Perspectives on Switching Oral Acyclovir from Prescription to Over‐the‐Counter Status: Report of a Consensus Panel

Ma, Sande; Armstrong, David; Corey, Lawrence; Wl, Drew; Gilbert, D; Rc, Moellering; Lg, Smith

doi:10.1086/514584

Cited by 20 publications

(13 citation statements)

References 22 publications

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“…The prevalence of ACV-resistant HSV isolates from immunocompetent patients has remained relatively unchanged over many years of antiviral use regardless of the introduction of long-term suppressive therapy for patients with recurrent genital herpes (12,37). These experiences, together with the lower mutation frequency associated with HSV-1 strains than with HSV-2 strains, suggest that the prevalence of antiviral resistance in infections caused by HSV-1 may be less than that suggested by HSV resistance prevalence studies predominantly based on diseases typical of HSV-2 infection (3,5).…”

Section: Discussionmentioning

confidence: 99%

Difference in Incidence of Spontaneous Mutations between Herpes Simplex Virus Types 1 and 2

Sarisky¹,

Nguyen²,

Duffy³

et al. 2000

Antimicrob Agents Chemother

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Virology 132:26-37, 1984). Typically, these resistance mutations map to the thymidine kinase (TK) gene and render the virus TK deficient. To examine this process more closely, a plating efficiency assay was used to determine whether the frequencies of naturally occurring mutations in populations of the laboratory strains HSV-1 SC16, HSV-2 SB5, and HSV-2 333 grown in MRC-5 cells were similar when scored for resistance to penciclovir (PCV) and ACV. Our results indicate that (i) HSV mutants resistant to PCV and those resistant to ACV accumulate at approximately equal frequencies during replication in cell culture, (ii) the spontaneous mutation frequency for the HSV-1 strain SC16 is similar to that previously reported for HSV-1 laboratory strains KOS and Cl101, and (iii) spontaneous mutations in the laboratory HSV-2 strains examined were 9-to 16-fold more frequent than those in the HSV-1 strain SC16. These observations were confirmed and extended for a group of eight clinical isolates in which the HSV-2 mutation frequency was approximately 30 times higher than that for HSV-1 isolates. In conclusion, our results indicate that the frequencies of naturally occurring, or spontaneous, HSV mutants resistant to PCV and those resistant to ACV are similar. However, HSV-2 strains may have a greater propensity to generate drug-resistant mutants than do HSV-1 strains.The antiviral drug standard for the treatment of herpes simplex virus (HSV) infections including herpes labialis and genital herpes for almost 2 decades has been acyclovir (ACV) [9-(2-hydroxyethoxymethyl)guanine]. However, with the more recent introduction of penciclovir (PCV) (BRL 39123) [9-(4-hydroxy-3-hydroxymethylbut-1-yl)guanine] and its oral prodrug, famciclovir, the usage of antivirals alternative to ACV for the management of herpesvirus infections has also increased. Identical activation pathways and similar modes of action suggest that the mechanisms of HSV resistance to PCV and ACV are likely to be analogous (2, 40). An assumption that the frequency with which resistance in HSV arises is identical for PCV and ACV can be based on the biochemical similarities of the two compounds and the cross-resistance of thymidine kinase (TK)-negative mutants; however, direct genetic evidence is not available.A low level of replication errors is typically associated with DNA synthesis (10, 33). Resistance to PCV or ACV can arise by a single base mutation in the DNA encoding the HSV TK protein which activates the antiviral agent (6, 23, 29). These spontaneous mutations occur during DNA replication and are independent of the presence of antiviral drug (16). These errors, or random mutations, provide genetic diversity to facilitate the adaptation and evolution of an organism (15). Data from a study of the molecular evolution of HSV type 1 (HSV-1) show that its evolution is slow; the mutation rate was estimated to be 3.5 ϫ 10 Ϫ8 substitutions per site per year (36). Mispaired deoxyribonucleoside triphosphates are often removed by the HSV polymerase (Pol) through its associat...

