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Systemic Antiviral Agents


Questions

  • Q11.1 What is the spectrum of dermatologic conditions that human herpes virus (HHV) infections can cause? (Pg. 115, Table 11.1 )

  • Q11.2 What are the two primary steps (one step with two parts) by which acyclovir reaches the form that inhibits viral replication (similar steps for valacyclovir and famciclovir) (Pg. 115, Fig. 11.2 )

  • Q11.3 How common is acyclovir resistance, and what are the clinical implications of this resistance? (Pgs. 118, 122)

  • Q11.4 What is the rationale for the use of acyclovir or valacyclovir in patients with recurrent erythema multiforme, and which regimens are most effective? (Pgs. 118, 120)

  • Q11.5 Of the three drugs for HHV infections discussed in this chapter, which two are defined as ‘prodrugs’ for another active drug? (Pgs. 119, 121)

  • Q11.6 What advantages does valacyclovir have over acyclovir in treating herpes zoster? ( Pgs. 119, 120)

  • Q11.7 How does the bioavailability differ between acyclovir, valacyclovir, and famciclovir? How might this relate to treating varicella-zoster virus (VZV) infections and herpes simplex virus (HSV) infections?) (Pg. 121)

  • Q11.8 What are the most important clinical circumstances that may justify long-term antiviral suppressive therapy for recurrent HSV infections? (Pg. 122)

  • Q11.9 What are the key points concerning the development of the VZV vaccine and the priorities for clinical use of this vaccine? (Pg. 122)

  • Q11.10 What are the two available vaccines to prevent shingles and how are they different? (Pg. 123)

  • Q11.11 Which human immunodeficiency virus (HIV) medications function as pharmacokinetic enhancers to boost the concentrations of other antiretroviral medications? (Pg. 124)

  • Q11.12 Concerning vaccine development for HIV prevention, (1) what are several of the methods of development used, and (2) what is the only vaccine that has demonstrated any efficacy in clinical trials? (Pg. 124x2)

Abbreviations used in this chapter

ACIP

Advisory Committee on Immunization Practices

ACV

Acyclovir

AIDS

Acquired immunodeficiency syndrome

AZT

Azidothymidine ( same as zidovudine)

CDC

Centers for Disease Control and Prevention

CYP

Cytochrome P-450

GI

Gastrointestinal

FCV

Famciclovir

FDA

US Food and Drug Administration

HAART

Highly active antiretroviral therapy

HHV

Human herpes virus

HIV

Human immunodeficiency virus

HSV

Herpes simplex virus

HZ

Herpes zoster

INSTI

Integrase strand transfer inhibitor

MMR

Measles/mumps/rubella

NRTI

Nucleoside reverse transcriptase inhibitor

NNRTI

Nonnucleoside reverse transcriptase inhibitor

PHN

Postherpetic neuralgia

PI

Protease inhibitor

PPC

Pregnancy prescribing category

Rx

Prescription or medication

SJS

Stevens–Johnson syndrome

TEN

Toxic epidermal necrolysis

TK

Thymidine kinase

VACV

Valacyclovir

VZV

Varicella-zoster virus

Acknowledgment

Thanks to Patricia C. Lee, George D. Magel, Kassie A. Haitz, Whitney J. Lapolla, Catherine M. DiGiorgio and Natalia Mendoza for their input into this chapter and/or prior editions of this chapter.

Introduction

Viral diseases in dermatology can be very frustrating to treat. Prevention strategies, such as vaccines, proper sanitation, vector control, blood testing, condom use/abstinence, and education remain essential to managing viral spread. Once viruses, such as human herpes viruses (HHV) and human immunodeficiency virus (HIV) are acquired, antiviral agents are essentially the sole method of treatment. A large number of antiviral medications have been approved by the US Food and Drug Administration (FDA) during the past 3 decades. New antiviral agents and vaccines are continuously being researched for more effective control of these viral diseases.

To date, there are over 30 FDA-approved systemic antiviral drugs for treatment of infections caused by HHV and HIV, as well as for hepatitis viruses, influenza, and so on. This chapter primarily addresses the current use of systemic antiviral agents (against HHV) in dermatology, as well as new agents currently under investigation. Also provided is a brief overview of antiviral therapy for HIV infections.

