Pharmacology and Treatment © 1990 Kargcr AG. Basel 0011-9075/90/1812-0134 $2.75/0
Dermatologica 1990; 181:134-138
Topical Alpha-Interferon in Recurrent Genital Herpes Simplex Infection A Double-Blind, Placebo-Controlled Clinical Trial ./. Shupack, M. Stiller, E. Knobler, C. Ackerman, L. Jondreau, C. Kenny Department of Dermatology. New York University Medical Center. New York, NY. USA
Key Words. Herpes simplex • Interferon • Nonoxynol-9 • Acyclovir resistance
Introduction With an estimated incidence of 260,000-500,000 cases per year, genital herpes virus infections are a source of significant physical and psychological morbidity |lj. Patients experience pain, discomfort and disruption in sexual relations as a result of herpes genitalis. Herpes sim plex virus (HSV) transmitted to newborns puts them at a very high risk for disseminated infection. The most suc cessful treatment to date for recurrent genital herpes infections, oral acyclovir, can safely decrease the fre quency of episodes in patients taking it daily for up to 2 years [2-6]. However, no topical agents, including topical acyclovir, have proven effective in treating recurrent HSV infections. In addition, there have been recent reports of acyclovir-resistant HSV infections in patients with acquired immune deficiency syndrome (AIDS) [7, 8]. In a recent publication Straus ct al. [9| reported that chronic suppressive oral acyclovir therapy does not reduce the rate of asymptomatic viral shedding. These investigators found an increased frequency of acyclovir resistance in HSV cultured from asymptomatic nonimmunocompromised patients [9]. A second agent, preferably
to be used topically, would be welcome as an adjunct to systemic acyclovir or as monotherapy to minimize the emergence of acyclovir-resistant strains of HSV and for use in patients who dislike taking oral medications. Since its discovery in 1957 interferon has shown pro mise in the treatment of human viral infections. The great est dermatologic success has been in treating condylomata acuminata with intralesional interferon [1()|. Results of clinical studies by Pazin ct al. [11, 12] assessing the effi cacy of systemic interferon in the treatment of HSV have been encouraging. Glezerman et al. [13] conducted a 2year double-blind study of (3-interferon in HSV labialis and genitalis. Patients treated with topical (3-interferon had a significantly shorter duration and a decreased recur rence rate of herpetic lesions [13], Friedman-Kicn ct al. [ 14] found that a-interferonat a concentration of It/’ IU in a nonoxynol-9 cream formulation decreased viral shed ding. the formation of new lesions and the time to lesion scabbing of recurrent genital HSV infections. We tested a topical interferon gel consisting of human leukocyte interferon in a base containing 1% nonoxynol-9 and aqueous methylccllulose. Nonoxynol-9 is a wellknown and safe surfactant which aids in the uniform dis
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Abstract. We conducted a double-blind placebo-controlled clinical trial on 98 subjects to assess the efficacy of two strengths of topical human leukocyte a-interferon, 104 and 106 IU/g in a 1% nonoxynol-9 base, in the treatment of recurrent genital herpes simplex virus (HSV). The study medication was applied during the prodromal phase or at the first sign of recurrence of the infection. The high-dose a-interferon was found to be significantly more effective than the low-dose interferon and placebo with respect to the duration of viral shedding as well as in reducing the time to the end of all subjective symptoms, including pain, burning and itching. No difference between the three groups was found in times to crusting or healing. Further studies of topical interferon in the treatment of HSV and other viral infections arc merited.
