Minimizing recurrences of genital herpes—a role for suppressive antiviral therapy

Michael Remington, PA

Mr. Remington practices at the University of Washington Virology Research Clinic and Remington Clinics, Seattle. The author has indicated no relationships to disclose relating to the content of this article.

Stress may contribute to recurrent episodes of genital herpes, which themselves cause more stress. Minimizing the frequency of recurrences—or eliminating them altogether—may help to break the cycle.

 

Earn Category I CME credit by reading this article and the associated article and successfully completing the post-test. Successful completion is defined as a cumulative score of at least 70% correct. This material has been reviewed and is approved for 1 hour of clinical Category I (Preapproved) CME credit by the AAPA. The term of approval is for 1 year from the publication date of August 2004.

Learning objectives Describe the incidence and pathology of genital herpes Explain the psychological impact of genital herpes infection Recognize the relationship between psychological factors and recurrences in genital herpes Discuss how suppressive antiviral therapy can reduce the psychological morbidity associated with genital herpes

In 1994, 19% of Americans between the ages of 19 and 49 years were seropositive for herpes simplex virus type 2 (HSV-2), the primary cause of genital herpes (see Figure 1).¹ This prevalence represents a 30% increase from 1976. The number of newly diagnosed genital herpes infections continues to rise at an alarming rate. In the United States, more than 1.6 million persons—most commonly between 20 and 29 years of age—are newly infected with HSV-2 each year.² Despite this pervasiveness, however, the disease goes undiagnosed in as many as 80% of patients who have it^1,3 (see "Pathophysiology and presentation").

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Pathophysiology and presentation Although herpes simplex virus type 2 (HSV-2) is the most common etiology of genital herpes, HSV type 1 (HSV-1)—the virus that causes cold sores—can also cause genital herpes.1 First episodes of genital herpes are increasingly caused by infection with HSV-1 rather than HSV-2.1,2 Both viruses can be transmitted from person to person via oral-genital or genital-genital contact. Although self-inoculation is possible, it is rare and typically occurs within 14 days after the initial infection. Herpetic whitlows can occur at extragenital sites—anywhere that the virus can enter the body through a scratch on the skin. A first episode of genital herpes may cause fever, malaise, and anogenital lesions.1 After the initial infection, HSV lies latent in the dorsal nerve root of the sensory nerve ganglia, just outside the spinal column. During reactivations, the virus may cause symptomatic disease (a recurrence) or result in asymptomatic shedding, in which the virus is present on the skin or mucosa in the absence of symptoms. Both HSV strains and the varicella zoster virus are double-stranded DNA viruses of the family Herpesviridae. During the initial establishment of infection, these viruses enter and take control of host cells, which they then program to create virus copies. Herpesvirus replication is a regulated, multistep process. After infection, viral genes that regulate the synthesis of proteins that are involved in viral genome replication, such as thymidine kinases and DNA polymerases, are transcribed. After DNA replication, additional herpesvirus genes are expressed. They encode proteins that are either incorporated into or aid in the assembly of viral progeny. In symptomatic patients, clinical signs of disease usually appear a few days after initial infection. After establishing infection on the skin or mucosa, viral particles are taken up by nerves and transported to the nerve cell bodies in the dorsal root ganglia of the spinal cord. Ganglia may become latently infected with herpesvirus. While the virus is latent, clinical disease does not occur, and the patient is asymptomatic. Reactivation of the virus causes infectious viruses to reproduce in the ganglia and migrate to the skin or mucous membranes, causing mucocutaneous symptoms or asymptomatic shedding. Symptomatic recurrences are characterized by mild malaise, the presence of lesions or rash along with burning and discomfort in the anogenital region, and urinary symptoms. Many recurrences go unnoticed, however. Nearly half of those who have symptomatic primary HSV-2 infection experience at least six recurrences each year.3 Regardless of whether symptoms occur, asymptomatic viral shedding is common. One study that measured viral shedding by polymerase chain reaction tests of daily swab samples from women infected with HSV-2 showed that shedding occurred on 28% of days.4 Because HSV-1 and HSV-2 can be shed regardless of whether overt signs of infection are present, even asymptomatic persons can spread genital herpes. The psychological impact of genital herpes can be devastating.5 The majority of more than 3,000 patients with genital herpes surveyed in one study reported that their first episode was accompanied by psychological distress, described as feelings of depression (82%), fear of rejection (75%), and isolation (69%).6 These and other psychological sequelae can persist for years after the initial diagnosis. Factors such as the stigma associated with having a sexually transmitted disease, the fear of spreading genital herpes, and the chronic, incurable nature of the disease contribute to psychological morbidity.7-9 For many patients, a key factor of psychological morbidity associated with genital herpes is symptomatic recurrences, which can be painful and often occur unpredictably.7-9 1. Drake S, Taylor S, Brown D, Pillay D. Improving the care of patients with genital herpes. BMJ. 2000;321:619-623. 2. 1998 Guidelines for Treatment of Sexually Transmitted Diseases: Genital Herpes Simplex Virus Infection. Centers for Disease Control. Available at: http://www.wonder.cdc.gov/wonder/prevguid/p0000480/p0000480.asp. Accessed July 13, 2001. 3. Corey L, Adams HG, Brown ZA, Holmes KK. Genital herpes simplex virus infections: Clinical manifestations, course, and complications. Ann Intern Med. 1983;98:958-972. 4. Wald A, Corey L, Cone R, et al. Frequent genital herpes simplex virus 2 shedding in immunocompetent women. Effect of acyclovir treatment. J Clin Invest. 1997;99:1092-1097. 5. Tétrault I, Boivin G. Recent advances in management of genital herpes. Can Fam Physician. 2000;46:1622-1629. 6. Catotti DN, Clarke P, Catoe KE. Herpes revisited. Still a cause of concern. Sex Transm Dis. March-April 1993;20:77-80. 7. VanderPlate C, Aral SO. Psychosocial aspects of genital herpes virus infection. Health Psychol. 1987;6(1):57-72. 8. Green J, Kocsis A. Psychological factors in recurrent genital herpes. Genitourin Med. August 1997;73:253-258. 9. Mindel A. Psychological and psychosexual implications of herpes simplex virus infections. Scand J Infect Dis. 1996;100(suppl):27-32.

