A. Chakrabarty, MD1, N. J. Anderson, MD2, R. Beutner, MD, PhD1,3, S. K. Tyring, MD, PhD, MBA4
1Solano Research, Davis, CA, USA
2Department of Dermatology, Loma Linda University School of Medicine, Loma Linda, CA, USA
3Department of Dermatology, San Francisco Solano Research, Vallejo, CA, USA
4University of Texas, Health Sciences Center, Houston, TX, USA
The Herpesviridae family (Types 1-8) continues to inflict considerable morbidity and social stigma upon humanity. Once infected with the herpes viruses, especially Types 1-3, they establish permanent residence within our nervous system and reactivate during periods of stress, trauma, and/or other precipitating factors. To date, there is no cure for herpes viral infections but antivirals can attenuate the symptoms and duration of episodic outbreaks. Prophylactic therapy can suppress recurrences. The first antiviral with selective activity against virus-infected cells is considered to be acyclovir. Our article will highlight the clinical indications of the current generation, valacyclovir, which is a prodrug of acyclovir. We consider valacyclovir as a second-generation antiviral, having taken into account the initial selectivity and safety profile of its progenitor, acyclovir.
Key Words: herpes virus, antiviral, herpes simplex, varicella-zoster
The hallmark of the herpes viruses is their ability to establish permanent residency within the neuronal ganglia of our nervous system and to reactivate during times of stress, trauma, and other precipitating factors. The herpes simplex virus-1 (HSV-1), herpes simplex virus-2 (HSV-2), and varicella-zoster virus (VZV) can be associated with painful, blistering outbreaks that, although they are self-limiting, have been associated with considerable morbidity.
Antiviral medications are the standard of practice in the management of herpes viral infections. Orally administered antivirals, such as valacyclovir (Valtrex®, GlaxoSmithKline) are prescribed to attenuate the signs and symptoms, reduce the duration of outbreak, and hasten lesion resolution. Our article will focus on the pharmacologic mechanism and diverse clinical indications of one of the second generation antivirals, valacyclovir. The development of the second generation antivirals has been tailored towards enhancing the oral bioavailability and intracellular pharmacokinetics. Valacyclovir provides an excellent safe and effective alternative to its more traditionally prescribed parent compound, acyclovir.
Mechanism of Action
Acyclovir was the first antiviral drug developed for systemic use that exhibited activity preferentially against herpes virus-infected cells. It is a 2′-deoxyguanosine analogue and requires activation by the viral-encoded thymidine kinase followed by cellular kinases. The final product, acyclovir triphosphate, irreversibly inhibits viral DNA polymerase via competition with deoxyguanosine triphosphate, preventing further chain elongation. Acyclovir triphosphate’s meager production in non-infected cells and its reduced affinity for cellular DNA polymerase limits its potential side-effects. However, acyclovir has poor oral bioavailability and requires either higher dosing or intravenous administration for severe manifestations of herpes infections (i.e., neonatal herpes, herpes encephalitis).
Valacyclovir provides a high bioavailability of acyclovir, 3- to 5-fold higher than that obtained with oral acyclovir, and it is equivalent to plasma levels achieved with doses of intravenous acyclovir (see Table 1).1 An L-valine ester of acyclovir, valacyclovir is rapidly metabolized into valine and acyclovir by the enzyme valacyclovir hydrolase in the gastrointestinal tract and liver. Being a prodrug, valacyclovir does not have any antiviral activity until it is biotransformed into acyclovir. The drug may be administered without regard to meals.
|Description||Oral prodrug of acyclovir|
|Antiviral Spectrum||Herpes simplex virus-1 (HSV-1)|
Herpes simples virus-2 (HSV-2)
Varicella zoster virus (VZV)
Table 1: Chemical description of valacyclovir.
The antiviral spectrum of valacyclovir encompasses HSV-1, HSV-2, VZV. The predominant clinical indications are orofacial herpes, genital herpes, herpes zoster and to a lesser degree, cytomegalovirus prophylaxis for transplant patients (Table 2). An alternative antiviral for these clinical indications is another second-generation antiviral, famciclovir (Famvir®, Novartis), the prodrug of penciclovir. These antivirals have limitations as they provide no cure for infections, but instead alter the clinical course of the disease.
|Orofacial Herpes (HSV-1)||Initial therapy: 2,000mg, po, b.i.d. for 1 day|
Prophylaxis after laser resurfacing: 500mg, po, b.i.d. for 10-14 days
(HSV-2 or HSV-1)
|Initial therapy: 1,000mg, po, b.i.d. for 10 days|
Episodic therapy: 500mg, po, b.i.d. for 3 days
Suppressive therapy (recurrence dependent):
• 500mg, po, qd for <10 recurrences
• 1,000mg, po, qd for >10 recurrences
HSV infections for HIV-positive: 1,000mg, po, qd
Suppressive dosing for primary episode: ongoing trial – 1,000mg, po, qd
|Herpes Zoster / Post-Herpetic Neuralgia||Immunocompetent: 1,000 mg, po, t.i.d. for 7 days|
Immunocompromised: ongoing trial – 2,000mg, po, t.i.d. for 7 days
|Cytomegalovirus||Prophylaxis: renal transplant patients – 2,000mg, po, q.i.d. for 90 days|
Table 2: Clinical indications and dosing for valacyclovir.