Drugs for Human Herpes Virus Infections

HHV are double-stranded, linear deoxyribonucleic acid (DNA) viruses that cause a variety of illnesses. Q11.1 The HHV family includes herpes simplex virus type 1 and type 2 (HSV-1 and HSV-2), which most frequently produce herpes labialis (cold sores) and genital herpes, respectively; however, both types of lesion can be caused by either virus. HSV-1 and -2 have also been shown to cause gingivostomatitis, ocular disease, herpes gladiatorum, eczema herpeticum, herpetic whitlow, neonatal herpes, lumbosacral herpes, herpetic keratoconjunctivitis, herpes encephalitis, cervicitis, and erythema multiforme. HHV type 3 is also known as varicella-zoster virus (VZV). It is more commonly called chickenpox in its primary form and herpes zoster (HZ) or shingles in its recurrent form. The remaining members of the HHV family and resulting conditions are listed in Table 11.1 . The three primary drugs that have efficacy against HSV-1, HSV-2, and VZV are acyclovir, valacyclovir, and famciclovir ( Table 11.2 ).

Table 11.1
Human Herpes Viruses
Hhv Number Older Nomenclature Resultant Diseases
HHV 1 Herpes simplex virus type 1 (HSV-1) Herpes labialis, etc.
HHV 2 Herpes simplex virus type 2 (HSV-2) Genital herpes, etc.
HHV 3 Varicella-zoster virus (VZV) Chicken pox, HZ
HHV 4 Epstein-Barr virus (EBV) Mononucleosis, Burkitt lymphoma
HHV 5 Cytomegalovirus (CMV) CMV retinitis
HHV 6 No specific name Roseola infantum, etc.
HHV 7 No specific name Roseola infantum, Pityriasis rosea a , etc.
HHV 8 Kaposi sarcoma herpes virus Kaposi sarcoma (classic and epidemic)
HZ , Herpes zoster.

a The causal role of HHV 7 in pityriasis rosea has not been fully established.

Table 11.2
Systemic Antiviral Agents Used To Treat Human Herpes Virus Infections
Generic Name Trade Name Generic Available Tablet Size Oral Suspensions Topical Preparation
Acyclovir Zovirax Yes 200, 400, 800 mg Yes Yes
Valacyclovir Valtrex Yes 500, 1000 mg No No
Famciclovir Famvir Yes 125, 250, 500 mg No No

Acyclovir

Pharmacology

Acyclovir (9-2-hydroxyethoxymethyl guanine or acycloguanosine) (ACV), a guanosine analog, is the most well-known and widely used antiviral drug in the world ( Fig. 11.1 ). ACV is available in intravenous, oral, and topical formulations, but its oral bioavailability is low (∼20%). Q11.2 Activation of ACV requires phosphorylation by herpes-specific thymidine kinase (TK) before bi- and triphosphorylation by host cellular enzymes. The active triphosphorylated ACV inhibits viral DNA polymerase by serving as an obligate chain terminator (i.e., complete and irreversible inhibition of further viral DNA synthesis) ( Fig. 11.2 ). Furman and co-authors suggested that activated triphosphate of ACV is substantially more effective in inactivating the viral polymerase than the cellular DNA polymerase. Table 11.3 contains the key pharmacologic concepts for ACV.

Fig. 11.1, Acyclovir, valacyclovir, famciclovir.

Fig. 11.2, Antiviral drug mechanism. DNA , Deoxyribonucleic acid; GMP , guanosine monophosphate.

Table 11.3
Key Pharmacologic Concepts
Drug Name Peak Levels Bioavailability (%) Protein Binding (%) Half-Life Metabolism Excretion
Acyclovir 1.5–2.0 hours 15–30 9–33 1.3–1.5 hours No hepatic microsomal metabolism Roughly equal urine and fecal
Valacyclovir Uncertain 54.50 13.5–17.9 2.5–3.3 hours No hepatic microsomal metabolism; conversion to acyclovir Roughly equal urine and fecal
Famciclovir 0.9 hours 77 <20 2.3–3.0 hours No hepatic microsomal metabolism; conversion to penciclovir 73% urine, 27% fecal; mostly penciclovir, also 6-deoxypenciclovir

Clinical Use

Indications for ACV are found in Box 11.1 . Box 11.2 details various risks of ACV.

Box 11.1
Indications for Acyclovir, Valacyclovir, Famciclovir
FDA, US Food and Drug Administration; HIV , human immunodeficiency virus; HSV , herpes simplex virus; HZ , herpes zoster.

