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July 3, 1996, Vol 276, No. 1 >
ARTICLE | July 3, 1996

Patient-Initiated, Twice-Daily Oral Famciclovir for Early Recurrent Genital Herpes: Title and subTitle BreakA Randomized, Double-blind Multicenter Trial FREE

Stephen L. Sacks, MD; Fred Y. Aoki, MD; Franciso Diaz-Mitoma, MD; John Sellors, MD; Stephen D. Shafran, MD
[+] Author Affiliations

A complete list of the Canadian Famciclovir Study Group appears at the end of the article.

Drs Sacks, Diaz-Mitoma, Sellors, and Shafran have received honoraria from SmithKline Beecham Pharmeceuticals (SKBP); Drs Diaz-Mitoma and Sellors have done contractual work for SKBP; Drs Sacks and Shafran have received grants-in-aid from SKBP; Dr Aoki has served on a herpes vaccine research advisory board for SKBP; and Dr Shafran has served as a paid consultant to SKBP. SmithKline Beecham Pharmeceuticals manufactures famciclovir under the name Famvir.

Reprints: Stephen L. Sacks, MD, Viridae Clinical Sciences, Inc, 1134 Burrard St, Vancouver, British Columbia, Canada V6Z 1Y8.


JAMA. 1996;276(1):44-49. doi:10.1001/jama.1996.03540010046029
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Article
References

Objective.  —To compare the efficacy and safety of episodic patient-initiated oral famciclovir with placebo in recurrent genital herpes.

Design.  —Randomized, double-blind, frequent-observation, dose-ranging study comparing twice-daily 125-mg, 250-mg, or 500-mg oral famciclovir with placebo. Patients initiated therapy after self-culturing, reported to the clinic within 12 hours, and were assessed twice daily for at least 5 days.

Setting.  —Fifteen Canadian university, private practice, or public outpatient clinics.

Patients.  —A total of 692 patients with culture-proven recurrent genital herpes were randomized; 467 patients experienced a symptomatic episode and commenced treatment.

Main Outcome Measure.  —Time to complete healing of all lesions.

Results.  —Famciclovir (all doses) was significantly more effective than placebo in reducing time to healing, time to cessation of viral shedding, and durations of lesion edema, vesicles, ulcers, and crusts. Times to cessation of all symptoms and of moderate to severe lesion tenderness, pain, and burning were also reduced. Patients who initiated famciclovir prior to viral shedding were more likely to not shed virus throughout. All doses were equally effective, safe, and well tolerated.

Conclusions.  —Oral famciclovir reduced the onset and duration of viral shedding, lesion persistence, and uncomfortable symptoms. Several individual symptoms and lesion stages were also reduced in duration by this episodic therapy. Additionally, our twice-daily observation trial design proved to be a helpful tool for studying recurrent disease. Episodic oral famciclovir provides a convenient and effective alternative for those patients with recurrent genital herpes whose frequency rates do not require continuous antiviral suppression.