135
Topical Interferon in Recurrent Herpes Infections
Methods The study population included 98 ambulatory patients (1 patient was ruled a protocol violator leaving 97 analyzable patients) aged 18 years or older with a history of culture-proven, recurrent herpes progcnitalis infections with a definite prodrome enabling them to predict a recurrent episode. Patients did not receive antiviral therapy, antibio tics or photoinactivation during the 2 weeks immediately preceding entry into the study. Patients who had received samllpox or BCG vacci nations shortly before the study were excluded. A medical history and physical examination was obtained from all study subjects at the time of enrollment. Patients who were known or strongly suspected to be immunocompromised were not permitted to participate in this study. Siudy Design This was a double-blind study. After the subjects had signed a writ ten informed consent, they were randomized to either a placebo or one of two treatment groups ( 10J or 10" IU/g of interferon) at the time of their last episode. At the first sign or symptom of recurrence the patients were to apply medication to all externally affected areas three times daily for 7 days. Evaluations were done on days 1,3. 5 and 7. Patients were evaluated for the following parameters during each visit: (1) viability of the herpes virus determined by laboratory culture at 24 and 72 h after application: (2) localized symptoms of pain, burning and itching, each evaluated as none. mild, moderate or severe: (3) impres sion of lesion morphology in terms of the overall stage of development to all lesions. Stages were coded as: none; macules/papules; vesicles/ pustules; erosions/ulcerations: crusts, and healed. In American dermatologic nomenclature, the term symptom refers only to subjective findings such as pruritus, pain, burning and dysesthe sia. Macules, papules, crusts and other objective findings are referred to as signs rather than symptoms. No adverse reactions were noted among the study subjects. Statistical Methods Categorical baseline variables were compared by the / ’ test or. when categories had small numbers, by Fisher's exact test; continuous baseline measures were compared using the Kruskal-Wallis nonparametric test. The primary outcomes were expressed as times in days to various end points indicative of lesion healing: namely, the efficacy analyses
focused on times to crusting, healing, negative viral culture and end of subjective symptoms. Because some patients could not be followed until all end points were observed, these patients provided censored data,and the end point times were analyzed by means of nonparametric survival analyses. The data were analyzed relative to the entire pateint population and also the subset of patients who applied the medication before the appearance of lesions, using analyses which were adjusted for sex. Treatment comparisons were obtained from the log rank test.
Results Of the 97 analyzable patients 72% were male, 34% were Caucasian and the average age was 34 years. The median number of episodes per year was 12.0. There were no significant differences dcmographically or in the seve rity or frequency of HSV infections between the three treatment groups. Time to Negative Culture High-dose cv-interfcron was significantly better com pared to low-dose cv-interfcron and placebo with regard to the duration of viral shedding. The median times to nega tive culture were 1.0 day for the high-dose cv-interferon versus 2.5 days for the low-dose cv-interferon and 2.1 days for the placebo (p = 0.005, based on log rank scores, sig nificant at 0 .0 1; table l.fig. 1). While the time to negative culture was minimally greater for the low-dose interferon versus the placebo, that difference was not statistically significant. Time to End o f Subjective Symptoms The high-dose a-interferon was more effective than placebo or low-dose interferon in reducing the time to the end of all subjective symptoms, i.e. the time until the com plete resolution of pain, burning and itching. Patients on the high dose of a-interferon had a resolution of subjec tive symptoms in a median time of 2.0 days compared to those on the low dose of interferon and placebo where resolution occurred in 2.6 and 3.7 days, respectively (p = 0.017 based on Wilcoxon scores, significant at the 0.05 level; table 1. fig. 2). It should be noted that the signifi cance of the p values for the time to negative culture and time to end of subjective symptoms were much more impressive in those patients who began applying the study drug during the prodrome prior to the occurrence of lesions (table 2). Time to Crusting/Healing The times to crusting or healing were not different among the treatment groups.
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persion of interferon into its gel base. Nonoxynol-9 is a potent inactivating agent of HSV in vitro and lias also been shown to act synergistically with human cv-interfcron against HSV in vitro where it was postulated that the nonoxynol-9 destroyed extracellular HSV while the inter feron disrupted intracellular viral replication [15]. How ever, as with other in vitro viricidal agents, nonoxynol-9 has not demonstrated any effect on genital herpes in vivo [16]. The current clinical trial was not designed to eval uate synergy. While the concept of synergy is theoretically interesting, the number of patients required to be studied in order to substantiate synergy would be exceedingly large.
136
Shupack/Stiller/Knoblcr/Ackerman/Jondrcau/Kcnny
Fig. 1 . Times to end of viral shedding of all patients. H = high-dose interferon; L = low-dose interferon; P = placebo. Days until negative viral culture
Table 1. Times to negative viral cultures and end of symptoms from initial application of study medication A. Times Initial application to negative culture Patients, n Median, days Mean, days Initial application to end of symptoms Patients, n Median, days Mean, days H. Statistic: p values
Initial application to negative culture Wilcoxon scores Log rank scores Initial application to end of symptoms Wilcoxon scores Log rank scores
Low
High
Placebo
41(10) 2.5 2.7
23(2) 1.6
30(6) 2.1 2.5
41(5) 2.6 2.9
25(5) 2.0 2.2
31(8) 3.7 3.4
Dose response
1.0
Overall
Low vs. high
Low
High
V S.