Acyclovir

FDA-Approved Indications

Herpes Simplex Infections

  • Primary episode

  • Recurrent episodes

  • Suppressive therapy

Varicella-Zoster Infections

  • Chicken pox

  • HZ

Herpes Simplex or Varicella-Zoster Infections

  • Immunocompromised patients (such as HIV infections)

Other Dermatologic Uses

  • Recurrent erythema multiforme (presumed/proven caused by HSV)

  • Other subsets of herpes simplex infections (see text)

Valacyclovir

FDA-Approved Indications

Herpes Simplex Infections

  • Primary episode

  • Recurrent episodes

  • Suppressive therapy

Varicella-Zoster Infections

  • HZ

Herpes Simplex or Varicella-Zoster Infections

  • Immunocompromised patients (such as HIV infections)

Other Dermatologic Uses

  • Recurrent erythema multiforme (presumed/proven caused by HSV)

  • Other subsets of herpes simplex infections (see text)

Famciclovir

FDA-Approved Indications

Herpes Simplex Infections

  • Primary episode

  • Recurrent episodes

  • Suppressive therapy

  • Immunocompromised patients (such as HIV infections)

Varicella-Zoster Infections

  • HZ

  • Immunocompromised patients (such as HIV infections)

Other Dermatologic Uses

  • Other subsets of herpes simplex infections (see text)

  • Primary varicella

Box 11.2
Drug Risks Profile—Oral Acyclovir (A), Valacyclovir (V) and Famciclovir (F)
Data from Facts & Comparisons eAnswers [online database]. St. Louis: Wolters Kluwer [ https://www.wolterskluwercdi.com/facts-comparisons-online/ ].
IV , Intravenous.

Contraindications

  • Hypersensitivity acyclovir/valacyclovir/famciclovir or formulation

Boxed Warnings

  • None listed

Warnings & Precautions a
General Concerns

  • a For varicella start therapy within 24 hours of rash onset

  • a Maintain adequate hydration during therapy

  • Famciclovir may contain lactose (caution patients with lactose intolerance)

Major Organ Toxicities

  • a Renal failure from rapid IV administration

  • Thrombotic microangiopathy in immunocompromised patients

  • Neurotoxicity with higher doses and reduced renal function

Pregnancy Prescribing Status

  • Traditional US Food and Drug Administration rating —category B

  • Newer rating b —(A) probably compatible; (V) compatible; (F) low risk

a Under “Warnings & Precautions” these adverse effects can be considered relatively high risk or important clinical scenarios to avoid.

b See Chapter 65 , Dermatologic Drugs During Pregnancy and Lactation, for detailed explanations of terms for “Newer rating” based on 2015 US Food and Drug Administration rulings.

US Food and Drug Administration-Approved Indications

Herpes Simplex Virus Infections

ACV can be administered topically, orally, and intravenously. The oral form is the most widely used for HSV infections. In the therapy of genital HSV, oral ACV is indicated for treatment of the initial episode and recurrent disease, as well as for suppressive therapy. For first-episode genital HSV, the original recommended dose was 200 mg 5 times daily for 10 days. Although ACV has greater efficacy when used for first-episode genital HSV, it also shows significant benefit in recurrent disease if therapy is initiated during the prodromal phase. For recurrent genital HSV, originally ACV was dosed as 200 mg 5 times daily for 5 days. Far more commonly, clinicians use ACV dosed as 400 mg 3 times daily (TID) for 10 days (first-episode HSV) or 5 days (HSV recurrences). The decreased frequency leads to greater convenience and increased patient compliance. Suppressive therapy is recommended for frequent recurrences. Continuous suppressive therapy with ACV 400 mg twice daily reduces recurrence of genital HSV by 80% to 90%, and reduces asymptomatic viral shedding of HSV-2 by 95%. Suppressive ACV in pregnant females beginning before 36 weeks’ gestation reduces the risk of perinatal transmission, viral shedding, and the number of caesarean deliveries.

ACV is also beneficial in recurrent orofacial HSV (herpes labialis). ACV 200 mg 5 times daily for 5 days expedites crusting, but does not appear to reduce healing time significantly. Maximal therapeutic benefits are seen when therapy is initiated during the prodromal stages before vesicle formation. Suppressive therapy should be considered for patients with severe or frequent recurrences defined as six or more episodes per year or those with a history of ocular HSV disease. This guideline no doubt has flexibility based on individual patient circumstances. ACV suppressive therapy following initial ocular herpes has been shown to reduce the recurrence by 45% in the first year. Topical ACV is also promoted for the treatment of orofacial HSV. Although it has been suggested that topical ACV has limited efficacy because of inadequate penetration of the drug through the stratum corneum, recent data demonstrate transdermal penetration of ACV can be enhanced by using different vehicles, percutaneous absorption enhancers (such as collagen microparticles, oleic acid, nonionic surfactants to name a few), and iontophoresis.

