Published on 18/03/2015 by admin
Filed under Dermatology
Last modified 22/04/2025
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Rachel A. Gordon, Rana Majd Mays and Stephen K. Tyring
Evidence Levels: A Double-blind study B Clinical trial ≥ 20 subjects C Clinical trial < 20 subjects D Series ≥ 5 subjects E Anecdotal case reports
Herpes genitalis, or genital herpes, is a recurrent vesicular eruption of the skin and mucosa in the region between the navel and the buttocks, usually preceded by prodromal symptoms including itching, burning, and tingling. It is a common sexually transmitted disease caused predominantly by herpes simplex virus type 2 (HSV-2), but can also be caused by HSV-1. Primary infection may have associated influenza-like systemic signs, including fever, headache, malaise, and myalgia, which occur two to 20 days post exposure. Tender lymphadenopathy may also develop in the second and third weeks. Recurrences generally lack systemic symptoms and are less severe than the primary outbreak. Lesions of recurrences occur in the same area but are fewer in number and heal more quickly. Typical lesions of recurrent outbreaks manifest as grouped papules on an erythematous base which progress to thin-walled vesicles, ulcers, and then soft crusts. Dry crusts form in 3 to 4 days, allowing for healing. Residual hypopigmentation, hyperpigmentation, and scarring may occur with healing.
As no cure exists for herpes genitalis, treatment is aimed at reducing the number of recurrences using suppressive therapy and at promoting rapid healing when a recurrence is present. In addition, treatment aims to reduce infectivity by reducing viral shedding, and to reduce complications such as urinary retention and aseptic meningitis. In the past, acyclovir, both topical and oral, was used as a first-line treatment for recurrences. Given acyclovir’s low bioavailability, it requires frequent dosing. The standard dosing of oral acyclovir for a recurrence is 200 mg five times daily for 5 days. Alternative regimens have also been shown to be effective, including 400 mg three times daily for 5 days, 800 mg three times daily for 2 days, and 800 mg twice daily for 5 days. The frequent dosing of acyclovir led to the development of valacyclovir and famciclovir (the prodrugs of acyclovir and penciclovir, respectively) as alternative therapies with improved bioavailability. The use of topical acyclovir should be discouraged as it is less effective than oral acyclovir. Valacyclovir has been shown to be effective when dosed 500 mg twice daily for 3 days or 1000 mg once daily for 5 days. A dosing regimen of oral valacyclovir, given 2000 mg twice daily for 1 day, has been studied and shown to be more convenient; however, further comparative studies are needed. Famciclovir is effective when prescribed as 1000 mg twice daily for 1 day. It may also be taken as 125 mg twice daily for 5 days. Acyclovir, valacyclovir, and famciclovir may all be used for suppressive therapy.
Immunocompromised individuals have more frequent recurrences and can develop more severe lesions, thus requiring longer treatment periods with higher doses than those used in the immunocompetent. Severe cases may require intravenous therapy. Suppressive dosage regimens have been used in this population. Long-term therapy may lead to the selection of resistant strains of virus. In acyclovir-resistant cases, intravenous therapy with foscarnet may be required.
Another important aspect of genital herpes management is psychosocial. The recurrent nature of genital HSV infection can have severe emotional and psychological impact on patients. Counseling serves to help them cope with the infection and to prevent sexual and perinatal transmission. A physician can empower patients, allowing them to better manage the disease by educating them about the disease process.
Viral culture
PCR
Serologic testing
Skin biopsy of atypical lesion
Diagnosis may be made clinically when the history and presentation are consistent with HSV infection. When possible, laboratory confirmatory testing should be used. Severe or refractory cases may be due to underlying immunosuppression, which should be investigated further.
Scoular A. Sex Transm Infect 2002; 78: 160–5.
Wald A, Huang M-L, Carrell D, Selke S, Corey L. J Infect Dis 2003; 188: 1345–51.
Whittington WL, Celum CL, Cent A, Ashley RL. Sex Transm Dis 2001: 28: 99–104.
Gupta R, Warren T, Wald A. Lancet 2007; 370: 2127–37.
Antiviral treatment should be initiated promptly, even before laboratory confirmation of the diagnosis, and should be continued for seven to 10 days. Treatment duration may be extended if adequate healing has not occurred. The following regimens may be used: acyclovir 400 mg three times daily or 200 mg five times daily; valacyclovir 1000 mg twice daily; or famciclovir 250 mg three times daily.