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Section: Discussionmentioning

confidence: 99%

Difference in Incidence of Spontaneous Mutations between Herpes Simplex Virus Types 1 and 2

Sarisky¹,

Nguyen²,

Duffy³

et al. 2000

Antimicrob Agents Chemother

View full text Add to dashboard Cite

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“…The historical prevalence of acyclovir-resistant HSV isolates from untreated, immunocompetent patients as detected by the plaque reduction assay is 0.3% (71). Furthermore, there has been no detectable change over time in this prevalence based on data for isolates collected during clinical trials, from patients who had not responded well to acyclovir, and from population-based surveys (Table 3), (2,8,14,17; Reyes et al, Abstr.…”

Section: Surveillance In the Immunocompetent Populationmentioning

confidence: 99%

“…Resistant HSV can develop spontaneously, reflecting the natural variability of the HSV population, as evidenced by the detection of acyclovir-resistant HSV in patients who had not been treated with acyclovir (14,71). Nonetheless, acquired resistance to acyclovir is extremely unusual in the immunocompetent population and almost all cases have occurred in severely immunocompromised patients.…”

Section: Factors Influencing the Emergence And Spread Of Resistancementioning

confidence: 99%

Herpes Simplex Virus Resistance to Acyclovir and Penciclovir after Two Decades of Antiviral Therapy

et al. 2003

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Acyclovir, penciclovir, and their prodrugs have been widely used during the past two decades for the treatment of herpesvirus infections. In spite of the distribution of over 2.3 × 106 kg of these nucleoside analogues, the prevalence of acyclovir resistance in herpes simplex virus isolates from immunocompetent hosts has remained stable at approximately 0.3%. In immuncompromised patients, in whom the risk for developing resistance is much greater, the prevalence of resistant virus has also remained stable but at a higher level, typically 4 to 7%. These observations are examined in the light of characteristics of the virus, the drugs, and host factors

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“…The apparent lack of transmission is likely a primary reason for the stable and low prevalence of resistant HSV. Resistant HSV arises spontaneously from the natural variability of the HSV population, as evidenced by the detection of acyclovir-resistant HSV in patients who had not been treated with acyclovir [43,64]. Indeed, each clinical HSV isolate has some percentage of resistant mutants, although very low (10 Ϫ4 -10 Ϫ5 ) [65][66][67].…”

Section: Factors Influencing the Emergence And Spread (Or Lack Thereomentioning

confidence: 99%

Resistance of Herpes Simplex Virus Infections to Nucleoside Analogues in HIV‐Infected Patients

2004

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Antiviral treatment of herpes simplex virus (HSV) infections with nucleoside analogues has been well established for >2 decades, but isolation of drug-resistant HSV from immunocompetent patients has remained infrequent (0.1%-0.7% of isolates) during this period. Even when drug-resistant HSV is isolated from an immunocompetent patient, this virus, with rare exceptions, is cleared normally without adverse clinical outcome. Although drug-resistant HSV is more commonly isolated from immunocompromised patients (4%-7% of isolates) and is more likely to be clinically significant, the prevalence of drug-resistant HSV even among these patients, has been stable over the past 2 decades. Despite this stable prevalence, disease due to drug-resistant HSV remains an important problem for many immunocompromised patients, including those with HIV infection. This article reviews the prevalence, pathogenesis, and implications of drug-resistant HSV infections in HIV-infected patients.

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Perspectives on Switching Oral Acyclovir from Prescription to Over‐the‐Counter Status: Report of a Consensus Panel

Cited by 20 publications

References 22 publications

Difference in Incidence of Spontaneous Mutations between Herpes Simplex Virus Types 1 and 2

Difference in Incidence of Spontaneous Mutations between Herpes Simplex Virus Types 1 and 2

Herpes Simplex Virus Resistance to Acyclovir and Penciclovir after Two Decades of Antiviral Therapy

Resistance of Herpes Simplex Virus Infections to Nucleoside Analogues in HIV‐Infected Patients

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