This article examines the relationship between recurrent episodes of genital herpes and the psychological distress they cause, and it describes the role of suppressive antiviral therapy in mitigating the psychological impact of genital herpes.

Psychological factors and recurrence in genital herpes

Patients who have genital herpes generally view psychological stress as a primary cause of recurrences.^4-7 Researchers in one study found that 78% of 90 respondents to a questionnaire about genital herpes cited stress as a factor in precipitating recurrences.⁴ A state of being "physically run down" was cited by 56% of respondents.

The results of empiric studies have, however, been less consistent than studies involving patient surveys in suggesting that stress causes recurrences of genital herpes. Some studies have found an association between stress and subsequent recurrences, but others have not.^8-11 Kemeny and coworkers found no evidence that the number of stressful life events predicts the number of recurrences,⁹ although two studies revealed that recurrences were preceded by a period of anxiety that lasted at least 4 days.^10,11 The latter finding is consistent with the hypothesis that stress precipitates recurrences. Alternatively, stress may be one aspect of a psychological prodrome that precedes but does not cause genital herpes recurrences.⁸

The chronicity of stress may determine the extent to which it is associated with subsequent recurrences. Studies examining acute stressors generally failed to find that they affected genital herpes recurrences, whereas studies examining long-term stressors generally show that stress precipitates recurrences.^9-15 A community-based study of 58 women with a history of at least one recurrence of genital herpes in the preceding 6 months examined the role of persistent and acute stress in recurrences. The researchers found that persistent stress (lasting longer than 1 week) predicted a recurrence of genital herpes during the subsequent week, but that depressive mood, anger, anxiety, and short-term stress (including discrete stressful life events) did not.¹⁴ The risk of a recurrence during a given week increased by 26% if the patient had had at least one moderately stressful experience lasting at least 7 days during the preceding week. Over the 6-month study period, the month with the highest level of anxiety was associated with a greater number of recurrences than the month with the lowest level of anxiety. No such effect on the incidence of recurrence was observed for short-term stress, depressive mood, or anger.

