Division of Dermatology, Department of Medicine, and Centre for Clinical Research, Dalhousie University, Halifax, NS, Canada

ABSTRACT

Famciclovir (Famvir®, Novartis) is an effective treatment for herpes zoster and herpes simplex. Two separate studies recently examined the effectiveness of single high doses of famciclovir for treating recurrent genital herpes and labial herpes (cold sores). In the randomized, placebo-controlled studies, patients initiated treatment at the first onset of symptoms. For the treatment of genital herpes, a 1,000mg b.i.d. dose of famciclovir had significant advantages over the placebo, reducing the time required to heal the lesions, preventing the development of lesions beyond the papule stage, and improving the time to resolution of all symptoms. For the treatment of labial herpes, a single 1,500mg dose of famciclovir shortened the lesion healing time, shortened the time to normal skin, and resulted in faster resolution of pain and tenderness.

Key Words:
famciclovir, herpes zoster, herpes simplex

Infections with herpes simplex virus type 1 and 2 (HSV-1 and HSV-2) are important, common, and worldwide in distribution. It has been estimated that 90% of individuals aged 20-40 years have antibodies to HSV-1, and HSV-2 is the most common sexually transmitted disease worldwide.1 HSV-1 is most frequently connected with orolabial herpes and HSV-2 with genital herpes, although either type can affect either location.
Infection with HSV can initially result in primary infection, followed by an establishment of latency as the viral genome remains in the neuronal bodies indefinitely. Patients may then have recurrences which may be symptomatic or asymptomatic.2 Certain patients can experience frequent recurrences which may be symptomatic, oral antivirals are the agents of choice in this setting.

Very recently, two clinical studies were completed in patients with recurrent labial and genital herpes using famciclovir. In this article these studies will be briefly reviewed and the implications identified.

Recurrent Genital Herpes

An international randomized, double-blind, multi-center, placebo-controlled study compared the effectiveness of a 1,000mg b.i.d. single-day dose of famciclovir with a placebo in patients with recurrent genital herpes (i.e., >4 episodes over 12 months).³

Three hundred twenty nine patients were randomized to receive famciclovir (n=163) or placebo (n=166). The patients in the treated and placebo arms were well-balanced in demographic and baseline disease characteristics. In this study, the major inclusion criteria were:

• aged 18 years or older
• history of recurrent genital herpes on the external genitalia or anogenital area, with four or more episodes in the previous 12 months.
• HSV-2 seropositivity
• if applicable, be willing to discontinue suppressive treatment.

Lesions requiring re-epithelialization were defined as lesions that underwent vesicular, ulcer, soft crust and/or hard crust formation. Aborted lesions were considered to be lesions that did not progress beyond the papule stage.

Efficacy Variables

The primary efficacy variable in the study was investigator-assessed time to healing of all nonaborted genital herpes lesions. Secondary efficacy variables included:

• the safety and tolerability of a 1,000mg b.i.d. dose of famciclovir
• the proportion of patients with aborted lesions
• the time to resolution of all symptoms, including burning, pain, tingling, itching, and tenderness.

Patients initiated dosing within 6 hours of the first symptoms. Patients returned to the clinic within 24 hours, and then visited the clinic for 3 consecutive days. They returned every other day until the lesions were healed or until day 14, whichever came first.

Adverse Events

Just over one-quarter of patients receiving famciclovir (26.4%) reported adverse events, of which 12.9% were deemed by the investigator to be drug related. These included gastrointestinal disorders (such as diarrhea or nausea) and headaches. The side-effects were mild and transient in the majority of patients. Patients receiving the placebo also reported these adverse events.

Conclusions

Two 1,000mg doses of famciclovir over a single day, started within 6 hours of prodromal symptoms or genital herpes lesions, were shown to:

• be well tolerated and safe
• play a significant role in reducing the time to healing of vesicular lesions
• significantly prevent the development or progression of lesions beyond the papule stage
• significantly improve the time to resolution of all symptoms, including burning, tingling, itching, and tenderness.

A single-day patient-initiated regimen is convenient and has the advantage of maximizing the window of opportunity for treatment when viral replication is most active. Famciclovir was shown to stop the progression to a full outbreak or shorten the duration of a recurrent genital herpes outbreak.

Recurrent Herpes Labialis

A randomized, double-blind, parallel group, placebo-controlled study examined the effectiveness of a single 1,500mg dose of famciclovir, two 750mg doses of famciclovir over a single day, and a matching placebo.4 Patients initiated therapy within 1 hour of prodromal symptoms. Patients returned to the clinic within 24 hours, and then visited the clinic for the 3 following consecutive days. After that they returned every other day until the lesions were healed or until day 14, whichever came first.