REFERENCES

1 +
Corey L, Wald A.  New developments in the biology of genital herpes . In: Sacks SL, Straus SE, Whitley RJ, Griffiths PD, eds. Clinical Management of Herpes Virus Infections . Amsterdam, the Netherlands: IOS Press; 1995;:43-53.
2 +
Christenson B, Bottiger M, Svennson A, Jeannsen S.  A 15-year surveillance study of antibodies to HSV-1&2 in a cohort of young girls . J Infect . 1992;;25:147-154.
3 +
Cunningham AL, Lee FK, Ho DWT, et al.  Herpes simplex virus type 2 antibody in patients attending antenatal or STD clinics . Med J Aust . 1993;;158:525-528.
4 +
Johnson RE, Nahmias AJ, Madger LS, Lee FK, Brooks CA, Snowden CB.  A seroepidemiological survey of the prevalence of herpes simplex virus type 2 infection in the United States . N Engl J Med . 1989;;321:7-12.
5 +
Kinghorn GR.  Epidemiology of genital herpes . J Int Med Res . 1994;;22( (suppl 1) ):14A-23A.
6 +
Sacks SL, Fox R, Levendusky P, et al.  Chronic suppression for six months compared with intermittent lesional therapy of frequently recurrent genital herpes using oral acyclovir: effects on lesions and nonlesional prodromes . Sex Transm Dis . 1988;;15:58-62.
7 +
Douglas JM, Critchlow C, Benedetti J, et al.  A double-blind study of oral acyclovir for suppression of recurrences of genital herpes simplex virus infection . N Engl J Med . 1984;;310:1551-1556.
8 +
Straus SE, Takiff HE, Seidlin M, et al.  Suppression of frequently recurring genital herpes: a placebo-controlled double-blind trial of oral acyclovir . N Engl J Med . 1984;;310:1545-1550.
9 +
Halsøs AM, Salo OP, Lassus A, et al.  Oral acyclovir suppression of recurrent genital herpes: a double-blind, placebo-controlled, crossover study . Acta Derm Venereol Suppl . 1985;;65:59-63.
10 +
Mindel A, Weller IV, Faherty A, et al.  Prophylactic oral acyclovir in recurrent genital herpes . Lancet . 1984;;2:57-59.
11 +
Gold D, Corey L.  Acyclovir prophylaxis for herpes simplex virus infection . Antimicrob Agents Chemother . 1987;;31:361-367.
12 +
Straus SE, Seidlin M, Takiff HE, et al.  Double-blind comparison of weekend and daily regimens of oral acyclovir for suppression of recurrent genital herpes . Antiviral Res . 1986;;6:151-159.
13 +
Goldberg LH, Kaufman R, Kurtz TO, et al, and the Acyclovir Study Group.  Long-term suppression of recurrent genital herpes with acyclovir: a 5-year benchmark . Arch Dermatol . 1993;;129:582-587.
14 +
Sacks SL.  Treatment of herpes genitalis . In: De Clercq E, ed. Clinical Use of Antiviral Drugs . Boston, Mass: Martinus Nijhoff Publishing; 1988;:87-114.
15 +
Sacks SL.  Genital herpes simplex virus infection and treatment . In: Sacks SL, Straus SE, Whitley RJ, Griffiths PD, eds. Clinical Management of Herpes Virus Infections . Amsterdam, the Netherlands: IOS Press; 1995;:55-74.
16 +
Sacks SL.  The role of oral acyclovir in the management of genital herpes simplex . Can Med Assoc J . 1987;;136:701-707.
17 +
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.
18 +
