Famciclovir for the treatment of recurrent genital herpes: A clinical and pharmacological perspective

Expert Opinion on Pharmacotherapy

Volumn 7, Issue 16, 2006, Pages 2271-2286

  Vinh, Donald C ^b   Aoki, Fred Y ^a  

^a UNIVERSITY OF MANITOBA   (Canada)

^b University of Manitoba ^*

Author keywords

Famciclovir; Recurrent genital herpes

Indexed keywords

2 AMINOPURINE; DRUG DERIVATIVE; FAMCICLOVIR;

ANIMAL; GENITAL HERPES; HUMAN; RECURRENT DISEASE; REVIEW;

2-AMINOPURINE; ANIMALS; HERPES GENITALIS; HUMANS; RECURRENCE;

EID: 34247473274     PISSN: 14656566     EISSN: None     Source Type: Journal    
DOI: 10.1517/14656566.7.16.2271     Document Type: Review

References (109)

1. MERTZ KJ, TREES D, LEVINE WC et al.: Aetiology of genital ulcers and prevalence of human immunodeficiency virus coinfection in 10 US cities. The Genital Ulcer Disease Surveillance Group. J. Infect. Dis. (1998) 178:1795-1798.
2. RISBUD A, CHAN-TACK K, GADKARI D et al.: The aetiology of genital ulcer disease by multiplex polymerase chain reaction and relationship to HIV infection among patients attending sexually transmitted disease clinics in Pune, India. Sex. Transm. Dis. (1999) 26:55-62. (Pubitemid 29031646)
3. AHMED HJ, MBWANA J, GUNNARSSON E et al.: Aetiology of genital ulcer disease and association with human immunodeficiency virus infection in two Tanzanian cities. Sex. Transm. Dis. (2003) 30:114-119.
4. BRUISTEN SM, CAIRO I, FENNEMA H et al.: Diagnosing genital ulcer disease in a clinic for sexually transmitted diseases in Amsterdam, The Netherlands. J. Clin. Microbiol. (2001) 39:601-605. (Pubitemid 32150825)
5. JENKINS FJ, ROWE DT, RINALDO CR Jr: Herpesvirus infections in organ transplant recipients. Clin. Diagn. Lab. Immunol. (2003) 10:1-7.
6. FLEMING DT, MCQUILLAN GM, JOHNSON RE et al.: Herpes simplex virus Type 2 in the United States, 1976 to 1994. N. Engl. J. Med. (1997) 16:1105-1111.
7. DIAZ-MITOMA F, SIBBALD RG, SHAFRAN SD et al.: Oral famciclovir for the suppression of recurrent genital herpes: a randomized controlled trial. Collaborative Famciclovir Genital Herpes Research Group. JAMA (1998) 280:887-892. (Pubitemid 28423915)
8. LAFFERTY WE, DOWNEY L, CELUM C et al.: Herpes simplex virus Type 1 as a cause of genital herpes: impact on surveillance and prevention. J. Infect. Dis. (2000) 181:1454-1457.
9. WHITLEY RJ, KIMBERLIN DW, ROIZMAN B: Herpes simplex viruses. Clin. Infect. Dis. (1998) 26:541-553.
10. KIMBERLIN DW, ROUSE DJ: Clinical practice. Genital herpes. N. Engl. J. Med. (2004) 350:1970-1977.
11. BENEDETTI J, COREY L, ASHLEY R: Recurrence rates in genital herpes after symptomatic first-episode infection. Ann. Intern. Med. (1994) 121:847-854.
12. BENEDETTI JK, ZEH J, COREY L: Clinical reactivation of genital herpes simplex virus infection decreases in frequency over time. Ann. Intern. Med. (1999) 131:14-20.
13. ENGELBERG R, CARRELL D, KRANTZ E et al.: Natural history of genital herpes simplex virus Type 1 infection. Sex. Transm. Dis. (2003) 30:174-177.
14. WALD A, ZEH J, SELKE S et al.: Reactivation of genital herpes simplex virus Type 2 infection in asymptomatic seropositive persons. N. Engl. J. Med. (2000) 342:844-850.
15. KOELLE DM, BENEDETTI J, LANGENBERG A et al.: Asymptomatic reactivation of herpes simplex virus in women after the first episode of genital herpes. Ann. Intern. Med. (1992) 116:433-437.