The 708 patients in the study population were adult immunocompetent patients with recurrent cold sores. The mean age was approximately 39 years, with the majority of patients being female and Caucasian. The study also examined the time to resolution of pain and tenderness. The median time to resolution was 1.7 days for those who received the 1,500mg dose of famciclovir, 2.1 days for those receiving two 750mg doses of famciclovir over a single day, and 2.9 days for those who received the placebo.

Conclusions

A single dose of famciclovir (1,500mg) taken within the first hour of prodromal symptoms resulted in the following statistically significant differences as compared with a placebo:

• shorter time to healing of vesicular herpes labialis lesions by approximately 2 days
• shorter time to resolution to normal skin by approximately 2 days
• Faster resolution of pain and tenderness by approximately 1 day.

The advantage of a single-dose, patient-initiated regimen is that it maximizes the window of opportunity for treatment when viral replication is the most active. A single dose can provide all the therapy up-front.

This study shows that a single dose (1,500mg) of famciclovir is effective in treating a herpes labialis outbreak, is well tolerated, and is convenient – a factor that may have the potential to improve patient compliance.

References

1. Nahmias AJ, Lee FK, Beckman-Nahmias S. Sero-epidemiological and sociological patterns of herpes simplex infection in the world. Scand J Infect Dis Suppl 69:19-36 (1990).
2. Kimberlin DW, Rouse DJ. Clinical practice. Genital herpes. N Engl J Med 350(19):1970-7 (2004 May).
3. Aoki FY, Tyring S, Diaz-Mitoma F, et al. One-day, patient-initiated famciclovir therapy for recurrent genital herpes: A randomized, double-blind, placebo-controlled trial. Presented at: The 16th biennial meeting of the International Society for Sexually Transmitted Diseases Research (ISSTDR), Amsterdam, July 14, 2005.
4. Spruance S, Bodsworth N, Resnick C, et al. One-day, high-dose, patient-initiated famciclovir reduces time to healing of recurrent herpes labialis lesions. Oral presentation at the 14th Congress of the European Academy of Dermatology and Venereology (EADV), London, England, October 12, 2005.

^aEndocrinologie de la reproduction, Hôpital St-François d’Assise, Département d’Obstétrique et Gynécologie, Université Laval, Québec, Canada
^bDivision of Dermatology, Department of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada

ABSTRACT

There is compelling evidence that oral contraceptives (OCs) are effective in the management of mild-moderate acne vulgaris, as well as cumulative evidence that elevated levels of androgens in acne patients, relative to appropriate controls, are an underlying pathophysiological factor in acne. All low dose OCs reduce serum free testosterone (T) to a similar extent, which is contrary to the traditional concept that a patient who has acne should not use an OC containing a progestin with androgenic properties. The efficacy of various OCs to improve acne has been reported in transverse, cohort and comparative studies, and more recently in multicenter, randomized, placebo-controlled trials. Recently, an ultra-low dose OC (Alesse®, Wyeth) was shown to effectively reduce non-inflammatory and inflammatory lesions in mild-to-moderate acne, while having a profile of side-effects similar to that of a placebo. Besides its contraceptive efficacy, an ultra-low dose OC represents an attractive alternative as a single or associated medication in the management of acne.

Key Words:
acne, androgens, anti-androgens, antibiotics, oral contraceptives

An ultra-low dose oral contraceptive (Alesse®, Wyeth) containing 20µg ethinyl estradiol (EE) and 100mg levonorgestrel (LNG) was approved by TPP Canada for the treatment of mild-to-moderate acne in January 2002.^1,2 Its contraceptive efficacy has been corroborated by ultrasonic evaluation of the ovaries showing inhibition of follicular development, and by hormonal measurements demonstrating suppression of estradiol and progesterone.³ It provides menstrual cycle control and tolerability that is equivalent to that of OCs containing 35µg of EE.⁴

Excess Androgens in Acne

A common notion is that neither acne vulgaris nor idiopathic hirsutism is associated with high serum levels of androgens in the absence of other associated signs and symptoms of hyperandrogenism. The range of reference androgen values has been established in laboratories mainly to rule out a secreting tumor. There is no established stratification of normal ranges to estimate androgen values for benign androgen conditions such as acne, hirsutism and polycystic ovarian syndrome. In this context, many believe that serum androgens are not elevated in typical acne. However, when appropriate controls were used, androgens of adrenal or ovarian origin increased in women presenting with otherwise unexplained acne^5-10 A recent study demonstrated that serum T levels in acne patients were at least twice the level of normal controls without acne.⁹ Dehydroepiandrosterone sulphate (DHEAS) was also found to be elevated in acne patients when compared to a control group.⁹ Recent data also showed no change in androgen metabolism (5α- reductase and 17β-hydroxysteroid dehydrogenase) in sebaceous glands between subjects with and without acne, providing evidence against possible local production of androgens in this condition.⁸ Thus, a relative increase in circulating ovarian and adrenal androgens appear to play a role in the pathophysiology of acne. The sebaceous gland, which is sensitive to androgens, and which is responsible for the associated seborrhea should be considered as an underlying pathophysiological component.

