Acyclovir Should Not Be Approved for Marketing Without Prescription

THE PROPOSAL THAT acyclovir be approved for treatment of genital herpes without prescription (over the counter [OTC]) is based on two premises related to its possible public health benefits and two others that counter arguments against approval. First, proponents believe there are many severely affected, symptomatic persons with genital herpes who do not have ready access to needed acyclovir therapy, and that OTC availability can help to solve this problem. This premise builds on the principles of patient autonomy and health care cost containment that contributed to OTC approval for vaginal antifungal therapy, H2-receptor blocking drugs, and others. The second potential benefit of OTC approval is one that, for regulatory reasons, the manufacturer cannot promote, although other spokespersons have done so: that increased use of acyclovir through self-treatment would help prevent transmission of herpes simplex virus (HSV) between sex partners. The third premise is that nonprescription use would not foster the selection of acyclovir-resistant strains of HSV. Fourth, it is argued that few persons with syphilis, chancroid, or other genital ulcer diseases would delay seeking health care while they treated themselves for presumed herpes. A final consideration is not a premise but a promise, that OTC marketing of acyclovir would be accompanied by a safer sex public education campaign sponsored by the manufacturer. The remainder of this commentary responds to each of these considerations. Toxicity and tolerance are not at issue; in these respects, acyclovir is extremely safe.

Premise 1: Personal Health Benefits

By the late 1980s, approximately 22% of the U.S. population was infected with HSV type 2 (HSV-¹; allowing for new infections in the past several years and for genital infection with HSV-1, it is likely that at least 25% and perhaps 30% of the population has genital herpes. Many of these persons indeed suffer greatly. On the other hand, one of the silver linings around the evolving data is that most persons with subclinical disease do not suffer physically, nor probably psychologically; the majority of genital HSV infections are asymptomatic or clinically trivial. A study conducted by the American Social Health Association² concluded that many persons with genital herpes are affected severely and that physician attitudes or patients' own embarrassment impair access to acceptable health care and therefore to therapy. However, that survey had a serious bias: The population was selected from subscribers to The Helper, ASHA's newsletter for persons with genital herpes (total circulation 10,000), and only 62% of those surveyed returned their questionnaires. Not surprisingly, the same severely affected minority and their representatives have been vocal beyond their numbers in supporting OTC approval. Doubtless many persons with symptomatic genital herpes would find it convenient to purchase acyclovir without prescription, but it is arguable that the expense of the drug is a greater barrier to access to treatment than the prescription limitation. It certainly is true that many clinicians trivialize genital herpes or are unaware of the efficacy of acyclovir, and therefore do not promote or prescribe treatment. However, this problem should be amenable to professional education and to advocacy by public health authorities. (Admittedly, many of the latter also require education about the public health impact of genital herpes.)

Premise 2: Reduced Transmission of Herpes Simplex Virus

Beyond the supposed personal health benefits, some proponents of OTC acyclovir argue that reduced transmission of HSV would result, helping to curtail the spread of infection-certainly a valid public health goal. Indeed, a recent study³ showed that in addition to suppressing the clinical manifestations of recurrent genital herpes, acyclovir markedly reduces subclinical viral shedding. Like the clinical response, however, break-through subclinical shedding occurs intermittently in treated patients, and there are as yet no data-aside from the anecdotal experiences of some clinicians-showing reduced transmission. (It is the lack of such data that precludes the manufacturer from promoting this potential benefit.)

In my view, it is a no-brainer that transmission efficiency will be lower in patients taking acyclovir, but the quantitative reduction is very difficult to estimate; it could be as low as 10% or as high as 90%, and clinical studies are necessary. Equally important, results in the subjects of a well-controlled study cannot be extrapolated to the uncontrolled environment of self-treatment without professional intervention; another no-brainer is that self-treatment without prescription would be characterized in part by intermittent use of acyclovir in variable dosage. Moreover, it seems likely that some self-treated persons would think they were less infectious and would be less attentive to subtle symptoms, to warning their partners, or to using condoms, perhaps resulting in a paradoxical increase in transmission. To the extent that acyclovir or other antiherpetic drugs might reduce transmission, it seems that goal could best be accomplished by increased prescription use with counseling by clinicians.

