herpes simplex virus isolates obtained between 1977 and 1996 in Japan

The susceptibility of genital herpes to acyclovir (ACV) in immunocompetent women was examined, as was the frequency of ACV-resistant viruses by analyzing 56 clinical isolates in Japan between 1977 and 1996. The mean susceptibilities of herpes simplex virus (HSV) type 1 and type 2 were 0.13±0.74 and 0.42±0.14 μg/ml, respectively, assessed by the 50% inhibitory concentration of plaque formation. The susceptibility to ACV of clinical isolates did not changed since 1977, and also that of nine pairs of HSV-1 and HSV-2 isolates was not affected by ACV treatment. In order to characterize the change in the virus population, the quantitation of the ACV-resistant virus in 104 plaque forming units (PFU) of clinical isolates was adopted. The mean frequencies of ACV-resistant viruses per 104 PFU for all strains of HSV-1 and HSV-2 were 0.31±0.41 and 9.74±14.83, respectively, and were not influenced by ACV treatment. Additionally, the phenotypes of ACV-resistance were not influenced by ACV treatment, and more than 90% of ACV-resistant viruses were found to be thymidine kinase-deficient. This study characterized clinical isolates with respect to ACV susceptibility as a population and the quantitative and qualitative characterization of ACV-resistant virus in the virus population of clinical isolates was also studied. The susceptibility of isolates from genital lesions, the frequency of ACV-resistant viruses, and also the phenotypic characterization of ACV-resistant viruses was maintained between 1977 and 1996, even after the introduction of ACV treatment for genital herpes in Japan. J. Med. Virol. 63:57–63, 2001. © 2001 Wiley-Liss, Inc.

Current recommendations for the treatment of genital herpes.

The incidence of genital herpes continues to increase in epidemic-like fashion. Aciclovir (acyclovir) has been the original gold standard of therapy. The recent addition of famciclovir and valaciclovir as antiherpes drugs has improved convenience as well as the efficacy of treatment. Although aciclovir remains a widely prescribed and reliable drug, its administration schedule falls short of the ease of usage that the newer nucleoside analogues offer, for both episodic and suppressive therapy. Suppression of symptomatic disease and asymptomatic shedding from the genitalia have both become popular approaches, if not the primary targets of antiviral therapy. Knowing that asymptomatic disease leads to most cases of transmission strongly suggests that suppression with antiviral agents could reduce transmission risk in discordant couples. Unfortunately, the role for antivirals in reducing transmission remains to be proven in clinical trials. Neonatal herpes is now successfully treated using aciclovir. Current randomised clinical trials are examining aciclovir and valaciclovir administration, as well as safety and efficacy for post-acute suppressive therapy. Prevention of recurrences in pregnancy is also a topic under investigation, with a view to reducing the medical need for Cesarean section, or alternatively (and far less likely to be accomplished) to protect the neonate. Although resistance is largely limited to the immunocompromised and a change in resistance patterns is not expected, several drugs are available for the treatment of aciclovir-resistant strains of herpes simplex. Foscarnet is the main alternative with proven efficacy in this setting. Unfortunately, administration of foscarnet requires intravenous therapy, although a single anecdote of topical foscarnet efficacy in this setting has been published. Alternatives include cidofovir gel, which is not commercially available but can be formulated locally from the intravenous preparation. Less effective alternatives include trifluridine and interferon. Future possibilities for treatment of genital herpes include a microparticle-based controlled-release formulation of aciclovir and resiquimod (VML-600; R-848). The search for an effective therapeutic vaccine for genital herpes has not been successful to date, although a live virus glycoprotein H-deficient (DISC) vaccine is currently in clinical trials. Recent data suggest that seronegative women are protected (albeit, not fully) by a glycoprotein D recombinant vaccine with adjuvant. Despite the established safety and convenience of current treatment options, better suppressive options and topical treatment options are much needed. Studies using existing agents as potential tools to avoid Cesarean section, or transmission to neonate or partner are ongoing. Both vaccines and antivirals may eventually play a role in prevention of infection.

Cost-Effectiveness of Management Stratagies for Chronic Recurrent Genital Herpes: A Pilot Analysis