16. EARNSHAW DL, BACON TH, DARLISON SJ et al.: Mode of antiviral action of penciclovir in MRC-5 cells infected with herpes simplex virus Type 1 (HSV-1), HSV-2, and varicella-zoster virus. Antimicrob. Agents Chemother. (1992) 36:2747-2757.
17. VERE HODGE RA, PERKINS RM: Mode of action of 9-(4-hydroxy-3- hydroxymethylbut-1-yl)gua nine (BRL 39123) against herpes simplex virus in MRC-5 cells. Antimicrob. Agents Chemother. (1989) 33:223-229.
18. PERRY CM, WAGSTAFF AJ: Famciclovir. A review of its pharmacological properties and therapeutic efficacy in herpesvirus infections. Drugs (1995) 50:396-415.
19. WEINBERG A, BATE BJ, MASTERS HB et al.: In vitro activities of penciclovir and acyclovir against herpes simplex virus types 1 and 2. Antimicrob. Agents Chemother. (1992) 36:2037-2038.
20. BOYD MR, BACON TH, SUTTON D: Antiherpesvirus activity of 9-(4-hydroxy-3-hydroxymethylbut-1-yl) guanine (BRL 39123) in animals. Antimicrob. Agents Chemother. (1988) 32:358-363.
21. VERE HODGE RA, SUTTON D, BOYD MR et al.: Selection of an oral prodrug (BRL 42810; famciclovir) for the antiherpesvirus agent BRL 39123 [9-(4-hydroxy-3-hydroxymethylbut-l-yl)gua nine; penciclovir]. Antimicrob. Agents Chemother. (1989) 33:1765-1773.
22. STEIN GE: Pharmacology of new antiherpes agents: famciclovir and valacyclovir. J. Am. Pharm. Assoc. (1997) NS37:157-163.
23. BACON TH, BOYD MR: Activity of penciclovir against Epstein-Barr virus. Antimicrob. Agents Chemother. (1995) 39:1599-1602.
24. SHEN H, ALSATIE M, ECKERT G et al.: Combination therapy with lamivudine and famciclovir for chronic hepatitis B infection. Clin Gastroenterol. Hepatol. (2004) 2:330-336.
25. THACKRAY AM, FIELD HJ: Differential effects of famciclovir and valaciclovir on the pathogenesis of herpes simplex virus in a murine infection model including reactivation from latency. J. Infect. Dis. (1996) 173:291-299.
26. THACKRAY AM, FIELD HJ: Famciclovir and valaciclovir differ in the prevention of herpes simplex virus Type 1 latency in mice: a quantitative study. Antimicrob. Agents Chemother. (1998) 42:1555-1562.
27. FIELD HJ, TEWARI D, SUTTON D et al.: Comparison of efficacies of famciclovir and valaciclovir against herpes simplex virus Type 1 in a murine immunosuppression model. Antimicrob. Agents Chemother. (1995) 39:1114-1119.
28. LOUTSCH JM, SAINZ B JR, MARQUART ME et al.: Effect of famciclovir on herpes simplex virus Type 1 corneal disease and establishment of latency in rabbits. Antimicrob. Agents Chemother. (2001) 45:2044-2053.
29. THACKRAY AM, FIELD HJ: Comparison of effects of famciclovir and valaciclovir on pathogenesis of herpes simplex virus Type 2 in a murine infection model. Antimicrob. Agents Chemother. (1996) 40:846-851.
30. THACKRAY AM, FIELD HJ: Persistence of infectious herpes simplex virus Type 2 in the nervous system in mice after antiviral chemotherapy. Antimicrob. Agents Chemother. (2000) 44:97-102.
31. PROBER CG: Herpesvirus infections: from bedside to bench and back again. Herpes (2001) 8:3. (Pubitemid 32290370)
32. STANBERRY LR, KERN ER, RICHARDS JT et al.: Genital herpes in guinea-pigs: pathogenesis of the primary infection and description of recurrent disease. J. Infect. Dis. (1982) 146(3):397-404.
33. SCRIBA M: Herpes simplex virus infection in guinea-pigs: an animal model for studying latent and recurrent herpes simplex virus infection. Infect. Immun. (1975) 12:162-165.
34. JENNINGS R, SMITH TL, MYHREN F et al.: Evaluation of a novel, antiherpes simplex virus compound, acyclovir elaidate (P-4010), in the female guinea-pig model of genital herpes. Antimicrob. Agents Chemother. (1999) 43:53-61.