Nilsen AE, Aasen T, Halsøs AM, et al.  Efficacy of oral acyclovir in the treatment of initial and recurrent genital herpes . Lancet . 1982;;2:571-573.
19 +
Pue MA, Benet LZ.  Pharmacokinetics of famciclovir in man . Antiviral Chem Chemother . 1993;;4( (suppl 1) ):47-55.
20 +
Vere Hodge RA.  Famciclovir and penciclovir: the mode of action of famciclovir including its conversion to penciclovir . Antiviral Chem Chemother . 1993;;4:67-84.
21 +
Boyd MR, Safrin S, Kern ER.  Penciclovir: a review of its spectrum of activity, selectivity, and cross-resistance pattern . Antiviral Chem Chemother . 1993;;4( (suppl 1) ):3-11.
22 +
Vere Hodge RA, Perkins RM.  Mode of action of 9-(4-hydroxy-3-hydroxymethylbut-1-yl) guanine (BRL 39123) against herpes simplex virus in MRC-5 cells . Antimicrob Agents Chemother . 1989;;33:223-229.
23 +
Sacks SL, Teh CZ, Lemchuck-Favel L.  Serotyping of herpes simplex virus isolates: a comparison of BVDU sensitivities, indirect immunofluorescence with monoclonal antibodies, and indirect immunofluorescnence with cross-adsorbed rabbit antibodies . J Virol Methods . 1983;;7:199-206.
24 +
Cox DR.  Regression models and life tables (with discussion) . J R Stat Soc Ser B . 1972;;34:187-220.
25 +
SAS Institute. SAS Procedures Guide, Version 6.07. Cary, NC: SAS Institute; 1988.
26 +
SAS Institute. SAS Technical Report P-229. Cary, NC: SAS Institute; 1982:433-479.
27 +
Hochberg Y.  A sharper Bonferroni procedure for multiple tests of significance . Biometrika . 1988;;75:800-802.
28 +
Armitage P, Berry G. Statistical Methods in Medical Research . 2nd ed. Oxford, England: Blackwell Scientific Publications; 1987;.
29 +
Sacks SL, Varner TL, Davies KS, et al.  Randomized, double-blind, placebo-controlled, patientinitiated study of topical high- and low-dose interferon-α with nonoxynol-9 in the treatment of recurrent genital herpes . J Infect Dis . 1990;;161:692-698.
30 +
Sacks SL, Tyrrell DL, Lawee D, et al, and the Canadian Cooperative Study Group.  Randomized, double-blind, placebo-controlled, clinic-initiated, Canadian multicenter trial of topical 3% edoxudine cream in the treatment of recurrent genital herpes . J Infect Dis . 1991;;164:665-672.
31 +
Ruhnek-Forsbeck M, Sandstrom E, Andersson B, et al.  Treatment of recurrent genital herpes simplex infections with oral acyclovir . J Antimicrob Chemother . 1985;;16:621-628.
32 +
Salo OP, Lassus A, Hovi T, Fiddian AP.  Double-blind placebo-controlled trial of oral acyclovir in recurrent genital herpes . Eur J Sex Transm Dis . 1983;;1:95-98.
33 +
de Miranda P, Blum MR.  Pharmacokinetics of acyclovir after intravenous and oral administration . J Antimicrob Chemother . 1983;;12( (suppl B) ):29-37.
34 +
Sacks SL, Martel A, Aoki FY, Shafran SD, St-Pierre C, Lassonde M. Early, Clinic-Initiated Treatment of Recurrent Genital Herpes Using Famciclovir: Results of a Canadian, Multi-Center Study. Abstract presented at the Clinical Research Meeting, American Federation of Clinical Research; 1994; Baltimore, Md.