A similar effect of chronic psychological stress on frequency of recurrences was observed in a study of 59 patients who had had genital herpes for at least 10 months.¹³ While patients' self-measured stress caused by discrete events did not significantly correlate with the past-year frequency of recurrence, patients' global rating of stress over the past year was significantly correlated with recurrence frequency: the higher the stress, the greater the number of recurrences.

How stress increases the risk of recurrence is not known. It is possible that stress indirectly modulates recurrences through an intervening variable. One theory suggests that stress itself does not cause recurrences but that it increases the probability of generalized illnesses that directly precipitate recurrences.¹⁶ Another theory arises from the belief that long-term stress diminishes the immune responses in humans, allowing reactivation of HSV.^17-19 A mouse model of HSV infection showed that stress suppressed HSV-specific T lymphocyte and natural killer cell responses, increased the titer of infectious HSV at the site of infection, and inhibited HSV-specific T lymphocyte memory.^20,21 Conversely, HSV reactivation may trigger neurophysiologic and immunologic responses that generate the subjective feeling of stress (increased heart and respiratory rates, nervousness, anxiousness).

Measuring quality of life with herpes

While persistent psychological stress may precipitate recurrences, the recurrences themselves may cause psychological distress. Numerous studies show that recurrences of genital herpes are associated with psychological morbidity, the magnitude of which appears to be directly related to the frequency of recurrences. For example, both emotional and social aspects of quality of life were impaired in a group of patients who had genital herpes compared with a group of noninfected persons matched for age, sex, and social status.²² Patients with genital herpes had impairments in emotional role functioning (ability to fulfill activities appropriate to one's emotional role), mental health, and social functioning. Another study showed that frequency of genital herpes recurrences predicted the magnitude of quality of life impairment: Patients having two or more recurrences during the year prior to the study were more impaired than those with one or no recurrences.²³ Another investigation that sought to measure the psychological impact of genital herpes found that the majority of 42 patients with an average of 11 recurrences during the year before the study felt less capable of physical intimacy (61%), less confident (71%), that they would not be accepted by others who knew of their herpes (73%), and that these were serious problems.²⁴

In addition to quality of life measurements, standard psychological assessments such as the Symptom Checklist-90 and the General Health Questionnaire (which measures nonpsychotic psychiatric illness) reveal a relationship between psychological morbidity and recurrences among those with genital herpes.^12,25-29 The degree of psychological dysfunction was related directly to the frequency and severity of recurrences and the degree to which the patient was bothered by these recurrences. Coping scores among patients with a high frequency of recurrences reflected a tendency to perceive that events, including the stress of genital herpes, were not subject to personal control.

Breaking the cycle with antiviral therapy

In the United States, the guanosine nucleoside antiviral drugs acyclovir (Zovirax), valacyclovir (Valtrex)—a prodrug of acyclovir—and famciclovir (Famvir) minimize pain and viral shedding, shorten duration of lesions, and act suppressively to decrease recurrences. The CDC treatment guidelines on sexually transmitted diseases note that suppressive antiviral therapy may be considered in patients who have six or more recurrences annually (see Table 1).³⁰

 

TABLE 1 CDC regimens of oral suppressive therapy for genital herpes

Acyclovir, 400 mg bid OR Famciclovir, 250 mg bid OR Valacyclovir, 500 mg/d* OR Valacyclovir, 1 g/d*

*May be less effective than other valacyclovir or acyclovir dosing regimens in persons with 10 or more recurrences per year.

Source: Sexually Transmitted Diseases Treatment Guidelines 2002. MMWR Morb Mortal Wkly Rep. May 10, 2002;51(RR-6).

Valacyclovir is the only antiviral that is approved for once-daily use in suppressive treatment of recurrent genital herpes, as a 3-day course for episodic therapy, and for prevention of transmission of HSV to a partner. A less frequent dosing with valacyclovir may render it more convenient for patients.

Famciclovir also offers less frequent dosing than acyclovir for its approved genital herpes indications. Famciclovir is unique among the three guanosine nucleoside analog antivirals in that the dosage of famciclovir approved for daily use in suppressive treatment of recurrent genital herpes in otherwise healthy adults is higher than the dosage for episodic treatment.

Valacyclovir, acyclovir, and famciclovir have been assessed in placebo-controlled trials of suppression of recurrent genital herpes. Given at the approved dosing regimens, the drugs appear to confer comparable efficacy in the suppression of genital herpes.