V S.
placebo
placebo
0.227 0.189
0.046' 0.0131
0.015*1 0.0052
0.295 0.246
0.171 0.105
0.0191 0.080
0.060 0.214
0.441 0.506
0.102 0.336
0.017' 0.055
Discussion Our results suggest that topical a-interferon at a con centration of 10'1IU/g may be efficacious in the treatment of genital HSV infections when applied during the pro dromal phase. Negative cultures were obtained signifi
cantly sooner, and the duration of the subjective symp toms pain, burning and pruritus was decreased with the application of the higher concentration of a-interferon. The time to healing, however, was about the same for all three groups - placebo, 104 and 10'’ IU/g of a-inter feron.
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Numbers of patients providing censored data are given in parentheses. Low = ct-Interfcron, 1 x 10J IU/g with 1% nonoxynol-9; high = a-interferon. I x 106 IU/g with 1% nonoxynol-9. Statistics are from survival analyses. 1 Significant at the 0.05 level. 2 Significant at the 0.01 level.
137
Topical Interferon in Recurrent Herpes Infections
Fig. 2. Times to end of symptoms of all patients. 11 = high-dose interferon: L = low-dose interferon: P = placebo. Days until end of all symptoms
Table 2. Times to negative cultures and end of symptoms from initial application of study medication for patients who applied medication be fore the appearance of a lesion A. Times Initial application to negative culture Patients, n Median, days Mean, days Initial application to end of symptoms Patients, n Median, days Mean, days B. Statistic: p values
Initial application to negative culture Wilcoxon scores Log rank scores Initial application to end of symptoms Wilcoxon scores Log rank scores
Low
High
Placebo
20(5) 2.8 3.2
11(0) 1.6
21(5) 1.6 2.5
20(1) 2.2 2.9
12(0) 1.9 2.1
21 (5) 3.9 3.4
Dose response
1.0
Overall
Low
Low
High
V S.
V S.
V S.
high
placebo
placebo
0.751 0.543
0.024' 0.029'
0.007* 12 0.0062
0.038' 0.100
0.606 0.439
0.0421 0.0311
0.125 0.059
0.548 0.221
0.274 0.540
0.021' 0.0072
The topical interferon preparation used by FriedmanKicn et al. [14] differed from that used in the currently reported study. The source of the interferon used by Friedman-Kienct al. was Life Sciences, while that used in this study was obtained from the New York Blood Center. In addition, Friedman-Kien ct al. used a cream base,
while we used a gel base to increase adherence and percu taneous absorption. Additionally, the present clinical trial was a patient-initated study, which means that patients with documented recurrent genital HSV infec tions were given medication to take home and start using immediately at the first sign of a prodrome. The earlier
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Numbers of patients providing censored data are given in parentheses. Low = «-Interferon. I x 104 IU/g with 1% nonoxynol-9: high = «-in terferon, 1 x 10'’ IU/g with 1% nonoxynol-9. Statistics are from survival analyses. 1 Significant at the 0.05 level. 2 Significant at the 0.01 level.
138
Shupack/Stiller/Knobler/Ackerman/Jondreau/Kenny
study was a clinic-initiated study, which required patients to report to the clinic after an outbreak had occurred. Only then were they given medication to treat the existing outbreak. Patient-initiated clinical trials, because they allow patients to treat recurrent HSV infections early at the first sign of a prodrome, arc preferable to physicianor clinic-initiated studies. Several small clinical trials by Israeli investigators have evaluated topical human fibroblast (p-)interferon in a carboxymethylcellulose cream base in the treatment of recurrent genital and facial HSV infections [13, 17, 18], Movshovitz et al. [17] in an open-label study on 19 patients with genital and 12 patients with facial HSV infections observed a decrease in the duration of epi sodes, severity of symptoms and recurrence rate. A 2-year double-blind placebo-controlled clinical trial by Glezerman et al. [13] testing the identical (1-interferon cream in 25 patients with recurrent herpes infections of the genitals and lips reported a similar decrease in both the recurrence rate and duration and severity of episodes. These studies help to reaffirm our belief in the potential usefulness of topical interferon in the treatment of HSV and other cuta neous viral infections. Reccurrent cutaneous HSV infections occur locally and episodically. Many physicians would prefer to treat such a condition with a topical agent as opposed to contin uous or even intermittent systemic medication. A safe, effective local treatment for recurrent HSV infections either as monotherapy or as an adjunct to existing therapy would be desirable. Additionally, clinical trials to assess other potential uses of topical a-interferon, such as in the treatment and prevention of the recurrence of condylomata acuminata and other human-papillomavirusinduccd dermatoses, are currently being contemplated.