Anti-Androgenic Action of Oral Contraceptives

Traditionally, clinicians believed that a patient with acne should not use an OC containing a progestin with androgenic properties.¹¹ Investigators have speculated that the androgenic effects of progestins evaluated in animal and in vitro systems may increase the likelihood of androgen-related side-effects, including acne and hirsutism. The evidence is to the contrary. The suppression of LH and FSH by OCs results in a decreased secretion of androstenedione and testosterone by theca cells in the ovary. Estrogen-progestin combinations also increase the level of sex hormone-binding globulin (SHBG), resulting in greater T binding and a reduction in free T. The use of an OC also causes a reduction in serum levels of ovarian and adrenal androstenedione, and of DHEAS, which originates exclusively from the adrenal glands. Thus, the use of an OC has complementary actions mainly to lower free T and the androgen precursors secreted by the ovaries and the adrenals. The decrease in androgen action is reflected by a diminution in 3 α-androstenediol–glucuronide, which is the cellular catabolite of DHT by the sebaceous gland among peripheral tissues sensitive to androgens.

Estrogen-progestin combinations differ somewhat in their efficacy to inhibit T production and to increase SHBG levels. However, the net effect is similar for free T, which decreases by 40-50% in the average woman. Direct comparisons between various OC formulations show that they all reduce free T to the same extent.^12,13 Since free T is the ultimate effector of circulating androgens, all OCs have a similar potential for improving acne.

Clinical Trials

Several studies have recognized a lower incidence of acne while using different OCs.^14-17 Five pilot studies have also reported a 50-80% improvement in comedone counts, as well as in the numbers of papules and pustules after a few cycles of OCs containing various doses of EE and various types of progestins.^13,18-21 These observations have now been recently confirmed by four multicenter, randomized, placebo-controlled trials using a triphasic OC formulation containing 35µg EE and 180-215-250µg NGM (Tri- Cyclen®)^22,23 and the low dose monophasic combination of 20µg EE and 100µg LNG (Alesse®).^24,25

Two similar Phase III trials (see Table 1) were conducted involving 35µg EE/180-215-250µg NGM (Ortho Tri- Cyclen®) vs. placebo for 6 months of treatment.^22,23 In the first study, 257 patients, aged 15 to 49 were randomized into a multi-center, double-blind, placebo-controlled trial if they had moderate acne (6-100 comedones, 10-50 inflammatory lesions, and fewer than 5 nodules). One hundred sixty patients completed the 6-month study in the efficacy evaluable population. The OC group showed a statistically significant improvement over the placebo group for all primary efficacy measures. The second trial included 250 women and the treatment group performed significantly better than the placebo group for all primary efficacy measures.²²

The second series of clinical studies of OCs in acne involved the use of the lower estrogen OC, Alesse®.^24,26 Two outpatient, multicenter, randomized, double blind, placebo-controlled trials following a similar protocol were conducted to determine the effects of 20µg EE and 100µg LNG (Alesse®) on the treatment of moderate acne. In the first study, healthy women, at least 14 years of age, with regular menstrual cycles and moderate facial acne were randomly assigned to receive the active treatment or placebo for 6 cycles. Inflammatory, noninflammatory, and total lesion counts at cycle 6 with 20µg EE and 100µg LNG (Alesse®) were significantly lower when compared to placebo. Patients in the OC group also had significantly better clinician global and patient self-assessment scores than those in the placebo group at cycle 6. Similar results were documented in the second trial with significant decreases in the mean inflammatory and total lesion counts after 6 cycles in the OC group compared to the placebo group.²⁵ In a sub study, biochemical markers of androgenicity were also assessed. Compared to placebo, use of this low dose OC resulted in significant reductions in free and bioavailable testosterone, androstenedione, 3α- androstanediol glucuronide (3α-G), and increased levels of SHBG after 6 cycles.

Table 1: Results of four Phase III Clinical Trials for OCs in the treatment of acne.