A large, double-blind, parallel-group study found that once-daily dosing of valacyclovir, 500 mg and 1 g, was more effective than placebo and just as effective as the regimen of acyclovir, 400 mg twice daily, in reducing the frequency of genital herpes recurrences over the course of 1 year.³¹ Compared with placebo, the 1-g/d regimen of valacyclovir yielded a 78% reduction in yearly recurrence rate and the 500-mg/d regimen yielded a 71% reduction. The percentages of patients free of recurrences at the end of the 1-year study period were 48% of the 1-g dosage group and 40% of the 500-mg group, compared to 5% for placebo.

Famciclovir, 250 mg twice daily, has also been shown to be effective in suppressing recurrences of genital herpes.³¹ In one study, 934 immunocompetent adults who had 6 or more recurrences per year were randomized into two double-blind, 1-year, placebo-controlled trials. Treatments included famciclovir 125 mg three times daily, 250 mg twice daily, 250 mg three times daily, and placebo. At 1 year, 60% to 65% of patients were still receiving famciclovir and 25% were receiving placebo. Patients receiving famciclovir had fewer recurrences than those given placebo. In the first famciclovir trial, the median time to recurrence exceeded 10 months for the 250-mg twice daily regimen compared to approximately 7 weeks for placebo. In the second famciclovir trial, the time to recurrence exceeded 120 days for the 250-mg twice daily regimen compared to 82 days for placebo.³²

The valacyclovir-acyclovir study also examined patients' psychological well-being before initiation of suppressive therapy and every 3 months during the study, using the Recurrent Genital Herpes Quality of Life Questionnaire, which measures the effects of genital herpes on parameters such as mental health, self-esteem, and social functioning. Once-daily valacyclovir and twice-daily acyclovir significantly improved health-related quality of life compared with placebo, beginning with the first quality of life assessment after 3 months of therapy.³³ The quality of life improvements with valacyclovir and acyclovir were maintained throughout the 1-year study period.

A recent study showed that 72% of patients who had tried both daily suppressive therapy with once-daily valacyclovir and episodic therapy with twice-daily valacyclovir prefer suppressive therapy to episodic treatment.³⁴ Similarly, at the end of a 1-year, open-label study with acyclovir, 9 of 10 patients with a history of at least six recurrent genital herpes episodes per year chose suppressive over episodic therapy.³⁵

Implementing suppressive therapy

The benefits of initiating suppressive therapy early in the course of the disease have not yet been evaluated in clinical studies. Nevertheless, genital herpes recurrences are typically more frequent and severe (although less severe than the primary infection) during the first months after the initial episode,³⁶ and recurrence patterns can be recognized within 4 to 6 months of the primary infection. Because of this, suppressive therapy may be most beneficial in the months following the initial episode.

More study is needed to develop management strategies and to determine optimum duration for long-term suppressive therapy. The duration is patient dependent and often determined by discontinuing therapy periodically (eg, once a year) and monitoring the patient for recurrences. A patient who has frequent or severe recurrences after stopping long-term suppressive therapy should restart it. Patients who have had two recurrences within 2 months may restart suppressive therapy with the second recurrence.

Additional support

In addition to antiviral therapy, intervention strategies for genital herpes include psychological counseling, social support, relaxation training, and stress management training.^27,37-41 These strategies are typically most effective when implemented in conjunction with pharmacotherapy.

Conclusions

Many patients who have genital herpes have significant psychological distress in addition to physical morbidity. Both the physical and the psychological impact of genital herpes can be effectively managed with daily suppressive antiviral therapy in combination with appropriate adjunctive psychological or psychosocial interventions.

 

KEY POINTS in this article Recurrent episodes of genital herpes can cause patients considerable psychological distress, which may itself help to provoke further episodes. Daily suppressive antiviral therapy may be considered early in the course of the disease to minimize or prevent recurrences. Suppressive antiviral therapy reduces but does not eliminate subclinical viral shedding, so the extent to which such therapy prevents transmission of herpes simplex virus is unknown.

Acknowledgment

The author acknowledges Jane Saiers, PhD, for assistance in writing this article.

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Michael Remington. Minimizing recurrences of genital herpes--a role for suppressive therapy. JAAPA August 2004;17:19-24.

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