Acknowledgements Statistical analyses were provided by Dr. Elizabeth R. DeLong, Quintiles. Chapel 1till N.C., USA. Funding for this study was provided by Exovir. Great Neck. N.Y.. USA.
3 Straus SE. Cruen KD. Sawyer MH. et al: Acyclovir suppression of frequently recurring genital herpes. Efficacy and diminishing need during successive years of treatment. JAMA 1988;260:2227-2230. 4 Mindel A. Faherty A, Hindley, D. etal: Prophylactic oral acyclovir in recurrent genital herpes. Lancet 1984;ii:57—59. 5 Fiddian AP. Halsos AM. Kinge BR. et al: Oral acyclovir in the treatment of genital herpes. Proceedings of a symposium on acyclo vir sponsored by Burroughs Welcome. Am J Med 1982;73(IA): 335-337. 6 Straus SE. Takiff HE. Seidlin M: Suppression of frequently re curring genital herpes. N Engl J Med 1984:310:1545-1550. 7 Erlich SK. Mills J, Chatis P. et al: Acyclovir resistant herpes sim plex virus infections in patients with the acquired immunodefi ciency syndrome. N Engl J Med 1988:320:293-296. 8 Chatis PA, Miller CH. Schräger LE. Crumpacker CS: Successful treatment with foscarnet of an acyclovir resistant mucocutaneous infection with herpes simplex virus in a patient with acquired immu nodeficiency syndrome. N Engl J Med 1989:320:297-300. 9 Straus SE. Mindcll S.Takif HE, et al: Effect of oral acyclovir treat ment on symptomatic and asymptomatic virus shedding in recur rent genital herpes. Sex Transm Dis 1989:16:107-112. 10 Eron LJ. Judson F. Tucker S.et al: Interferon therapy forcondylomata acuminata. N Engl J Med 1986:315:1059-1064. 11 Pazin GJ. Armstrong JA, Lam MT.ctal: Prevention of reactivated herpes simplex infection by human leukocyte interferon after ope ration on the trigeminal root. N Engl J Med 1979:301:225-230. 12 Pazin GJ, Harger JH. Armstrong JA. et al: Leukocyte interferon for treating first episodes of genital herpes in women. J Infect Dis 1987:156:891-898. 13 Glczcrman M, Cohen, V. Movshovitz M. et al: Placebo controlled trial of topical interferon in labial and genital herpes. Lancet 1988;i: 150—152. 14 Friedman-Kien AE. Klein RJ. Glaser RD. Czelusniak SM: Treat ment of recurrent genital herpes with topical alpha interferon gel combined with nonoxynol-9. J Am Acad Dermatol 1986:15: 989-994. 15 RappF. Wrzos 11: Synergistic effect of human leukocyte interferon and nonoxynol-9 against herpes simplex virus type 2. Antimicrob Agents Chemother 1985:28>49-451. 16 Vontver LA. Reeves WC, Rattray M. et al: Clinical course and diagnosis of genital herpes simplex virus infection and evaluation of topical surfactant therapy. Am J Obstet Gynecol 1979:133: 548-554. 17 Movshovitz M. Schwach-Millet M. Kriss-Lcvcnton S. etal: Topical treatment of recurrent facial and genital herpes with human inter feron ß cream: in Kono R(ed): Herpes Virus Chemotherapy. Ams terdam. Elsevier Science Publishers. 1985. pp 285-292. 18 Isacsohn M. Bcrson B, Sternberg I. Murag A: Human fibroblast interferon in treatment of viral diseases of the skin and mucous membranes. Isr J Med Sei 1983;19:959-962.
References Received: September 14. 1989 Accepted: December 15. 1989 Dr. Jerome Shupack New York University Medical Center Department of Dermatology 550 First Avenue New York. NY 10016 (USA)
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1 Burnett JW, Crutcher WA: Viral and rickettsial infections; in Moschella SL. Hurley HJ (eds); Dermatology. Philadelphia, Saun ders. 1985. vol 1. pp 681-683. 2 Mcrtz GJ. Lawrence E. 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.