Johnston C, Saracino M, Kuntz S, Magaret A, Selke S, Huang ML, et al. Lancet 2012; 379(9816): 641–7. Erratum in: 2012. Lancet. 379(9816): 616.
Three separate, complementary open-label cross-over studies compared no medication with acyclovir 400 mg twice daily (standard dose), valacyclovir 500 mg daily (standard dose) with acyclovir 800 mg three times daily (high dose), and standard-dose valacyclovir with valacyclovir 1 g three times daily (high dose). Participants were HIV negative, HSV-2 seropositive and collected genital swabs four times daily. Treatment lasted between four and seven weeks; the primary end-point was shedding rate. High-dose acyclovir was associated with less viral shedding than standard-dose valacyclovir, but there was no significant difference in time to lesion healing between the groups. High-dose valacyclovir had less viral shedding and shorter lesion healing time when compared to its standard dose. Viral shedding persisted even in high-dose regimens, and more potent therapy is needed to prevent HSV transmission.
Bavaro JB, Drolette L, Koelle DM, Almekinder J, Warren T, Tyring S, et al. Sex Transm Dis 2008; 35: 383–6.
A dosing regimen of oral valacyclovir, given 2000 mg twice daily for 1 day, may be a more convenient treatment for genital herpes recurrences but requires further comparative investigation.
Tyring S, Berger T, Yen-Moore A, Tharp M, Hamed K. Am J Clin Dermatol 2006; 7: 209–11.
A multicenter, randomized, double-blind placebo-controlled clinical trial found that famciclovir 1000 mg twice daily for 1 day, taken within 6 hours of prodrome onset, showed a significant reduction in lesion healing time and reduced the time of all symptom resolution compared to placebo. A greater proportion of subjects who took famciclovir did not progress to a full genital herpes outbreak compared to those taking placebo (23.3% vs 12.7%, respectively).
Centers for Disease Control and Prevention. MMWR Recomm Rep 2006; 55: 16–20.
Antiviral therapy should be initiated during the prodrome or within 1 day of lesion onset. Therefore, it is important that patients have a supply of drug on hand, whether acyclovir, valacyclovir or famciclovir, in order to initiate treatment immediately.
Aoki FY, Tyring S, Diaz-Mitoma F, Gross G, Gao J, Hamed K. Clin Infect Dis 2006; 42: 8–13.
This study proved that in addition to being convenient (potentially a boon for increased patient compliance), single-day therapy is safe and effective for the treatment of recurrent genital herpes. Subjects receiving 1000 mg famciclovir orally twice daily for 1 day healed approximately 2 days faster than those on placebo.
Tyring SK, Douglas JM, Corey LC, Spruance SL, Esmann J. Arch Dermatol 1998; 134: 185–91.
This multicenter, double-blind, placebo-controlled, randomized parallel-design study showed that oral valacyclovir 1000 mg twice daily for 5 days was as effective and well tolerated, as was acyclovir five times daily for 5 days for the treatment of recurrent genital herpes.
Prophylactic treatmen for frequent reactivation, recurrent severe attacks, at bone marrow transplantation, or before delivery.
Johnston C, Saracino M, Kuntz S, Magaret A, Selke S, Huang ML, et al. Lancet 2012; 379(9816): 641–7. Epub 2012 Jan 4. Erratum in: 2012. Lancet 379(9816): 616.
Three separate, complementary open-label cross-over studies compared no medication with acyclovir 400 mg twice daily (standard dose), valacyclovir 500 mg daily (standard dose) with acyclovir 800 mg three times daily (high dose), and standard-dose valacyclovir with valacyclovir 1 g three times daily (high-dose). Participants were HIV negative, HSV-2 seropositive and collected genital swabs four times daily. Treatment lasted between four and seven weeks; the primary end-point was shedding rate. High-dose acyclovir was associated with less viral shedding than standard-dose valacyclovir, but there was no significant difference in time to lesion healing between the groups. High-dose valacyclovir had less viral shedding and shorter lesion healing time when compared to its standard dose. Viral shedding persisted even in high-dose regimens, and more potent therapy is needed to prevent HSV transmission.
Fife KH, Warren TJ, Ferrera RD, Young DG, Justus SE, Heitman CK, et al. Mayo Clin Proc 2006; 81: 1321–7.
Over a 60-day period 1 g of valacyclovir daily was well tolerated and effectively reduced clinical and subclinical HSV-2 shedding compared to placebo.