PURPOSE: Genital herpes management has concentrated on episodic treatment or prophylaxis of recurrences. However, significant morbidity arises from stigma surrounding the diagnosis. We investigated the effect of including treatment of disease stigma on the cost-effectiveness of genital herpes treatment. METHODS: Using a Markov decision model, we estimated the incremental cost-effectiveness of four strategies for genital herpes management: no intervention, counseling only, chronic antiviral suppression only, or both counseling and suppression. All strategies used antivirals for symptomatic recurrences. The Markov cycle length was 1 week with a 10 year time horizon. A societal perspective was taken, with costs and benefits discounted at 3%/yr. We used literature and expert estimates of parameter values, and assumed that counseling decreases disutility from stigma but has no effect on symptomatic recurrences, while chronic antiviral suppression decreases both. The disutility of stigma was estimated at 0.05 (for a utility of 0.95 on a scale where 0 = death & 1 = perfect health), and the disutility of a symptomatic recurrence was 0.10 (a utility of 0.90). Multiple sensitivity analyses were performed. RESULTS: In the baseline analysis, the incremental cost-effectiveness of counseling only compared to no intervention is $2570 per quality adjusted life year (QALY) gained. Antiviral suppression without counseling is weakly dominated by counseling plus suppressive therapy, which costs $68,500/QALY gained compared to counseling only. Results are not sensitive to variation of counseling costs (baseline $500, range $200–1000), symptomatic recurrence treatment costs (baseline $24.50, range $0–100), recurrence frequency while on suppressive therapy (baseline 1/yr, range 0–6/yr), or time horizon (1–10 years). Counseling plus antiviral suppression costs less than $50,000/QALY when: suppression costs less than $19.74/wk (baseline $26.32/wk), recurrences without suppression are more frequent than 11.5/yr (baseline 6/yr), stigma utility is less than 0.92, recurrence utility is less than 0.82, counseling decreases stigma by less than 17% (baseline 50%), or antiviral suppression decreases stigma by more than 77% (baseline 50%). CONCLUSION: Although suppressive therapy is being aggressively marketed for genital herpes, this analysis suggests that counseling to reduce stigma is more cost-effective than antiviral suppression unless genital herpes is very severe, suppression is less expensive, or herpes recurrence utilities are relatively low. These results suggest a need for more definitive determination of utilities for recurrent genital herpes and a basic understanding of the determinants and modifying factors of genital herpes stigma.

Tratamiento del herpes genital con interferón alfa-2b

ObjectiveTo evaluate the efficacy and safety of the alfa-2b Interferon in the treatment of genital herpes. Methods75 patients were treated with alfa-2b Interferon, 41 males (4 homosexuals) and 34 females, age range between 18 and 44 years. The symptom and recurrences were evaluated. The Interferon was administered at 10 million/week intradermic during 4 to 12 weeks. ResultsThe Interferon causes improvement in the symptoms and the recurrences were presented in 17 cases (22,6%). The mean in recurrences was 1,4 episodes per year. ConclusionsThe alpha-2b Interferon lowers the symptoms, the recurrences in time and number. Allows pregnant women that have been treated to have a normal delivery.

Susceptibility to acyclovir of herpes simplex virus isolates obtained between 1977 and 1996 in Japan

The susceptibility of genital herpes to acyclovir (ACV) in immunocompetent women was examined, as was the frequency of ACV-resistant viruses by analyzing 56 clinical isolates in Japan between 1977 and 1996. The mean susceptibilities of herpes simplex virus (HSV) type 1 and type 2 were 0.13+/-0.74 and 0.42+/-0.14 microg/ml, respectively, assessed by the 50% inhibitory concentration of plaque formation. The susceptibility to ACV of clinical isolates did not changed since 1977, and also that of nine pairs of HSV-1 and HSV-2 isolates was not affected by ACV treatment. In order to characterize the change in the virus population, the quantitation of the ACV-resistant virus in 10(4) plaque forming units (PFU) of clinical isolates was adopted. The mean frequencies of ACV-resistant viruses per 10(4) PFU for all strains of HSV-1 and HSV-2 were 0.31+/-0.41 and 9.74+/-14.83, respectively, and were not influenced by ACV treatment. Additionally, the phenotypes of ACV-resistance were not influenced by ACV treatment, and more than 90% of ACV-resistant viruses were found to be thymidine kinase-deficient. This study characterized clinical isolates with respect to ACV susceptibility as a population and the quantitative and qualitative characterization of ACV-resistant virus in the virus population of clinical isolates was also studied. The susceptibility of isolates from genital lesions, the frequency of ACV-resistant viruses, and also the phenotypic characterization of ACV-resistant viruses was maintained between 1977 and 1996, even after the introduction of ACV treatment for genital herpes in Japan.

Antiviral Agents for Non-Human Immunodeficiency Virus Infections

Several new agents for treating viral infections have been developed in recent years. All available agents are virustatic, inhibiting specific steps in the process of viral replication. No agent is active against nonreplicating or latent viruses. Acyclovir is useful in the treatment of genital herpes, herpes simplex encephalitis, mucocutaneous herpetic infection, varicella infection in the immunosuppressed host, and herpes zoster infection in the normal and the immunosuppressed host. It can also be used for prevention of herpesvirus infection in immunocompromised patients. Ganciclovir is indicated for the treatment of cytomegalovirus retinitis in patients with the acquired immunodeficiency syndrome and is effective in the treatment and prevention of cytomegalovirus infection in other immunocompromised patients. Famciclovir and valacyclovir are effective in the management of herpes simplex and varicella-zoster infection. Amantadine and rimantadine are useful therapeutically and prophylactically in the management of influenza A virus infection. Chronic hepatitis B infection can respond to lamivudine therapy, and the optimal treatment of hepatitis C is the combination of interferon alfa and ribavirin. Despite pronounced toxic effects, foscarnet and cidofovir are effective antiviral agents in specific settings.