Valacyclovir is utilized for the management of orofacial herpes. HSV-1 is primarily associated with this condition. A short course of high dose valacyclovir at 2,000mg twice daily for 1 day is the recommended dose for initial treatment of orofacial herpes, usually commenced during the prodromal phase.2 Another study demonstrated that valacyclovir 500mg, po, b.i.d. for 10-14 days is an effective prophylactic strategy against orofacial herpes recurrence starting 1 day prior to laser cutaneous resurfacing.3 Smaller placebo-controlled trials have demonstrated the benefit of valacyclovir 500mg once daily for 4 months as a well-tolerated and effective therapy for the suppression of recurrent herpes labialis.4 The higher bioavailability of valacyclovir enables less frequent administration compared to acyclovir.
HSV-2 is accountable for the majority of genital herpes, although HSV-1 is playing an increasing role in the epidemic. Treatment of genital herpes is categorized into primary, episodic, and suppressive regimens. Valacyclovir is approved by the US FDA at 1,000mg, po, two times daily for 10 days for initial onset of genital herpes and at a 3-day, 500mg, twice-daily course for episodic management of recurrent herpes.5 Suppressive therapy is preferred when recurrences are frequent, severe, and/or emotionally disturbing. An open-label study demonstrated the preference of suppressive therapy with valacyclovir as once-daily therapy over the episodic dose of twice-daily therapy with lower recurrence rates and higher satisfaction levels noted in the suppressive cohort.6 The treatment stratification of suppressive therapy is based on the annual number of recurrences.7 For patients with <10 annual recurrences, 500mg of daily valacyclovir is recommended. For patients with >10 recurrences, 1,000mg valacyclovir daily, 250mg valacyclovir twice daily, or 400mg acyclovir twice daily were noted to be beneficial according to a subgroup analysis for different dosages. The once daily dosing provides a more patient-friendly approach, enabling greater compliance with antiviral therapy.7 For HIV positive patients, valacyclovir 500mg twice daily or 1,000mg once daily is considered effective.8 The suppressive strategy of valacyclovir therapy is being explored for primary episodes of genital herpes. This study is being conducted by Dr. Beutner in Davis. The treatment strategy will evaluate whether suppressive dosing can reduce the frequency and duration of recurrences as initial management for primary genital herpes.
Genital herpes transmission reduction is a recent supplemental indication for valacyclovir. Corey, et al. demonstrated the significant reduction of HSV-2 transmission among heterosexual, discordant couples with once-daily, 500mg valacyclovir.9 The study revealed a 50% decrease in HSV-2 acquisition among susceptible partners and a more dramatic 75% symptomatic reduction of HSV-2 among susceptible partners when the infected partner received once-daily valacyclovir for 8 months. When combined with safe sexual practices (i.e., condom use), valacyclovir has been shown to reduce the transmission of genital herpes. The same study noted a reduction in asymptomatic viral shedding as an additional benefit. Most cases of transmission occur during periods of asymptomatic viral shedding.
Valacyclovir is indicated for the management of herpes zoster. Beutner, et al. demonstrated the benefit of valacyclovir 1,000mg 3x daily for 7 days in reducing the duration and proportion of postherpetic neuralgia at 6 months for patients >50 years old in comparison to acyclovir.10 As well, no additional benefit was noted beyond 7 days of valacyclovir therapy when compared to a 14 day regime. Tyring, et al. conducted a comparison trial of valacyclovir vs. famciclovir, which did not reveal any significant differences between either antiviral in the treatment of herpes zoster.11 The main advantage of valacyclovir would be cost-effectiveness which takes into consideration the cost of patient hospital stay. Although acyclovir is cheaper, the intravenous route is offset by the costs of inpatient hospitalization. Combination strategies for the management of herpes zoster are also being considered. When incorporating an anticonvulsant, such as gabapentin, with an antiviral, such as valacyclovir, paients exhibited pain reduction in an open-label, pilot trial.12 Immunocompromised patients, such as HIV and cancer patients, can suffer from more severe manifestations of herpes zoster than immunocompetent patients. There are no current published studies documenting the benefit of valacyclovir for herpes zoster among the immunocompromised. A higher dosing regimen of valacyclovir for acute herpes zoster may provide a convenient, efficacious, cost-effective, and practical alternative to intravenous acyclovir administration for immunocompromised patients. Dr. Tyring is evaluating a higher dose of valacyclovir at 2,000mg, po, 3x daily vs. 1,000mg, po, 3x daily for 7 days as management of acute herpes zoster in immunocompromised patients. The benefit of the higher dosing valacyclovir will be determined after completion of the randomized, double-blinded study. Valacyclovir provides an effective antiviral in the treatment of herpes zoster and further trials of various dosing regimens of the antiviral pertaining to different clinical manifestations of herpes zoster are ongoing.