Dermatologica 1990; 181:134-138
Topical Alpha-Interferon in Recurrent Genital Herpes Simplex Infection A Double-Blind, Placebo-Controlled Clinical Trial ./. Shupack, M. Stiller, E. Knobler, C. Ackerman, L. Jondreau, C. Kenny Department of Dermatology. New York University Medical Center. New York, NY. USA
Key Words. Herpes simplex • Interferon • Nonoxynol-9 • Acyclovir resistance
Introduction With an estimated incidence of 260,000-500,000 cases per year, genital herpes virus infections are a source of significant physical and psychological morbidity |lj. Patients experience pain, discomfort and disruption in sexual relations as a result of herpes genitalis. Herpes sim plex virus (HSV) transmitted to newborns puts them at a very high risk for disseminated infection. The most suc cessful treatment to date for recurrent genital herpes infections, oral acyclovir, can safely decrease the fre quency of episodes in patients taking it daily for up to 2 years [2-6]. However, no topical agents, including topical acyclovir, have proven effective in treating recurrent HSV infections. In addition, there have been recent reports of acyclovir-resistant HSV infections in patients with acquired immune deficiency syndrome (AIDS) [7, 8]. In a recent publication Straus ct al. [9| reported that chronic suppressive oral acyclovir therapy does not reduce the rate of asymptomatic viral shedding. These investigators found an increased frequency of acyclovir resistance in HSV cultured from asymptomatic nonimmunocompromised patients [9]. A second agent, preferably
to be used topically, would be welcome as an adjunct to systemic acyclovir or as monotherapy to minimize the emergence of acyclovir-resistant strains of HSV and for use in patients who dislike taking oral medications. Since its discovery in 1957 interferon has shown pro mise in the treatment of human viral infections. The great est dermatologic success has been in treating condylomata acuminata with intralesional interferon [1()|. Results of clinical studies by Pazin ct al. [11, 12] assessing the effi cacy of systemic interferon in the treatment of HSV have been encouraging. Glezerman et al. [13] conducted a 2year double-blind study of (3-interferon in HSV labialis and genitalis. Patients treated with topical (3-interferon had a significantly shorter duration and a decreased recur rence rate of herpetic lesions [13], Friedman-Kicn ct al. [ 14] found that a-interferonat a concentration of It/’ IU in a nonoxynol-9 cream formulation decreased viral shed ding. the formation of new lesions and the time to lesion scabbing of recurrent genital HSV infections. We tested a topical interferon gel consisting of human leukocyte interferon in a base containing 1% nonoxynol-9 and aqueous methylccllulose. Nonoxynol-9 is a wellknown and safe surfactant which aids in the uniform dis
Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 3/5/2018 6:42:11 PM
Abstract. We conducted a double-blind placebo-controlled clinical trial on 98 subjects to assess the efficacy of two strengths of topical human leukocyte a-interferon, 104 and 106 IU/g in a 1% nonoxynol-9 base, in the treatment of recurrent genital herpes simplex virus (HSV). The study medication was applied during the prodromal phase or at the first sign of recurrence of the infection. The high-dose a-interferon was found to be significantly more effective than the low-dose interferon and placebo with respect to the duration of viral shedding as well as in reducing the time to the end of all subjective symptoms, including pain, burning and itching. No difference between the three groups was found in times to crusting or healing. Further studies of topical interferon in the treatment of HSV and other viral infections arc merited.