35. SARISKY RT, BACON TH, BOON RJ et al.: Profiling penciclovir susceptibility and prevalence of resistance of herpes simplex virus isolates across eleven clinical trials. Arch. Virol. (2003) 148:1757-1769.
36. SARISKY RT, QUAIL MR, CLARK PE et al.: Characterization of herpes simplex viruses selected in culture for resistance to penciclovir or acyclovir. J. Virol. (2001) 75:1761-1769. (Pubitemid 32110165)
37. COEN DM, SCHAFFER PA: Two distinct loci confer resistance to acycloguanosine in herpes simplex virus Type 1. Proc. Natl. Acad. Sci. USA (1980) 77:2265-2269.
38. SCHNIPPER LE, CRUMPACKER CS: Resistance of herpes simplex virus to acycloguanosine: role of viral thymidine kinase and DNA polymerase loci. Proc. Natl. Acad. Sci. USA (1980) 77:2270-2273.
39. CHIBO D, DRUCE J, SASADEUSZ J et al.: Molecular analysis of clinical isolates of acyclovir resistant herpes simplex virus. Antiviral Res. (2004) 61:83-91. (Pubitemid 37506095)
40. BOYD MR, BACON TH, SUTTON D et al.: Antiherpesvirus activity of 9-(4-hydroxy-3-hydroxy-methylbut-1-yl)gu anine (BRL 39123) in cell culture. Antimicrob. Agents Chemother. (1987) 31:1238-1242.
41. THUST R, SCHACKE M, WUTZLER P: Cytogenetic genotoxicity of antiherpes virostatics in Chinese hamster V79-E cells. I. Purine nucleoside analogues. Antiviral Res. (1996) 31:105-113.
42. PUE MA, PRATT SK, FAIRLESS AJ et al.: Linear pharmacokinetics of penciclovir following administration of single oral doses of famciclovir 125, 250, 500 and 750 mg to healthy volunteers. J. Antimicrob. Chemother. (1994) 33:119-127.
43. MOOMAW MD, CORNEA P, RATHBUN RC et al.: Review of antiviral therapy for herpes labialis, genital herpes and herpes zoster. Expert Rev. Anti-Infect. Ther. (2003) 1:283-295.
44. PUE MA, BENET LZ: Pharmacokinetics of famciclovir in man. Antiviral Chem. Chemother. (1993) 4:47-55.
45. FILER CW, ALLEN GD, BROWN TA et al.: Metabolic and pharmacokinetic studies following oral administration of 14C-famciclovir to healthy subjects. Xenobiotica (1994) 24:357-368. (Pubitemid 24169009)
46. FOWLES SE, PIERCE DM, PRINCE WT et al.: The tolerance to and pharmacokinetics of penciclovir (BRL 39,123A), a novel antiherpes agent, administered by intravenous infusion to healthy subjects. Eur. J. Clin. Pharmacol. (1992) 43:513-516.
47. BOIKE SC, PUE MA, FREED MI et al.: Pharmacokinetics of famciclovir in subjects with varying degrees of renal impairment. Clin. Pharmacol. Ther. (1994) 55:418-426.
48. GILL KS, WOOD M: The clinical pharmacokinetics of famciclovir. Clin. Pharmacokinet. (1996) 31:1-8.
49. BOIKE SC, PUE M, AUDET PR et al.: Pharmacokinetics of famciclovir in subjects with chronic hepatic disease. J. Clin. Pharmacol. (1994) 34:1199-1207.
50. OBACH RS: Potent inhibition of human liver aldehyde oxidase by raloxifene. Drug Metab. Dispos. (2004) 32:89-97.
51. AL-SALMY HS. Individual variation in hepatic aldehyde oxidase activity. IUBMB Life (2001) 51:249-253. (Pubitemid 32848156)
52. FOWLES SE, PRATT SK, LAROCHE J et al.: Lack of a pharmacokinetic interaction between oral famciclovir and allopurinol in healthy volunteers. Eur. J. Clin. Pharmacol. (1994) 46:355-359.
53. LASKIN OL, DE MIRANDA P, KING DH et al.: Effects of probenecid on the pharmacokinetics and elimination of acyclovir in humans. Antimicrob. Agents Chemother. (1982) 21:804-807.
54. DE BONY F, TOD M, BIDAULT R et al.: Multiple interactions of cimetidine and probenecid with valaciclovir and its metabolite acyclovir. Antimicrob. Agents Chemother. (2002) 46:458-463.
