Recurrent Genital Herpes
12 year history of recurrent herpes, treated with long term acyclovir leading to marrow suppression. The reason for this maybe an element of resistance.
Acyclovir:
Acyclovir is rapidly has demonstrated antiviral activity against herpes simplex virus types 1 (HSV-1) and 2 (HSV-2) and varicella-zoster virus (VZV).
MECHANISM OF ACTION:
Acyclovir (9-[2-hydroxymethyl]guanine) is a nucleoside analog which selectively inhibits the replication of HSV (types 1 and 2) and VZV.
After intracellular uptake, it is converted to acyclovir monophosphate by virally-encoded thymidine kinase; this step does not occur to any significant degree in uninfected cells and thereby lends specificity to the drug's activity. The monophosphate derivative is subsequently converted to acyclovir triphosphate by cellular enzymes.
Acyclovir triphosphate, acting as an analog to deoxyguanosine triphosphate (dGTP), competitively inhibits viral DNA polymerase; incorporation of acyclovir triphosphate into DNA results in chain termination because the absence of a 3' hydroxyl group prevents the attachment of additional nucleosides. Acyclovir triphosphate has a much higher affinity for viral DNA polymerase than for the cellular homolog, yielding a high therapeutic ratio which makes the inhibition of native DNA polymerase clinically unimportant.
Spectrum of activity — Acyclovir is active against, in descending order of susceptibility, HSV types 1 and 2 (HSV-1, HSV-2), VZV, and Epstein-Barr virus (EBV). Cytomegalovirus (CMV), which does not encode thymidine kinase, is resistant at clinically achievable levels. Activity versus human herpes viruses 6, 7 and 8 is not well defined.
Mechanism of resistance — Three mechanisms have been shown to endow herpes simplex viruses with resistance to acyclovir, a phenomenon rare in the immunocompetent host:
- Reduced or absent thymidine kinase.
- Altered thymidine kinase activity resulting in decreased acyclovir phosphorylation.
- Altered viral DNA polymerase with decreased affinity for acyclovir triphosphate.
Recurrent episodes — When compared to primary infection, recurrent genital HSV is typically less severe, with fewer lesions that are often in a unilateral, rather than bilateral distribution. In addition, treatment of the primary infection does not appear to reduce the frequency of subsequent recurrences.
Lesions in recurrent infection, especially in women, may be minor, asymptomatic, and not vesicular; fissures or vulvar irritation can be atypical presentations in women. In addition, the mean duration of lesions is less than with first episodes (10 versus 19 days) and the duration of viral shedding is shorter.
Antiviral therapy for recurrent episodes can be dispensed either episodically to address active lesions as they occur, or continuously as suppressive therapy. Multiple trials have evaluated the efficacy of the three drugs in the treatment of recurrent episodes of genital herpes. Suppression of recurrence is discussed in the next section.
Acyclovir — Acyclovir produces modest benefit in the treatment of recurrent genital herpes, shortening the outbreak duration by one to two days if therapy is initiated within 24 hours of onset. The magnitude of benefit was demonstrated in a randomized double-blind trial that compared two days of acyclovir (800 mg PO three times daily) to placebo in patients with recurrent genital herpes; treatment was begun within 12 hours of first signs or symptoms. The duration of lesions (four versus six days) and viral shedding (25 versus 59 hours) were significantly shortened in those receiving acyclovir. Acyclovir therapy was also associated with a higher proportion of aborted clinical HSV episodes.
Famciclovir — The efficacy of famciclovir for recurrent episodes of HSV was illustrated in a multicenter trial of patient-initiated treatment with either famciclovir (125, 250 or 500 mg twice daily for five days) or placebo in people with a history of recurrences at least every four months. Subjects were instructed to perform cultures and to start therapy within six hours of lesion or symptom onset and were required to report to the study center within 12 hours; they were treated twice daily for five days and then once daily until all lesions were healed.
In this case, we chose Famciclovir. Reason: different mode of action, as well as better tolerability.
Indication: Acute herpes zoster in the immunocompetent host.
Mechanism of Action: Reduce viral replication by inhibiting viral DNA polymerase.
Pharmacokinetics: Valacyclovir is a prodrug of, and metabolized to acyclovir; the oral bioavailability of acyclovir from valacyclovir is 54% as compared to 15-30% for acyclovir. Famciclovir is a prodrug for the active metabolite penciclovir; the mean oral bioavailability of penciclovir from famciclovir is 77%. Penciclovir plus acyclovir are primarily eliminated unchanged by the kidneys and have mean half-lives of 2.5 hours.
Evidence of efficacy: If given within 72 hours of the first herpes zoster lesion, famciclovir and valacyclovir (like acyclovir) provide modest decreases in the time to full crusting (e.g. median 5.5 days for famciclovir, 7 days for placebo), healing and cessation of pain . The benefit is greatest in patients with the most severe infections (many lesions and severe pain). At present the evidence is inconclusive as to whether any antiviral or other therapy has an effect on the overall clinical impact of post-herpetic neuralgia. The new prodrugs have not been studied in children or immunocompromised hosts.
Major adverse effects: These drugs, like acyclovir, produce a low incidence (similar to placebo) of minor adverse effects, including diarrhea, nausea and headache.
Dose and Cost: Acute herpes zoster: famciclovir, 500 mg tds for 7 days, valacyclovir, 1 g TID for 7 days, acyclovir, 800 mg 5 times daily for 7 days. Longer durations of therapy are not more effective; shorter courses have not been tested.
Conclusions: Anti-viral drugs have a modest beneficial effect if given early (rash <72 hr) to immunocompetent patients (>50 yr) with moderate to severe rash or pain associated with acute herpes zoster.
AMH
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