Corey L, Wald A, Patel R, Sacks SL, Tyring SK, Warren T, et al. N Engl J Med 2004; 350: 11–20.
Among heterosexual HSV-2 discordant couples, once-daily valacyclovir (500 mg) significantly reduced the risk of transmission of genital herpes. Clinically symptomatic HSV-2 infection was reduced by 75%, and acquisition of HSV-2 was reduced by 48% in the valacyclovir group versus placebo.
Andrews WW, Kimberlin DF, Whitley R, Cliver S, Ramsey PS, Deeter R. Am J Obstet Gynecol 2006; 194: 774–81.
This double-blind, placebo-controlled, randomized trial showed that daily valacyclovir, initiated at 36 weeks’ gestation in HSV-positive pregnant women with a history of recurrences, significantly reduced the number of women with subsequent clinical HSV recurrences. However, this suppressive regimen did not reduce shedding of HSV within 7 days of delivery compared to placebo. The number of women with clinical HSV lesions at delivery was similar for both the placebo and the treatment group.
Brown ZA, Wald A, Morrow RA, Selke S, Zeh J, Corey L. JAMA 2003; 289: 203–9.
Among women with HSV in genital secretions at the time of labor, the risk of neonatal HSV was significantly reduced in those who had a cesarean delivery.
Severe HSV infection, or complications requiring hospitalization, such as disseminated infection, pneumonitis, hepatitis, meningitis, or encephalitis, requires intravenous antiviral therapy. A regimen of acyclovir 5–10 mg/kg intravenously every 8 hours for a minimum of 2 days until clinical improvement occurs is recommended. Transition to oral antiviral therapy is recommended to complete a 10-day course.
Posavad CM, Wald A, Kuntz S, Huang ML, Selke S, Krantz E, et al. J Infect Dis 2004; 190: 693–6.
In HIV-infected individuals, antiretroviral therapy reduced the frequency and severity of symptomatic genital herpes. However, frequent asymptomatic viral shedding occurred.
Acyclovir, valacyclovir, and famciclovir are safe to use in immunocompromised patients. Treatment duration is generally for 5 to 10 days for the following: acyclovir 400 mg three times daily; famciclovir 500 mg twice daily; or valacyclovir 1 g twice daily. Intravenous therapy may be required in severe cases.
Dignani MC, Mykietiuk A, Michelet M, Intile D, Mammana L, Desmery P, et al. Bone Marrow Transplant 2002; 29: 263–7.
In over 100 patients following bone marrow transplantation, equal efficacy between intravenous acyclovir and oral valacyclovir was seen when compared to no prophylaxis.
Sacks SL, Shafran SD, Diaz-Mitoma F, Trottier S, Sibbald RG, Hughes A, et al. Antimicrob Agents Chemother 1998; 42: 2996–9.
A randomized, double-blind, clinic-initiated, sequential dose-escalation pilot study compared the safety and efficacy of single applications of 1%, 3%, and 5% cidofovir gel with placebo in the treatment of early, lesional, recurrent genital herpes. At all strengths, cidofovir significantly reduced the median time to negative virus culture in a dose-dependent fashion. Single-dose application of cidofovir gel confers a significant antiviral effect on lesions of recurrent genital herpes.
De Clercq E. Clin Microbiol Rev 2003; 16: 569–96.
The acyclic nucleoside phosphonate HPMPC (cidofovir) has proved effective in vitro and in vivo against a wide variety of DNA virus and retrovirus infections, including HSV types 1 and 2.
Hardy WD. Am J Med 1992; 92: 30s–5s.
Twenty-five patients with AIDS and acyclovir-resistant HSV infection were treated with foscarnet infusions for two weeks, followed by eight more weeks with 40 mg/kg daily or without further treatment. Lesions healed most quickly in those treated for a total of 10 weeks.
McCune MA, Perry HO, O’Fallon WM. Cutis 1984; 34: 366–73.
This double-blind, placebo-controlled, crossover trial showed significantly fewer recurrences in subjects during the 24-week period of receiving high-dose (1000 mg daily) lysine than during the 24-week placebo period. No significant difference was noted in those receiving low-dose (500 mg daily) lysine compared to placebo. All subjects were prescribed a high-lysine, low-arginine diet.
Karadi I, Karpati S, Romics L. Ann Intern Med 1998; 128: 696–7.