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1 +
Corey L, Wald A.  New developments in the biology of genital herpes . In: Sacks SL, Straus SE, Whitley RJ, Griffiths PD, eds. Clinical Management of Herpes Virus Infections . Amsterdam, the Netherlands: IOS Press; 1995;:43-53.
2 +
Christenson B, Bottiger M, Svennson A, Jeannsen S.  A 15-year surveillance study of antibodies to HSV-1&2 in a cohort of young girls . J Infect . 1992;;25:147-154.
3 +
Cunningham AL, Lee FK, Ho DWT, et al.  Herpes simplex virus type 2 antibody in patients attending antenatal or STD clinics . Med J Aust . 1993;;158:525-528.
4 +
Johnson RE, Nahmias AJ, Madger LS, Lee FK, Brooks CA, Snowden CB.  A seroepidemiological survey of the prevalence of herpes simplex virus type 2 infection in the United States . N Engl J Med . 1989;;321:7-12.
5 +
Kinghorn GR.  Epidemiology of genital herpes . J Int Med Res . 1994;;22( (suppl 1) ):14A-23A.
6 +
Sacks SL, Fox R, Levendusky P, et al.  Chronic suppression for six months compared with intermittent lesional therapy of frequently recurrent genital herpes using oral acyclovir: effects on lesions and nonlesional prodromes . Sex Transm Dis . 1988;;15:58-62.
7 +
Douglas JM, Critchlow C, Benedetti J, et al.  A double-blind study of oral acyclovir for suppression of recurrences of genital herpes simplex virus infection . N Engl J Med . 1984;;310:1551-1556.
8 +
Straus SE, Takiff HE, Seidlin M, et al.  Suppression of frequently recurring genital herpes: a placebo-controlled double-blind trial of oral acyclovir . N Engl J Med . 1984;;310:1545-1550.
9 +
Halsøs AM, Salo OP, Lassus A, et al.  Oral acyclovir suppression of recurrent genital herpes: a double-blind, placebo-controlled, crossover study . Acta Derm Venereol Suppl . 1985;;65:59-63.
10 +
Mindel A, Weller IV, Faherty A, et al.  Prophylactic oral acyclovir in recurrent genital herpes . Lancet . 1984;;2:57-59.
11 +
Gold D, Corey L.  Acyclovir prophylaxis for herpes simplex virus infection . Antimicrob Agents Chemother . 1987;;31:361-367.
12 +
Straus SE, Seidlin M, Takiff HE, et al.  Double-blind comparison of weekend and daily regimens of oral acyclovir for suppression of recurrent genital herpes . Antiviral Res . 1986;;6:151-159.
13 +
Goldberg LH, Kaufman R, Kurtz TO, et al, and the Acyclovir Study Group.  Long-term suppression of recurrent genital herpes with acyclovir: a 5-year benchmark . Arch Dermatol . 1993;;129:582-587.
14 +
Sacks SL.  Treatment of herpes genitalis . In: De Clercq E, ed. Clinical Use of Antiviral Drugs . Boston, Mass: Martinus Nijhoff Publishing; 1988;:87-114.
15 +
Sacks SL.  Genital herpes simplex virus infection and treatment . In: Sacks SL, Straus SE, Whitley RJ, Griffiths PD, eds. Clinical Management of Herpes Virus Infections . Amsterdam, the Netherlands: IOS Press; 1995;:55-74.
16 +
Sacks SL.  The role of oral acyclovir in the management of genital herpes simplex . Can Med Assoc J . 1987;;136:701-707.
17 +
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.
18 +
Nilsen AE, Aasen T, Halsøs AM, et al.  Efficacy of oral acyclovir in the treatment of initial and recurrent genital herpes . Lancet . 1982;;2:571-573.
19 +
Pue MA, Benet LZ.  Pharmacokinetics of famciclovir in man . Antiviral Chem Chemother . 1993;;4( (suppl 1) ):47-55.
20 +
Vere Hodge RA.  Famciclovir and penciclovir: the mode of action of famciclovir including its conversion to penciclovir . Antiviral Chem Chemother . 1993;;4:67-84.
21 +
Boyd MR, Safrin S, Kern ER.  Penciclovir: a review of its spectrum of activity, selectivity, and cross-resistance pattern . Antiviral Chem Chemother . 1993;;4( (suppl 1) ):3-11.
22 +
Vere Hodge RA, Perkins RM.  Mode of action of 9-(4-hydroxy-3-hydroxymethylbut-1-yl) guanine (BRL 39123) against herpes simplex virus in MRC-5 cells . Antimicrob Agents Chemother . 1989;;33:223-229.
23 +
Sacks SL, Teh CZ, Lemchuck-Favel L.  Serotyping of herpes simplex virus isolates: a comparison of BVDU sensitivities, indirect immunofluorescence with monoclonal antibodies, and indirect immunofluorescnence with cross-adsorbed rabbit antibodies . J Virol Methods . 1983;;7:199-206.
24 +
Cox DR.  Regression models and life tables (with discussion) . J R Stat Soc Ser B . 1972;;34:187-220.
25 +
SAS Institute. SAS Procedures Guide, Version 6.07. Cary, NC: SAS Institute; 1988.
26 +
SAS Institute. SAS Technical Report P-229. Cary, NC: SAS Institute; 1982:433-479.
27 +
Hochberg Y.  A sharper Bonferroni procedure for multiple tests of significance . Biometrika . 1988;;75:800-802.
28 +
Armitage P, Berry G. Statistical Methods in Medical Research . 2nd ed. Oxford, England: Blackwell Scientific Publications; 1987;.
29 +
Sacks SL, Varner TL, Davies KS, et al.  Randomized, double-blind, placebo-controlled, patientinitiated study of topical high- and low-dose interferon-α with nonoxynol-9 in the treatment of recurrent genital herpes . J Infect Dis . 1990;;161:692-698.
30 +
Sacks SL, Tyrrell DL, Lawee D, et al, and the Canadian Cooperative Study Group.  Randomized, double-blind, placebo-controlled, clinic-initiated, Canadian multicenter trial of topical 3% edoxudine cream in the treatment of recurrent genital herpes . J Infect Dis . 1991;;164:665-672.
31 +
Ruhnek-Forsbeck M, Sandstrom E, Andersson B, et al.  Treatment of recurrent genital herpes simplex infections with oral acyclovir . J Antimicrob Chemother . 1985;;16:621-628.
32 +
Salo OP, Lassus A, Hovi T, Fiddian AP.  Double-blind placebo-controlled trial of oral acyclovir in recurrent genital herpes . Eur J Sex Transm Dis . 1983;;1:95-98.
33 +
de Miranda P, Blum MR.  Pharmacokinetics of acyclovir after intravenous and oral administration . J Antimicrob Chemother . 1983;;12( (suppl B) ):29-37.
34 +
Sacks SL, Martel A, Aoki FY, Shafran SD, St-Pierre C, Lassonde M. Early, Clinic-Initiated Treatment of Recurrent Genital Herpes Using Famciclovir: Results of a Canadian, Multi-Center Study. Abstract presented at the Clinical Research Meeting, American Federation of Clinical Research; 1994; Baltimore, Md.

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