Placebo effects are commonly seen in dermatology trials, acne trials in particular. This can be explained in part by trial protocols that include careful skin-care (e.g., proper skin cleansing and avoidance of comedogenic skin-care products). Patient compliance with meticulous skin-care practices is encouraged by regular visits to trial investigators. Such skin care alone may have a positive effect on acne. Furthermore, acne is known to have a fluctuating course with regression to the mean over time in a given cohort of patients. Because of this, the trial period includes spontaneous improvement in some women and the resolution of some acne flares present at baseline. Finally, many dermatologists attribute the large placebo effect to investigator and patient optimism.

Efficacy and Safety of Alesse® in Acne

One very interesting aspect of these studies was the unique opportunity to compare the side-effects associated with an OC to those of a placebo. In the 20µg EE and 100µg LNG (Alesse®) acne studies, symptoms usually attributed to the estrogen and/or progestin components of an OC were not different from those observed during the use of the placebo. As seen in Table 2, the very low dose EE/LNG combination did not induce significant modifications in the incidence of weight gain, breast tenderness, nausea, vomiting, headache and migraine.²⁶

OCs and anti-androgen agents

The estro-progestin combination Diane-35®, containing 35ug EE combined with 2mg cyproterone acetate, a progestin having direct anti-androgen effects, is known to be quite effective in the treatment of acne and hirsutism, although there is no Class I evidence (randomized, doubleblind, controlled studies) supporting the efficacy of this prediction.²⁷ Several OC formulations have been compared to Diane-35® and found to be as effective or somewhat less effective than this anti-androgenic combination.^28-33 However, comparisons were limited to 6 cycles of treatment and the side-effect profiles were not compared. Although there seems to be improvement of acne after treatment with the anti-androgen spironolactone (Aldactone®), the few studies done to date have been methodologically weak. There are, as yet, no reports for the treatment of acne using flutamide (Euflex®), a nonsteroidal androgen receptor antagonist, or finasteride (Proscar®, Propecia®), an inhibitor of the 5-α-reductase enzyme converting T into the more active compound dihydrotestosterone (DHT) within the sebaceous gland. In theory, the addition of an anti-androgen would be more effective in hirsutism than in acne, since excess androgens are the main causative factor in hirsutism, whereas other factors are involved in the pathophysiology of acne. In practice, prescribing an anti-androgen for women of reproductive age requires effective contraception to prevent the possible occurrence of fetal anomalies induced by a compound having direct anti-androgenic actions.

Table 2: Alesse® vs. Placebo: frequency of adverse events commonly associated with OCs.
* Fisher’s exact.
Pooled data of intended to treat population.²⁶

Concomitant Use of OC and Antibiotics in Acne

Several pharmacokinetic and pharmacodynamic studies indicate that the antibiotics currently prescribed for acne treatment do not modify serum concentrations of EE and of various progestins.^34-38 They do not interfere with the suppression of gonadotropins (LH and FSH) and ovarian sex steroid hormones (estradiol and progesterone).^35,36,39-41 According to a recent bulletin from the American College of Obstetrics and Gynecology, the anti-infective agents tetracycline, doxycycline, ampicillin, metronidazole and quinolones do not reduce steroid levels in OC users.⁴² In a recent review of available data, the Pearl Index (number of pregnancies per 1000 women years) during the concomitant use of antibiotics and various OCs in acne was established at 1.6, which favorably compares with the failure rate of users who have not taken antibiotics.⁴³ However, these data have been estimated on rather small numbers. In one Australian study, 209 inadvertent pregnancies in oral contraceptive users were studied to determine the associated factors. Forty-eight of the 209 patients (23%) took an antibiotic in the last two cycles before conception and were included as one of several reasons for OC failure.⁴⁴ Caution should be exerted and another effective contraceptive method should be used whenever a patient is taking other antibiotics or doses of antibiotics higher than those prescribed in the usual treatment of acne. The patient taking an antibiotic should also be told to use another effective contraceptive means in case she experiences diarrhea or breakthrough bleeding, which could then suggest decreased absorption or efficacy of the OC, or inadequate compliance.

Conclusion

Based on the multiple factors involved in the pathogenesis of acne and on the severity of lesions, choosing one of the various treatment approaches depends on the needs of the patient and on the objectives of the physician. Dermatologists most frequently prescribe agents to normalize dyskeratinization and to reduce the proliferation of P. acnes and inflammatory skin changes. Sebum production, which is sensitive to a mild elevation of androgens can be reduced by a low dose OC. Besides its contraceptive and other non-contraceptive benefits, a low dose OC has a side-effect profile similar to that of a placebo and has been determined to have significant efficacy in the treatment of mild-to-moderate acne. The effects of using an oral contraceptive are usually not seen in chemical practice for 3-6 cycles. The application of another acne treatment during treatment with an OC is actually done in regular practice, but has yet to be evaluated in clinical research studies.

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