THE ARTICLE IN THIS ISSUE by Romanowski et al 1 raises some interesting issues that are worthy of discussion.
This study compared patients given suppressive valacyclovir with those not given suppressive therapy, in whom recurrences were treated promptly with the same drug (episodic treatment). As expected, chemosuppression reduced the frequency of recurrences by about 80%, consistent with the findings of numerous prior studies (e.g., Patel et al, 2 Reitano et al, 3 and Mindel et al 4). Not surprisingly, patients preferred chemosuppression to episodic therapy, and they felt that chemosuppression improved their quality of life, with regard to treatment satisfaction, convenience, and lifestyle.
Recurrent genital herpes has been shown previously to cause significant psychological morbidity, 5 and earlier studies had shown that chemosuppression with acyclovir would reduce psychological morbidity, as measured by a variety of testing methods. 6 There is no reason to believe that suppression with valacyclovir would be any different from that with acyclovir, given that both drugs are very well tolerated.
Romanowski et al 1 also showed that patients preferred chemosuppression to episodic therapy, on the basis of measures of convenience, lifestyle, and overall satisfaction with therapy (i.e., quality of life). Although some of this benefit is undoubtedly due to the benefits of preventing recurrences with chemosuppression, i.e., treatment satisfaction, some of the difference in favor of suppression may be due to the way in which episodic therapy was managed in this trial. Probably because of their need to quantify recurrence rates, Romanowski and colleagues required that patients experiencing recurrences attend the clinic to receive their valacyclovir therapy, thereby subjecting patients to a delay in initiation of therapy (a practice which is known to reduce the efficacy of therapy 7) and some inconvenience related to the need for a clinic visit. A more common practice is to allow patient-initiated therapy, which appears to abort some recurrences and obviates the need for a clinic visit, with both valacyclovir and famciclovir treatment. 7,8
As the Romanowski study showed relatively small benefits of chemosuppression on lifestyle measures (the differences in scores for the two management groups were less than 20%, albeit statistically significant), it is likely that a comparison of patient-initiated intermittent therapy with chemosuppression would show less striking preferences for the suppression management strategy.
Given these considerations, what represents an ideal management strategy for recurrent genital herpes infections?
Dose-ranging studies of acyclovir, valacyclovir, and famciclovir chemosuppression have shown a steep and direct relation between drug dose, dosing interval, and antiviral efficacy. In the best study with acyclovir, both dose and dosing interval affected efficacy; the best efficacy (95% of patients were recurrence-free after 3 months) was achieved with 200 mg given four times a day; the worst was with 200 mg given once a day, a regimen which was probably no more effective than placebo. 4 Giving acyclovir two or three times a day was better than giving it once a day, but not as good as administering it four times daily. An acyclovir dose of 400 mg twice daily was better than 200 mg twice daily. 4 With valacyclovir, 250 mg twice daily was equivalent to acyclovir 400 mg twice daily; when valacyclovir was given once daily, an increasing the dose (250, 500, or 1000 mg) was associated with improved suppression of recurrences (approximately 49%, 68%, and 73% were recurrence-free at 3 months, respectively, versus 18% with placebo), and the differences were sustained for the 1.5 years of the study. 3 Patients with high recurrence rates (i.e., >10 per year) are more sensitive to differences in suppressive efficacy. 3
We are not aware of a comparison of a higher, twice-daily dose of valacyclovir (e.g., 500 mg) with once-daily therapy with 500 or 1000 mg, but it seems reasonable to assume that the efficacy of the twice-daily regimen would be greater, especially for patients with frequent recurrences. The likelihood of recurrences with suppressive famciclovir has also been shown to be dependent on the frequency of dosing. Famciclovir at dosages of 250 mg twice a day and 125 mg twice a day—but not 500 mg once a day—reduced the frequency of outbreaks. 9
If dosing regimens more frequent than once daily offer improved suppression of recurrent genital herpes, why the pressure to use once-daily regimens? Studies of many other diseases support the fact that simplifying and improving the tolerance of drug regimens—by decreasing pill counts, increasing dosing intervals, and reducing adverse drug reactions—improve compliance and treatment outcomes. 10–13 Although compliance might be better with once-daily chemosuppression of HSV recurrences, efficacy might be reduced because missing a single dose would result in a 48-hour therapeutic gap with once-daily therapy and only a 24-hour gap with twice-daily therapy. If the near-optimum therapy is twice daily, then any of the three available drugs (acyclovir, valacyclovir, or famciclovir) could be used.
The choice between chemosuppression and intermittent therapy is usually made on the basis of recurrence frequency and the patient's need to prevent recurrences. Clearly, the more frequent the recurrences, the greater the benefit of chemosuppression. The frequency of recurrences required to initiate chemosuppression is primarily a matter for discussion between the patient and the health care provider. But how will third-party payers (and indeed those patients who must pay for their own treatment) view the choice between chemosuppression and intermittent therapy? Putting aside the recent observation that chemosuppression prevents transmission (see below), intermittent therapy offers significant cost benefits.
In the Romanowski study, unsuppressed patients had an average of six recurrences per year. A simple calculation shows that in this patient population intermittent therapy would be about six times less expensive than chemosuppression, on the basis of drug costs alone. In addition, a recent randomized double-blind placebo-controlled trial showed that treating each episode with acyclovir for 2 days (800 mg three times daily) markedly reduced the duration of lesions, viral shedding, and aborted episodes. 14 It is likely but as yet unproven that similar efficacy will be demonstrated with high-dose, short-course episodic therapy with valacyclovir or famciclovir. Such ultrashort intermittent treatment for recurrent genital herpes may further reduce costs. For this reason, the need for chemosuppression should be evaluated carefully by the treating doctor, using guidelines based on the frequency of recurrences (e.g., five or more a year). The low cost of generic acyclovir in some jurisdictions may alter this balance.
For patients with recurrent genital (or orofacial) HSV infections who are candidates for chemosuppression, our strong preference is to begin administration of an HSV antiviral (acyclovir, famciclovir, or valacyclovir) with twice-daily dosing. The effect of once-daily therapy (with valacyclovir or famciclovir) can be tested after satisfactory efficacy of twice-daily therapy has been demonstrated for the patient being treated. For monogamous, HSV-serodiscordant couples there is now an additional consideration. Suppression with valacyclovir (and presumably that with acyclovir and famciclovir) has been shown to reduce the risk of acquisition of genital HSV-2 by a seronegative partner by 50% over an 8-month period. 15 Consequently, there will probably be a major shift in the public health imperative and the cost-benefit equation, and presumably many more patients will be considered for long-term chemosuppression.
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