This study showed that patients treated with aspirin 125 mg daily had significantly fewer days of active HSV infection than controls who took no antiviral or anti-inflammatory drugs. Of the 21 subjects, only two had recurrent genital HSV; the remainder had recurrent oral HSV. All subjects who received aspirin reported milder skin involvement than before aspirin treatment. Nine of the 21 subjects took aspirin long term (several months) and had longer symptom-free periods.
Mark KE, Corey L, Meng TC, Magaret AS, Huang ML, Selke S, et al. J Infect Dis 2007; 195: 1324–31.
A randomized, double-blind, vehicle-controlled trial assessed the efficacy of resiquimod 0.01% gel for reducing human anogenital HSV-2 mucosal reactivation. Adults with genital HSV-2 applied topical resiquimod or vehicle to anogenital lesions twice weekly for three weeks. Daily swabs were then collected for 60 days for HSV DNA PCR. Recurrences over the next seven months were treated with study gel. Resampling for an additional 60 days with swabs was done to assess shedding. The median lesion and shedding rates were lower for the treatment group than in the vehicle group for both sampling periods. The length of recurrence was not influenced by resiquimod treatment.
Spruance SL, Tyring SK, Smith MH, Meng T. J Infect Dis 2001; 184: 196–200.
In this pilot study in human subjects, resiquimod (a topically active immune response modifier) appeared to reduce the frequency of genital herpes recurrences. Over a six-month observation period after treatment, the median period to first recurrence after resiquimod was 169 days, compared to 57 days for the vehicle group.
Hirokawa D, Woldow A, Lee SN, Samie F. Cutis 2011; 88: 276–7.
In this case report, an HIV positive man with valacyclovir-resistant genital HSV-2 was successfully treated with topical imiquimod 5% cream three times weekly for eight weeks.
Helicase primase inhibitors
Psychosocial counseling
Hygiene techniques: keep area clean and dry to prevent secondary infections, avoid touching lesions, and wash hands after any contact with sores
Loose-fitting clothing and cotton underwear
Ice pack/cool compress
Tyring S, Wald A, Zadeikis N, Dhadda S, Takenouchi K, Rorig R. J Infect Dis 2012; 205: 1100–10.
This randomized trial evaluated the safety and efficacy of a novel helicase primase inhibitor for the treatment of recurrent genital herpes. The primary efficacy end-point was time to lesion healing. Groups that received single and 3-day courses of ASP2151 had comparable time to healing as those that received the standard course of valacyclovir 500 mg twice daily for 3 days. Treatment-related adverse events were similar across all groups.
Counseling of infected individuals serves to prevent sexual and perinatal infection and to help individuals cope with infection. Education for infected individuals seems to be of benefit both at the time of diagnosis and after resolution of the acute infection, to further their understanding of the chronic nature of the disease.
Beauman JG, Maj MC. Am Fam Phys 2005; 72: 1527–34, 1541–2.
Prevention of secondary infection and spread of the infection can be achieved by keeping the affected area clean and dry, wearing loose-fitting clothing and cotton underwear, avoiding contact with the lesions, and by washing hands immediately should contact with any sores occur.
Condoms
Vaccine
Wald A, Langenberg AG, Link K, Izu AE, Ashley R, Warren T, et al. JAMA 2001; 285: 3100–6.
In heterosexual discordant couples in which the male is infected with herpes simplex virus type 2, the use of condoms offers significant protection against HSV-2 transmission in susceptible women. A concurrent reduction in sexual activity when the source partner had lesions also occurred as a result of counseling on sexual behavior.
Belshe RB, Leone PA, Bernstein DI, Wald A, Levin MJ, Stapleton JT, et al.; Herpevac Trial for Women. N Engl J Med 2012; 366: 34–43.
In this randomized double-blind trial, 8323 women seronegative for HSV-1 and HSV-2 received the investigational vaccine (20 µg of glycoprotein D from HSV-2 with alum and 3-O-deacylated monophosphoryl lipid A as an adjuvant) at months 0, 1, and 6. The hepatitis A vaccine was used in the control group. The primary efficacy end-point was occurrence of genital herpes from HSV-1 or HSV-2, which was monitored between one and 19 months after the second dose of the vaccine. The vaccine was found to be effective in preventing HSV-1, but not HSV-2 disease and infection.
Treatment of Skin Disease Comprehensive Therapeutic Strategies 4e
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Valacyclovir (Valtrex)
Acyclovir (Zovirax)
Famciclovir (Famvir)
Foscarnet
Cidofovir
L-Lysine
Aspirin
Resiquimod
Topical imiquimod