55. TYRING S, BELANGER R, BEZWODAW et al.: A randomized, double-blind trial of famciclovir versus acyclovir for the treatment of localized dermatomal herpes zoster in immunocompromised patients. Cancer Invest. (2001) 19:13-22. (Pubitemid 32233797)
56. FOWLES SE, PUE MA, DM P et al.: Pharmacokinetics of penciclovir in healthy elderly subjects following a single oral administration of 750 mg famciclovir. Br. J. Clin. Pharmacol. (1992) 34:450P.
57. SACKS SL, AOKI FY, DIAZ-MITOMA F et al.: Patient-initiated, twice-daily oral famciclovir for early recurrent genital herpes. A randomized, double-blind multicenter trial. Canadian Famciclovir Study Group. JAMA (1996) 276:44-49.
58. SACKS SL, AOKI FY, MARTEL AY et al.: Clinic-initiated, twice-daily oral famciclovir for treatment of recurrent genital herpes: a randomized, double-blind, controlled trial. Clin. Infect. Dis. (2005) 41:1097-1104.
59. CHOSIDOW O, DROUAULT Y, LECONTE-VEYRIAC F et al.: Famciclovir versus aciclovir in immunocompetent patients with recurrent genital herpes infections: a parallel-groups, randomized, double-blind clinical trial. Br. J. Dermatol. (2001) 144:818-824.
60. WORKWOWSKI KA, LEVINE WC, CENTERS FOR DISEASE CONTROL AND PREVENTION: Sexually Transmitted Diseases Treatment Guidelines 2002. MMWR Recomm. Rep. (2002) 51:1-78.
61. AOKI FY, TYRING S, DIAZ-MITOMA F et al.: Single-day, patient-initiated famciclovir therapy for recurrent genital herpes: a randomized, double-blind, placebo-controlled trial. Clin. Infect. Dis. (2006) 42:8-13.
62. REICHMAN RC, BADGER GJ, MERTZ GJ et al.: Treatment of recurrent genital herpes simplex infections with oral acyclovir. A controlled trial. JAMA (1984) 251:2103-2107. (Pubitemid 14133504)
63. MERTZ GJ, ERON L, KAUFMAN R et al.: Prolonged continuous versus intermittent oral acyclovir treatment in normal adults with frequently recurring genital herpes simplex virus infection. Am. J. Med. (1988) 85:14-19.
64. MERTZ GJ, LOVELESS MO, LEVIN MJ et al.: Oral famciclovir for suppression of recurrent genital herpes simplex virus infection in women. A multicenter, double-blind, placebo-controlled trial. Collaborative Famciclovir Genital Herpes Research Group. Arch. Intern. Med. (1997) 157:343-349.
65. AOKI FY: Management of genital herpes in HIV-infected patients. Herpes (2001) 8:41-45. (Pubitemid 32625614)
66. WALD A, ZEH J, SELKE S et al.: Virologic characteristics of subclinical and symptomatic genital herpes infections. N. Engl. J. Med. (1995) 333:770-775.
67. WALD A, ZEH J, SELKE S et al.: Genital shedding of herpes simplex virus among men. J. Infect. Dis. (2002) 186:S34-S39.
68. KRONE MR, WALD A, TABET SR et al.: Herpes simplex virus Type 2 shedding in human immunodeficiency virus-negative men who have sex with men: frequency, patterns, and risk factors. Clin. Infect. Dis. (2000) 30:261-267.
69. WALD A, HUANG ML, CARRELL D et al.: Polymerase chain reaction for detection of herpes simplex virus (HSV) DNA on mucosal surfaces: comparison with HSV isolation in cell culture. J. Infect. Dis. (2003) 188:1345-1351.
70. WALD A, LANGENBERG AG, LINK K et al.: Effect of condoms on reducing the transmission of herpes simplex virus Type 2 from men to women. JAMA (2001) 285:3100-3106. (Pubitemid 32578207)
71. WALD A, ZEH J, BARNUM G et al.: Suppression of subclinical shedding of herpes simplex virus Type 2 with acyclovir. Ann. Intern. Med. (1996) 124:8-15.