Intravenous ACV is reserved for severe illness and in the immunocompromised because of its markedly greater bioavailability (∼100%). Indications include disseminated HSV disease, complicated primary infection, neonatal infection, eczema herpeticum, herpes encephalitis, and other HSV subsets that fails oral therapy. Several randomized, placebo-controlled trials have found ACV suppressive therapy among people dually infected with HSV-2 and HIV-1 to reduce risk of HIV-1 progression and slowed CD4 cell count falling to less than 350 cells per μL. The effect of ACV on the clinical course of HIV is mediated through decreases in HIV viral load, the primary determinant of HIV disease progression, and via suppression of HSV-2-mediated inflammation.

Q11.3 Although ACV resistance is low in immunocompetent patients, HSV-2-resistant isolates are more common in immunocompromised patients. In ACV-resistant strains, antiviral susceptibilities should be determined and foscarnet or cidofovir used as primary therapy. See Tables 11.4 and 11.5 regarding the use of ACV for HHV infections in immunocompetent and immunocompromised patients.

Table 11.4
Clinical Regimen for Human Herpes Virus Infections in Immunocompetent Patients
Clinical Scenario Acyclovir Valacyclovir Famciclovir
Herpes simplex—primary 200 mg 5×/day for 10 days a 1000 mg BID for 10 days 250 mg TID for 10 days
Herpes simplex—recurrences 200 mg 5×/day for 5 days a 500 mg BID for 3 days b 125 mg BID for 5 days
Herpes simplex—suppression 400 mg BID 500 mg qD c 250 mg BID
HZ—acute treatment 800 mg 5×/day for 7–10 days 1000 mg TID for 7 days 500 mg TID for 7 days
Primary varicella—children 20 mg/kg QID up to 800 mg/dose for 5–7 days 20 mg/kg TID up to 1000 mg/dose for 5 days Not well evaluated
BID , Twice a day; HZ , herpes zoster; qD ; on prescription; QID , 4 times a day; TID , 3 times a day.

a Less frequent dosing regimens include ACV 400 mg TID 10 days (primary); ACV 400 mg TID 5 days (recurrences).

b Shorter dosing regimen VACV 1000 mg 2 BID x1 day.

c Recommended VACV 1000 mg daily suppressive dose (single dose) if 10 or more HSV recurrences each year.

Table 11.5
Clinical Regimen for Human Herpes Virus Infections in Immunocompromised Patients
Clinical Scenario Acyclovir Valacyclovir Famciclovir
Herpes simplex—primary 200–400 mg 5×/day for 10 days or 5 mg/kg IV q8h for 7–10 days 500–1000 mg BID for 7–10 days 250 mg TID for 7–10 days
Herpes simplex—recurrent At least 400 mg TID for 5 days 500 mg BID for 3 days or 1000 mg daily for 5 days 250–500 mg BID for 5 days
Herpes simplex—suppression At least 400 mg BID 500 mg or 1000 mg daily 250–500 mg BID
HZ—adults 800 mg 5×/day for 7–10 days 1000 mg TID for 7–10 days 500 mg TID for 7–10 days
Primary varicella—children 10–20 mg/kg IV q8h for 5 days or 1000 mg TID for 5–7 days 1000 mg TID for 5–7 days No studies reported
BID , Twice a day; IV , intravenous; q , every; TID , 3 times a day.

Chickenpox

When used to treat first-episode VZV, the recommended adult dose of oral ACV is 800 mg 5 times daily for 7 days and 20 mg/kg 4 times daily (up to a maximum of 800 mg per dose) for children. For efficacious treatment, ACV must be initiated within the first 24 to 72 hours after appearance of the characteristic skin eruption. A meta-analysis revealed that ACV can shorten the duration of fever and reduce the number of lesions; however, its effects on pruritus and onset of new lesions were not consistent. ACV treatment of chickenpox, even in otherwise healthy children, is considered cost effective because it allows the child to return to school at least 2 days earlier, thus enabling the parent to return to work sooner. Intravenous ACV is recommended for pregnant women with any evidence of pneumonia because of the high fetal morbidity and mortality. No ACV directly-related fetal risk has been documented.

Herpes Zoster

ACV is used for recurrences of VZV known as HZ (or shingles ). Acute HZ requires 800 mg of ACV to be taken 5 times daily for 7 to 10 days. Placebo-controlled trials indicate accelerated healing time when therapy is initiated within 1 to 2 days of the initial symptoms and signs of infection. Although there is much controversy regarding the effects of ACV on postherpetic neuralgia (PHN), recent studies have demonstrated reduction in zoster-related pain following antiviral treatments. Intravenous ACV (10 mg/kg TID for 7–10 days) is used in the immunocompromised and those with severe trigeminal nerve distribution.

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