Cytomegalovirus (CMV) is a major pathogen resulting in considerable morbidity and mortality subsequent to solid organ and bone marrow transplantation. Antiviral prophlyaxis offers an effective strategy compared to the wait and treat approach. Prophylactic therapy with valacyclovir 2,000mg, 4x daily for 90 days immediately after renal transplantation reduced the incidence of CMV disease, as well as delaying its onset.13 A separate comparison trial of oral valacyclovir vs. oral ganciclovir demonstrated similar levels of safety and efficacy in the prophylaxis of CMV disease after renal transplantation.14 Valacyclovir is also utilized as preventive therapy for CMV for cardiac and bone marrow transplant recipients.
The role of valacyclovir in the management of herpes viral infections has been illustrated and is being explored for new clinical scenarios. Valacyclovir provides a unique mechanism of enhancing the oral bioavailability of the parent compound, acyclovir, while maintaining the same safety level profile. The simpler dosing schedule allows patients more convenient dosing regimens with less interruption of their activities of daily living. Current trials of valacyclovir for herpes infections among the immunocompromised as well as new dosing regimens for previously established therapeutic indications are ongoing and will serve to enhance our knowledge of the various clinical indications of valacyclovir.
- Soul-Lawton J, Seaber E, On N, Wootton R, Rolan P, Posner J. Absolute bioavailability and metabolic disposition of valacyclovir, the L-valyl ester of acyclovir, following oral administration to humans. Antimicrob Agents Chemother 39(12):2759-64 (1995 Dec).
- Spruance SL, Jones TM, Blatter MM, et al. High-dose, short-duration, early valacyclovir therapy for episodic treatment of cold sores: results of two randomized, placebo-controlled, multicenter studies. Antimicrob Agents Chemother 47(3):1072-80 (2003 Mar).
- Beeson WH, Rachel JD. Valacyclovir prophylaxis for herpes simplex virus infection or infection recurrence following laser skin resurfacing. Dermatol Surg 28(4):331-6 (2002 Apr).
- Baker D, Eisen D. Valacyclovir for prevention of recurrent herpes labialis: 2 double-blind, placebo-controlled studies. Cutis 71(3):239-42 (2003 Mar).
- Lin P, Torres G, Tyring SK. Changing paradigms in dermatology: antivirals in dermatology. Clin Dermatol 21(5):426-46 (2003 Sep-Oct).
- Romanowski B, Marina RB, Roberts JN; Valtrex HS230017 Study Group. Patients’ preference of valacyclovir once-daily suppressive therapy versus twice-daily episodic therapy for recurrent genital herpes: a randomized study. Sex Transm Dis 30(3):226-31 (2003 Mar).
- Reitano M, Tyring S, Lang W, et al. Valacyclovir for the suppression of recurrent genital herpes simplex virus infection: a large-scale dose range-finding study. International Valaciclovir HSV Study Group. J Infect Dis 178(3):603-10 (1998 Sep).
- Conant MA, Schacker TW, Murphy RL, Gold J, Crutchfield LT, Crooks RJ; International Valaciclovir HSV Study Group. Valacyclovir versus acyclovir for herpes simplex virus infection in HIV-infected individuals: two randomized trials. Int J STD AIDS 13(1):12-21 (2002 Jan).
- Corey L, Wald A, Patel R, et al. Once-daily valacyclovir to reduce the risk of transmission of genital herpes. N Engl J Med 350(1):11-20 (2004 Jan 1).
- Beutner KR, Friedman DJ, Forszpaniak C, Andersen PL, Wood MJ. Valaciclovir compared with acyclovir for improved therapy for herpes zoster in immunocompetent adults. Antimicrob Agents Chemother 39(7):1546-53 (1995 Jul).
- Tyring SK, Beutner KR, Tucker BA, Anderson WC, Crooks RJ. Antiviral therapy for herpes zoster: randomized, controlled clinical trial of valacyclovir and famciclovir therapy in immunocompetent patients 50 years and older. Arch Fam Med 9(9):863-9 (2000 Sep-Oct).
- Brentjens MH, Torres G, He J, Lee P, Tyring SK. Reduction of PostHerpetic Neuralgia: A Study of the Effects of Gabapentin with Valacyclovir During Acute Zoster Outbreaks. Presented at: the American Academy of Dermatology 61st Annual Meeting. March 21-26, 2003; San Francisco, CA; Abstract #P38.
- Lowance D, Neumayer HH, Legendre CM, et al. Valacyclovir for the prevention of cytomegalovirus disease after renal transplantation. International Valacyclovir Cytomegalovirus Prophylaxis Transplantation Study Group. N Engl J Med 340(19):1462-70 (1999 May 13).
- Reischig T, Opatrny K Jr, Bouda M, Treska V, Jindra P, Svecova M. A randomized prospective controlled trial of oral ganciclovir versus oral valacyclovir for prophylaxis of cytomegalovirus disease after renal transplantation. Transpl Int 15(12):615-22 (2002 Dec).