72. GUPTA R, WALD A, KRANTZ E et al.: Valacyclovir and acyclovir for suppression of shedding of herpes simplex virus in the genital tract. J. Infect. Dis. (2004) 190:1374-1381.
73. SACKS SL: Famciclovir suppression of asymptomatic and symptomatic recurrent anogenital herpes simplex virus shedding in women: a randomized, double-blind, double-dummy, placebo-controlled, parallel-group, single-center trial. J. Infect. Dis. (2004) 189:1341-1347.
74. WALD A, SELKE S, WARREN T et al.: Comparative efficacy of famciclovir and valacyclovir for suppression of recurrent genital herpes and viral shedding. Sex. Transm. Dis. (2006) 33(9):529-533.
75. COREY L, WALD A, PATEL R et al.: Once-daily valacyclovir to reduce the risk of transmission of genital herpes. N. Engl. J. Med. (2004) 350:11-20.
76. SCHACKER T, RYNCARZ AJ, GODDARD J et al.: Frequent recovery of HIV-1 from genital herpes simplex virus lesions in HIV-1-infected men. JAMA (1998) 280:61-66. (Pubitemid 28414998)
77. KREISS JK, COOMBS R, PLUMMER F et al.: Isolation of human immunodeficiency virus from genital ulcers in Nairobi prostitutes. J. Infect. Dis. (1989) 160:380-384.
78. GRAY RH, WAWER MJ, BROOKMEYER R et al.: Probability of HIV-1 transmission per coital act in monogamous, heterosexual, HIV-1-discordant couples in Rakai, Uganda. Lancet (2001) 357:1149-1153. (Pubitemid 32378686)
79. HENG MC, HENG SY, ALLEN SG: Co-infection and synergy of human immunodeficiency virus-1 and herpes simplex virus-1. Lancet (1994) 343:255-258. (Pubitemid 24039624)
80. ALBRECHT MA, DELUCA NA, BYRN RA et al.: The herpes simplex virus immediate-early protein, ICP4, is required to potentiate replication of human immunodeficiency virus in CD4+ lymphocytes. J. Virol. (1989) 63:1861-1868. (Pubitemid 19107778)
81. GOLDEN MP, KIM S, HAMMER SM et al.: Activation of human immunodeficiency virus by herpes simplex virus. J. Infect. Dis. (1992) 166:494-499.
82. MOLE L, RIPICH S, MARGOLIS D et al.: The impact of active herpes simplex virus infection on human immunodeficiency virus load. J. Infect. Dis. (1997) 176:766-770.
83. DUFFUS WA, MERMIN J, BUNNELL R et al.: Chronic herpes simplex virus type-2 infection and HIV viral load. Int. J. STD AIDS (2005) 16:733-735. (Pubitemid 41659532)
84. SIEGAL FP, LOPEZ C, HAMMER GS et al.: Severe acquired immunodeficiency in male homosexuals, manifested by chronic perianal ulcerative herpes simplex lesions. N. Engl. J. Med. (1981) 305:1439-1444.
85. BAGDADES EK, PILLAY D, SQUIRE SB et al.: Relationship between herpes simplex virus ulceration and CD4+ cell counts in patients with HIV infection. AIDS (1992) 6:1317-1320.
86. AUGENBRAUN M, FELDMAN J, CHIRGWIN K et al.: Increased genital shedding of herpes simplex virus Type 2 in HIV-seropositive women. Ann. Intern. Med. (1995) 123:845-847.
87. AUGENBRAUN M, COREY L, REICHELDERFER P et al.: Herpes simplex virus shedding and plasma human immunodeficiency virus RNA levels in coinfected women. Clin. Infect. Dis. (2001) 33:885-890.
88. SCHACKER T, ZEH J, HU HL et al.: Frequency of symptomatic and asymptomatic herpes simplex virus Type 2 reactivations among human immunodeficiency virus-infected men. J. Infect. Dis. (1998) 178:1616-1622.
89. SULIGOI B, DORRUCCI M, VOLPI A et al.: No protective effect of acyclovir on HIV disease progression in a cohort of HSV-2-HIV-infected individuals. Antivir. Ther. (2002) 7:289-291.