135
Topical Interferon in Recurrent Herpes Infections
Methods The study population included 98 ambulatory patients (1 patient was ruled a protocol violator leaving 97 analyzable patients) aged 18 years or older with a history of culture-proven, recurrent herpes progcnitalis infections with a definite prodrome enabling them to predict a recurrent episode. Patients did not receive antiviral therapy, antibio tics or photoinactivation during the 2 weeks immediately preceding entry into the study. Patients who had received samllpox or BCG vacci nations shortly before the study were excluded. A medical history and physical examination was obtained from all study subjects at the time of enrollment. Patients who were known or strongly suspected to be immunocompromised were not permitted to participate in this study. Siudy Design This was a double-blind study. After the subjects had signed a writ ten informed consent, they were randomized to either a placebo or one of two treatment groups ( 10J or 10" IU/g of interferon) at the time of their last episode. At the first sign or symptom of recurrence the patients were to apply medication to all externally affected areas three times daily for 7 days. Evaluations were done on days 1,3. 5 and 7. Patients were evaluated for the following parameters during each visit: (1) viability of the herpes virus determined by laboratory culture at 24 and 72 h after application: (2) localized symptoms of pain, burning and itching, each evaluated as none. mild, moderate or severe: (3) impres sion of lesion morphology in terms of the overall stage of development to all lesions. Stages were coded as: none; macules/papules; vesicles/ pustules; erosions/ulcerations: crusts, and healed. In American dermatologic nomenclature, the term symptom refers only to subjective findings such as pruritus, pain, burning and dysesthe sia. Macules, papules, crusts and other objective findings are referred to as signs rather than symptoms. No adverse reactions were noted among the study subjects. Statistical Methods Categorical baseline variables were compared by the / ’ test or. when categories had small numbers, by Fisher's exact test; continuous baseline measures were compared using the Kruskal-Wallis nonparametric test. The primary outcomes were expressed as times in days to various end points indicative of lesion healing: namely, the efficacy analyses
focused on times to crusting, healing, negative viral culture and end of subjective symptoms. Because some patients could not be followed until all end points were observed, these patients provided censored data,and the end point times were analyzed by means of nonparametric survival analyses. The data were analyzed relative to the entire pateint population and also the subset of patients who applied the medication before the appearance of lesions, using analyses which were adjusted for sex. Treatment comparisons were obtained from the log rank test.
Results Of the 97 analyzable patients 72% were male, 34% were Caucasian and the average age was 34 years. The median number of episodes per year was 12.0. There were no significant differences dcmographically or in the seve rity or frequency of HSV infections between the three treatment groups. Time to Negative Culture High-dose cv-interfcron was significantly better com pared to low-dose cv-interfcron and placebo with regard to the duration of viral shedding. The median times to nega tive culture were 1.0 day for the high-dose cv-interferon versus 2.5 days for the low-dose cv-interferon and 2.1 days for the placebo (p = 0.005, based on log rank scores, sig nificant at 0 .0 1; table l.fig. 1). While the time to negative culture was minimally greater for the low-dose interferon versus the placebo, that difference was not statistically significant. Time to End o f Subjective Symptoms The high-dose a-interferon was more effective than placebo or low-dose interferon in reducing the time to the end of all subjective symptoms, i.e. the time until the com plete resolution of pain, burning and itching. Patients on the high dose of a-interferon had a resolution of subjec tive symptoms in a median time of 2.0 days compared to those on the low dose of interferon and placebo where resolution occurred in 2.6 and 3.7 days, respectively (p = 0.017 based on Wilcoxon scores, significant at the 0.05 level; table 1. fig. 2). It should be noted that the signifi cance of the p values for the time to negative culture and time to end of subjective symptoms were much more impressive in those patients who began applying the study drug during the prodrome prior to the occurrence of lesions (table 2). Time to Crusting/Healing The times to crusting or healing were not different among the treatment groups.
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persion of interferon into its gel base. Nonoxynol-9 is a potent inactivating agent of HSV in vitro and lias also been shown to act synergistically with human cv-interfcron against HSV in vitro where it was postulated that the nonoxynol-9 destroyed extracellular HSV while the inter feron disrupted intracellular viral replication [15]. How ever, as with other in vitro viricidal agents, nonoxynol-9 has not demonstrated any effect on genital herpes in vivo [16]. The current clinical trial was not designed to eval uate synergy. While the concept of synergy is theoretically interesting, the number of patients required to be studied in order to substantiate synergy would be exceedingly large.
136
Shupack/Stiller/Knoblcr/Ackerman/Jondrcau/Kcnny
Fig. 1 . Times to end of viral shedding of all patients. H = high-dose interferon; L = low-dose interferon; P = placebo. Days until negative viral culture
Table 1. Times to negative viral cultures and end of symptoms from initial application of study medication A. Times Initial application to negative culture Patients, n Median, days Mean, days Initial application to end of symptoms Patients, n Median, days Mean, days H. Statistic: p values
Initial application to negative culture Wilcoxon scores Log rank scores Initial application to end of symptoms Wilcoxon scores Log rank scores
Low
High
Placebo
41(10) 2.5 2.7
23(2) 1.6
30(6) 2.1 2.5
41(5) 2.6 2.9
25(5) 2.0 2.2
31(8) 3.7 3.4
Dose response
1.0
Overall
Low vs. high
Low
High
V S.