Premise 3: Potential for Selection of Resistant Herpes Simplex Virus

Concern about selection of HSV strains resistant to acyclovir and other thymidine kinase-dependent, antiherpetic drugs was the main factor that led 104 virologists and other specialists in infectious diseases to sign a position statement on behalf of a task force of the Infectious Diseases Society of America, urging the US Food and Drug Administration (FDA) not to approve acyclovir for OTC marketing.⁴ The occasional development of resistance is well documented in immunodeficient HIV-infected patients on chronic acyclovir therapy.^5,6 The risk seems to be low in persons without immunodeficiency. A recent review⁶ cites only three such cases, including an especially well-documented case reported by Kost et al.⁷ Including another recently reported patient,⁸ four cases are known. In one study, none of 239 patients receiving suppressive therapy with acyclovir for 6 or more years developed clinically significant resistance.⁹ Unfortunately, this information is not fully reassuring. All four of the known immunocompetent patients with clinical herpes caused by acyclovir-resistant strains were reported in the past 3 years,^6-8 perhaps suggesting a new and growing problem. The biologic ability of HSV to develop acyclovir resistance is unquestioned, and it seems likely that a low-frequency mutation-too low to detect in studies of the size conducted to date-could pose substantial risk under certain conditions. If one sought to create those conditions, one might arrange for widespread, intermittent use of the drug in variable dosage, and although the current prescription limitation does not preclude such use, OTC availability surely would promote it. Some proponents have suggested the drug be given provisional approval, with potential withdrawal from the OTC market if significant resistance develops. However, there are few, if any, such precedents, and it might be politically difficult to rescind approval once substantial numbers of infected persons were using OTC therapy.

As a clinician and epidemiologist with limited virological expertise, I suspect widespread resistance would develop slowly, if at all, if acyclovir were freed from prescription restrictions. But what level of risk are we willing to take? Are the benefits of OTC acyclovir sufficient to embark on a societal experiment to test the hypothesis that resistance will not be a problem? The burden of proof is on the proponents, not to show that selection of resistance probably would not result, but that it cannot or will not develop. Most virologists agree that such assurance is not possible at our current state of knowledge.⁴ Two related, almost philosophical questions might also be raised: When as a society we finally have come to understand the worldwide havoc caused by indiscriminate antibiotic use, should we make any systemic anti-infective drug available over the counter? And do we want to take this step with the most effective and least toxic class of antiviral agents?

Premise 4: Effect on Other Genital Ulcer Diseases

I have spoken with venereologists who express the fear that persons with syphilis or chancroid would treat themselves with acyclovir, delaying accurate diagnosis and therapy, but the importance of this problem is uncertain. A recent study¹⁰ suggested that at STD clinics few, if any, patients with syphilis or chancroid would have sought empirical therapy for herpes before obtaining professional health care. The flaw in this conclusion is that the study surveyed patients who had already come to STD clinics for professional care. However, there probably is little overlap between the populations at risk for syphilis or chancroid in the United States and those at risk for symptomatic herpes or, perhaps more important, those who would be able to afford OTC acyclovir at anticipated prices. This problem also might be amenable to suitable education efforts, such as a package insert with photographs of both herpetic and non-herpetic lesions, which the manufacturer undoubtedly would support. Delayed diagnosis of other STDs clearly would occur from time to time, but perhaps not with sufficient frequency to argue strongly against OTC approval.

Public Education

The manufacturer has stated an intent to link OTC marketing of acyclovir with sophisticated, aggressive marketing of safer sex (presumably with direct or indirect emphasis on the risk for genital herpes). Indeed, a prototype television advertisement was the best safer sex education videotape I have seen, a tantalizing taste of the power of private sector investment in public education to prevent STD. One benefit of OTC approval to the manufacturer-perhaps the major benefit-is that FDA often grants an extension of patent exclusivity when a drug is converted to nonprescription use, delaying competition by generic drug producers. This may explain the education campaign's link to OTC approval, because Glaxo Wellcome's patent for acyclovir will expire in 1997.

It is difficult to gainsay the manufacturer's economic and market analyses, but perhaps there are other options. For example, direct marketing of prescription drugs to the public seemingly has been effective for some products, and one wonders whether such an approach for acyclovir or valacyclovir (also a Glaxo Wellcome product) could help finance a safer sex public education campaign. In any case, even if OTC acyclovir were approved and a sophisticated education campaign were begun, there would be no guarantee of its intensity or duration. The Glaxo Wellcome staff involved in the OTC acyclovir effort are dedicated professionals, and I have no doubt about their personal commitment to STD education, but market forces and cash flow from drug sales simply cannot be predicted with certainty, especially beyond a year or two. The potential for such sophisticated public education may be the single strongest reason to support OTC approval, but this benefit does not seem to outweigh the possible disadvantages.

A Public Health Perspective

I have great empathy for persons with genital herpes, especially those with frequent or severe recurrences and those who want to protect their uninfected sex partners and future children, and I believe antiviral drugs are greatly underused. Many genital herpes sufferers would benefit from reduced health care costs if acyclovir were available OTC, and some infected persons and their partners would have improved psychological well-being. On balance, however, the advantages do not outweigh the potential harm. It is time for recognition of genital herpes as a serious public health problem and for national policy recommendations for prevention. New tools to this end are at hand: There is reason for optimism that one or more effective vaccines to prevent HSV-2 infection will be available within the next two to three years; studies are likely to show substantial reductions in HSV transmission by suppressive antiviral therapy; and lower cost, truly type-specific serological tests are likely to be available for diagnosis and case finding to facilitate counseling, immunization, and antiherpetic therapy. But OTC acyclovir does not have to be part of this paradigm.

Acknowledgment

The author thanks Dr. Michael Oxman for his helpful advice.