90. ROMANOWSKI B, AOKI FY, MARTEL AY et al.: Efficacy and safety of famciclovir for treating mucocutaneous herpes simplex infection in HIV-infected individuals. Collaborative Famciclovir HIV Study Group. AIDS (2000) 14:1211-1217. (Pubitemid 30420665)
91. SCHACKER T, HU HL, KOELLE DM et al.: Famciclovir for the suppression of symptomatic and asymptomatic herpes simplex virus reactivation in HIV-infected persons. A double-blind, placebo-controlled trial. Ann. Intern. Med. (1998) 128:21-28.
92. DEJESUS E, WALD A, WARREN T et al.: Valacyclovir for the suppression of recurrent genital herpes in human immunodeficiency virus-infected subjects. J. Infect. Dis. (2003) 188:1009-1016.
93. CHEN KT, SEGU M, LUMEY LH et al.: Genital herpes simplex virus infection and perinatal transmission of human immunodeficiency virus. Obstet. Gynecol. (2005) 106:1341-1348.
94. BROWN Z: Preventing herpes simplex virus transmission to the neonate. Herpes (2004) 11:175A-186A.
95. AOKI FY: Canadian Guidelines on Sexually Transmitted Infections, 2006 Edition: Genital Herpes Simplex Virus (HSV) Infections. Public Health Agency of Canada (2006).
96. ANDREWS WW, KIMBERLIN DF, WHITLEY R et al.: Valacyclovir therapy to reduce recurrent genital herpes in pregnant women. Am. J. Obstet. Gynecol. (2006) 194:774-781.
97. AVGIL M, ORNOY A: Herpes simplex virus and Epstein-Barr virus infections in pregnancy: consequences of neonatal or intrauterine infection. Reprod. Toxicol. (2006) 21:436-445.
98. MALKIN JE: Herpes Simplex Virus Infection in Pregnancy. Herpes (1999) 6:50-54. (Pubitemid 30072324)
99. HUTTO C, ARVIN A, JACOBS R et al.: Intrauterine herpes simplex virus infections. J. Pediatr. (1987) 110:97-101. (Pubitemid 17211892)
100. BALDWIN S, WHITLEY RJ: Intrauterine herpes simplex virus infection. Teratology (1989) 39:1-10.
101. BROWN ZA, SELKE S, ZEH J et al.: The acquisition of herpes simplex virus during pregnancy. N. Engl. J. Med. (1997) 337:509-515.
102. SALTZMAN R, JUREWICZ R, BOON R: Safety of famciclovir in patients with herpes zoster and genital herpes. Antimicrob. Agents Chemother. (1994) 38:2454-2457.
103. BELL WR, CHULAY JD, FEINBERG JE: Manifestations resembling thrombotic microangiopathy in patients with advanced human immunodeficiency virus (HIV) disease in a cytomegalovirus prophylaxis trial (ACTG 204). Medicine (1997) 76:369-380.
104. RIVAUD E, MASSIANI MA, VINCENT F et al.: Valacyclovir hydrochloride therapy and thrombotic thrombocytopenic purpura in an HIV-infected patient. Arch. Intern. Med. (2000) 160:1705-1706.
105. SACKS SL, BISHOP AM, FOX R et al.: A double-blind, placebo (PLB)-controlled trial of the effect of chronically administered oral famciclovir (FCV; BRL 42810) on sperm production in men with recurrent genital herpes (RGH) infection. Antivir. Res. (1994) 23:72.
106. NOVARTIS PHARMACEUTICALS CORP.: Famvir (famciclovir) prescribing information. East Hanover (NJ) USA (2002).
107. MOORE HL JR, SZCZECH GM, RODWELL DE et al.: Preclinical toxicology studies with acyclovir: teratologic, reproductive and neonatal tests. Fundam. Appl. Toxicol. (1983) 3:560-568.
108. STONE KM, REIFF-ELDRIDGE R, WHITE AD et al.: Pregnancy outcomes following systemic prenatal acyclovir exposure: Conclusions from the International Acyclovir Pregnancy Registry, 1984-1999. Birth Defects Res. A Clin. Mol. Teratol. (2004) 70:201-207. (Pubitemid 38581386)
109. TYRING SK, BAKER D, SNOWDEN W: Valacyclovir for herpes simplex infection: long-term safety and sustained efficacy after 20 years experience with acyclovir. J. Inf. Dis. (2002) 186:S40-S46.