V S.
placebo
placebo
0.227 0.189
0.046' 0.0131
0.015*1 0.0052
0.295 0.246
0.171 0.105
0.0191 0.080
0.060 0.214
0.441 0.506
0.102 0.336
0.017' 0.055
Discussion Our results suggest that topical a-interferon at a con centration of 10'1IU/g may be efficacious in the treatment of genital HSV infections when applied during the pro dromal phase. Negative cultures were obtained signifi
cantly sooner, and the duration of the subjective symp toms pain, burning and pruritus was decreased with the application of the higher concentration of a-interferon. The time to healing, however, was about the same for all three groups - placebo, 104 and 10'’ IU/g of a-inter feron.
Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 3/5/2018 6:42:11 PM
Numbers of patients providing censored data are given in parentheses. Low = ct-Interfcron, 1 x 10J IU/g with 1% nonoxynol-9; high = a-interferon. I x 106 IU/g with 1% nonoxynol-9. Statistics are from survival analyses. 1 Significant at the 0.05 level. 2 Significant at the 0.01 level.
137
Topical Interferon in Recurrent Herpes Infections
Fig. 2. Times to end of symptoms of all patients. 11 = high-dose interferon: L = low-dose interferon: P = placebo. Days until end of all symptoms
Table 2. Times to negative cultures and end of symptoms from initial application of study medication for patients who applied medication be fore the appearance of a lesion A. Times Initial application to negative culture Patients, n Median, days Mean, days Initial application to end of symptoms Patients, n Median, days Mean, days B. Statistic: p values
Initial application to negative culture Wilcoxon scores Log rank scores Initial application to end of symptoms Wilcoxon scores Log rank scores
Low
High
Placebo
20(5) 2.8 3.2
11(0) 1.6
21(5) 1.6 2.5
20(1) 2.2 2.9
12(0) 1.9 2.1
21 (5) 3.9 3.4
Dose response
1.0
Overall
Low
Low
High
V S.
V S.
V S.
high
placebo
placebo
0.751 0.543
0.024' 0.029'
0.007* 12 0.0062
0.038' 0.100
0.606 0.439
0.0421 0.0311
0.125 0.059
0.548 0.221
0.274 0.540
0.021' 0.0072
The topical interferon preparation used by FriedmanKicn et al. [14] differed from that used in the currently reported study. The source of the interferon used by Friedman-Kienct al. was Life Sciences, while that used in this study was obtained from the New York Blood Center. In addition, Friedman-Kien ct al. used a cream base,
while we used a gel base to increase adherence and percu taneous absorption. Additionally, the present clinical trial was a patient-initated study, which means that patients with documented recurrent genital HSV infec tions were given medication to take home and start using immediately at the first sign of a prodrome. The earlier
Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 3/5/2018 6:42:11 PM
Numbers of patients providing censored data are given in parentheses. Low = «-Interferon. I x 104 IU/g with 1% nonoxynol-9: high = «-in terferon, 1 x 10'’ IU/g with 1% nonoxynol-9. Statistics are from survival analyses. 1 Significant at the 0.05 level. 2 Significant at the 0.01 level.
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study was a clinic-initiated study, which required patients to report to the clinic after an outbreak had occurred. Only then were they given medication to treat the existing outbreak. Patient-initiated clinical trials, because they allow patients to treat recurrent HSV infections early at the first sign of a prodrome, arc preferable to physicianor clinic-initiated studies. Several small clinical trials by Israeli investigators have evaluated topical human fibroblast (p-)interferon in a carboxymethylcellulose cream base in the treatment of recurrent genital and facial HSV infections [13, 17, 18], Movshovitz et al. [17] in an open-label study on 19 patients with genital and 12 patients with facial HSV infections observed a decrease in the duration of epi sodes, severity of symptoms and recurrence rate. A 2-year double-blind placebo-controlled clinical trial by Glezerman et al. [13] testing the identical (1-interferon cream in 25 patients with recurrent herpes infections of the genitals and lips reported a similar decrease in both the recurrence rate and duration and severity of episodes. These studies help to reaffirm our belief in the potential usefulness of topical interferon in the treatment of HSV and other cuta neous viral infections. Reccurrent cutaneous HSV infections occur locally and episodically. Many physicians would prefer to treat such a condition with a topical agent as opposed to contin uous or even intermittent systemic medication. A safe, effective local treatment for recurrent HSV infections either as monotherapy or as an adjunct to existing therapy would be desirable. Additionally, clinical trials to assess other potential uses of topical a-interferon, such as in the treatment and prevention of the recurrence of condylomata acuminata and other human-papillomavirusinduccd dermatoses, are currently being contemplated.