Increasing prevalence of genital herpes in developing countries: implications for heterosexual HIV transmission and STI control programmes.

The recognition that sexually transmitted infections (STI) facilitate HIV transmission among heterosexuals has led to a rejuvenated focus on improving STI control as a component of HIV prevention programmes in developing countries. While efforts so far have focused mainly on all STI, there is increasing evidence that genital ulcers facilitate a considerable proportion of HIV transmission among heterosexuals and that this effect has been underestimated. This paper focuses on the epidemiology of genital herpes in developing countries past and present. To review the scientific literature about the epidemiology of genital herpes in developing countries and discuss the implications of the findings for STI control and HIV prevention programmes. SEARCH METHODOLOGY: A Medline search for June 1966 to August 1999 using the keywords, genital herpes, STD and developing countries, and genital ulcers in MeSH and free text. Abstract books from recent international AIDS conferences and other international STD conferences were reviewed. The annual reports of the medical officers of heath for Harare 1982-1998 and Durban 1989-1997 were reviewed to detect trends in genital herpes diagnoses. Genital herpes, formerly regarded as a minor STI in most developing countries, has now emerged as a leading cause of genital ulceration in many countries where syphilis and chancroid were more prevalent previously. This increased recognition of genital herpes reflects both a change in the pattern of STI epidemiology through a decline in syphilis and chancroid as a response to HIV control programmes and improved techniques for diagnosing herpetic infection. Countries with significant heterosexual HIV epidemics also appear to have rapidly increasing numbers of genital herpes cases. The emergence of this herpes epidemic must be addressed through innovative strategies that will be viable, sustainable, acceptable, and effective in developing countries. In countries where genital herpes is a significant problem, local adaptation of WHO treatment algorithms should be made. STI service providers should be trained about issues around the transmission of herpes and how best to advise clients about dealing with, and recognising, recurrences. The effectiveness of antiviral treatment for genital herpes should be investigated in core groups at high risk of HIV.

New therapies and prevention strategies for genital herpes.

Genital herpes is among the most prevalent sexually transmitted diseases. Optimal management of genital herpes includes accurate diagnosis, antiviral therapy, and counseling of patients about complications and transmission of herpes simplex virus (HSV). Antiviral therapy offers significant palliation, and the option of episodic or suppressive treatment should be offered to all patients with genital herpes. Valacyclovir and famciclovir are two newer antiviral agents that are effective and safe for the treatment of genital herpes. Prevention strategies for sexual and perinatal transmission of HSV have not been well defined. Availability of type-specific serological tests for HSV antibodies may assist in identifying persons at risk for acquiring or transmitting HSV infection. Further research is needed to define strategies to prevent the spread of this epidemic infection.

Perspectives on switching oral acyclovir from prescription to over-the-counter status: report of a consensus panel.

The proposed switching of oral acyclovir from prescription to over-the-counter (OTC) status for the 5-day episodic treatment of genital herpes was considered by a consensus panel. It was concluded that self-diagnosis/misdiagnosis, misuse, and adverse drug effects were potential problems with the OTC use of acyclovir. While acyclovir reduces asymptomatic shedding of herpes simplex virus type 2, the reduction in transmission of virus potentially resulting from increased acyclovir use was felt to be of unknown extent but likely to be of benefit overall. The availability of acyclovir would likely be improved. There were differences in opinion as to whether widespread availability of acyclovir (prescription or OTC) may speed the development of viral resistance. However, all panel members felt that granting OTC status may set an undesirable precedent for the switch from prescription to OTC use of other systemically administered antiinfective agents. The effect of this precedent, in terms of accelerating development of multidrug-resistant bacteria, was a major concern of all panel members. The consensus was that the switch of acyclovir to OTC status could not be supported.

A review of famciclovir in the management of genital herpes.

The frequent occurrence of genital herpes continues to be a serious clinical problem. Although not life threatening, the physical symptoms of the disease, and the ensuing psychosocial complications, can be overwhelming to patients. The life cycle of the herpes simplex virus is complex, comprising multiple stages. Following infection, the virus establishes life-long latency in its host and can reactivate at any time as a recurrent infection. Successful management of genital herpes simplex infections involves patient education and psychological support, as well as antiviral agents. The antiviral agent famciclovir has been shown to shorten the course and decrease the severity of episodes of recurrent genital herpes. In addition, famciclovir has been shown to be effective in suppressing recurrent genital herpes. A review of the clinical experience with famciclovir in the treatment of genital herpes is presented.