Acknowledgements Statistical analyses were provided by Dr. Elizabeth R. DeLong, Quintiles. Chapel 1till N.C., USA. Funding for this study was provided by Exovir. Great Neck. N.Y.. USA.
3 Straus SE. Cruen KD. Sawyer MH. et al: Acyclovir suppression of frequently recurring genital herpes. Efficacy and diminishing need during successive years of treatment. JAMA 1988;260:2227-2230. 4 Mindel A. Faherty A, Hindley, D. etal: Prophylactic oral acyclovir in recurrent genital herpes. Lancet 1984;ii:57—59. 5 Fiddian AP. Halsos AM. Kinge BR. et al: Oral acyclovir in the treatment of genital herpes. Proceedings of a symposium on acyclo vir sponsored by Burroughs Welcome. Am J Med 1982;73(IA): 335-337. 6 Straus SE. Takiff HE. Seidlin M: Suppression of frequently re curring genital herpes. N Engl J Med 1984:310:1545-1550. 7 Erlich SK. Mills J, Chatis P. et al: Acyclovir resistant herpes sim plex virus infections in patients with the acquired immunodefi ciency syndrome. N Engl J Med 1988:320:293-296. 8 Chatis PA, Miller CH. Schräger LE. Crumpacker CS: Successful treatment with foscarnet of an acyclovir resistant mucocutaneous infection with herpes simplex virus in a patient with acquired immu nodeficiency syndrome. N Engl J Med 1989:320:297-300. 9 Straus SE. Mindcll S.Takif HE, et al: Effect of oral acyclovir treat ment on symptomatic and asymptomatic virus shedding in recur rent genital herpes. Sex Transm Dis 1989:16:107-112. 10 Eron LJ. Judson F. Tucker S.et al: Interferon therapy forcondylomata acuminata. N Engl J Med 1986:315:1059-1064. 11 Pazin GJ. Armstrong JA, Lam MT.ctal: Prevention of reactivated herpes simplex infection by human leukocyte interferon after ope ration on the trigeminal root. N Engl J Med 1979:301:225-230. 12 Pazin GJ, Harger JH. Armstrong JA. et al: Leukocyte interferon for treating first episodes of genital herpes in women. J Infect Dis 1987:156:891-898. 13 Glczcrman M, Cohen, V. Movshovitz M. et al: Placebo controlled trial of topical interferon in labial and genital herpes. Lancet 1988;i: 150—152. 14 Friedman-Kien AE. Klein RJ. Glaser RD. Czelusniak SM: Treat ment of recurrent genital herpes with topical alpha interferon gel combined with nonoxynol-9. J Am Acad Dermatol 1986:15: 989-994. 15 RappF. Wrzos 11: Synergistic effect of human leukocyte interferon and nonoxynol-9 against herpes simplex virus type 2. Antimicrob Agents Chemother 1985:28>49-451. 16 Vontver LA. Reeves WC, Rattray M. et al: Clinical course and diagnosis of genital herpes simplex virus infection and evaluation of topical surfactant therapy. Am J Obstet Gynecol 1979:133: 548-554. 17 Movshovitz M. Schwach-Millet M. Kriss-Lcvcnton S. etal: Topical treatment of recurrent facial and genital herpes with human inter feron ß cream: in Kono R(ed): Herpes Virus Chemotherapy. Ams terdam. Elsevier Science Publishers. 1985. pp 285-292. 18 Isacsohn M. Bcrson B, Sternberg I. Murag A: Human fibroblast interferon in treatment of viral diseases of the skin and mucous membranes. Isr J Med Sei 1983;19:959-962.
References Received: September 14. 1989 Accepted: December 15. 1989 Dr. Jerome Shupack New York University Medical Center Department of Dermatology 550 First Avenue New York. NY 10016 (USA)
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1 Burnett JW, Crutcher WA: Viral and rickettsial infections; in Moschella SL. Hurley HJ (eds); Dermatology. Philadelphia, Saun ders. 1985. vol 1. pp 681-683. 2 Mcrtz GJ. Lawrence E. 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.