Treatment of Genital Herpes in Males with Imiquimod 1% Cream

The aim of this randomised, double-blind, placebo-controlled study was to examine the clinical significance, efficacy and tolerability of imiquimod 1% cream to manage patients exposed to first episodes of genital herpes. Male patients (n = 60), ranging in age between 18 and 50 years (mean 25.7 years), presenting for <6 days (mean 4.4 days) with culture-confirmed diagnosis of genital herpes, and bearing a total of 696 lesions (mean 11.6 lesions/ patient), entered the study and were randomised to receive a precoded 40g tube and instructions on how to apply the trial medication to their lesions twice for 5 consecutive days per week. A marked clinical benefit from self-application of imiquimod 1% cream was demonstrated, resulting in both significantly shorter mean duration of healing than with the placebo (5.2 vs 14 days; p < 0.001) and more healed patients [23 of 30 (76.7%) vs 2 of 30 (6.7%); p < 0.0001]. Of the 60 patients, 54 (90%) reported no drug-related adverse effects. Two patients in the imiquimod group reported non-objective mild burning sensation and four experienced a transitory increase in their body temperature (>38 degrees C) accompanied by mild headache and malaise; however, such indications were not severe enough to cause discontinuation of the treatment, and resolved within 24 hours. Treatment was well tolerated by all the patients, with no dropouts. Among 25 healed patients, four had a relapse after 9 months. Although the analogue of imiquimod 1% cream demonstrated mild to moderate subjective adverse effects, it was significantly more effective than placebo in treating patients with a first episode of genital herpes. Further clinical studies appear warranted.

A Review of Famciclovir in the Management of Genital Herpes

The frequent occurrence of genital herpes continues to be a serious clinical problem. Although not life threatening, the physical symptoms of the disease, and the ensuing psychosocial complications, can be overwhelming to patients. The life cycle of the herpes simplex virus is complex, comprising multiple stages. Following infection, the virus establishes life-long latency in its host and can reactivate at any time as a recurrent infection. Successful management of genital herpes simplex infections involves patient education and psychological support, as well as antiviral agents. The antiviral agent famciclovir has been shown to shorten the course and decrease the severity of episodes of recurrent genital herpes. In addition, famciclovir has been shown to be effective in suppressing recurrent genital herpes. A review of the clinical experience with famciclovir in the treatment of genital herpes is presented.

A review of famciclovir in the management of genital herpes

The frequent occurrence of genital herpes continues to be a serious clinical problem. Although not life threatening, the physical symptoms of the disease, and the ensuing psychosocial complications, can be overwhelming to patients. The life cycle of the herpes simplex virus is complex, comprising multiple stages. Following infection, the virus establishes life-long latency in its host and can reactivate at any time as a recurrent infection. Successful management of genital herpes simplex infections involves patient education and psychological support, as well as antiviral agents. The antiviral agent famciclovir has been shown to shorten the course and decrease the severity of episodes of recurrent genital herpes. In addition, famciclovir has been shown to be effective in suppressing recurrent genital herpes. A review of the clinical experience with famciclovir in the treatment of genital herpes is presented. Infect. Dis. Obstet. Gynecol. 6:38–43, 1998. © 1998 Wiley-Liss, Inc.

The Value of Antivirals in Genital Herpes

Although aciclovir has been the most extensively used nucleoside analogue for the treatment of genital herpes, its poor bioavailability, frequent dosing (five times daily), and the short intracellular half-life of the active triphosphate (≤1–2 h) has led to the development of a new generation of agents. The prodrug valaciclovir (active agent aciclovir), and famciclovir (active agent penciclovir) have improved pharmacokinetics compared with aciclovir. Compared with oral aciclovir, valaciclovir yields aciclovir with three-fivefold higher serum levels and the oral prodrug famciclovir yields even higher serum levels of penciclovir. The active agent, penciclovir triphosphate, has a prolonged intracellular half-life in vitro [10 h for cells infected with herpes simplex virus type 1 (HSV-1) and 20 h for HSV-2-infected cells]. Evidence also suggests that famciclovir may have an effect on the establishment of latency in primary infection, thus reducing the risk of subsequent recurrent disease. Ongoing clinical trials are underway exploring this possibility. For patients with frequent recurrences of genital herpes, or patients psychologically disabled by the condition, twice-daily antiviral therapy offers the most effective reduction in the frequency of clinical recurrence. Twice-daily therapy also has the advantage that patients are at less risk of asymptomatic breakthrough and the potential risk of transmission if they forget to take one dose.

S238 New antivirals — Implications for treatment of genital herpes

S238 New antivirals — Implications for treatment of genital herpes