ults in slower absorption, decreased clearance, and more sustained

serum IFN concentrations, thereby permitting a more convenient,

once-weekly dosing schedule. In many instances, pegylated IFN has

supplanted standard IFN.

Adverse effects of IFN include fever, myalgia, fatigue, somnolence,

depression, confusion, leukopenia, and development of autoantibodies,

including antithyroid antibodies. Pegylated IFN-α2a is approved by the

FDA for therapy in patients with chronic hepatitis B. While pegylated

IFN-α2b has been reported to be useful for HBV infection, this drug is

not approved for treatment of hepatitis B in the United States.

IFNs have undergone extensive study in the treatment of chronic

HBV infection. The administration of standard IFN-α2b for 16–24 weeks

to patients with stable chronic HBV infection resulted in the loss of

markers for HBV replication (e.g., HBeAg and HBV DNA) in 33–37%

of cases; 8% of patients also cleared HBsAg. In most patients who lose

HBeAg and HBV DNA, serum aminotransferases return to normal

levels, and both short- and long-term improvements in liver histopathology have been described. Predictors of a favorable response to

standard IFN therapy include low pretherapy levels of HBV DNA, high

pretherapy serum levels of alanine aminotransferase (ALT), a short

duration of chronic HBV infection, and active liver inflammation on

biopsy. Poor responses are seen in immunosuppressed patients, including those infected with HIV.

At high doses, IFN-α and pegylated IFN-α are active against hepatitis D virus infection. In hepatitis D, a sustained virologic response

(SVR) was achieved in 25–35% of patients treated with IFN-α but in

only 17–43% of patients treated with pegylated IFN-α.

Several IFN preparations have been studied and approved as therapeutic options for chronic HCV infection; often these preparations

combine IFN with ribavirin, a nonspecific nucleoside analogue with

the antiviral effects discussed below. The approval of directly acting

antiviral agents in 2014 led to revised guidance, and IFN therapy is no

longer recommended for the treatment of hepatitis C.

ANTIVIRAL DRUGS FOR HEPATITIS C

INFECTION

Several targeted therapies with directly acting antiviral drugs (DAAs)

are effective against HCV (Table 191-4). Combination DAA therapy is

now the standard of care for the treatment of chronic HCV infection,

regardless of genotype or fibrosis stage. HCV therapeutics have three

drug targets: the NS5B RNA-dependent RNA polymerase, the NS3/4

protease, and NS5A, a zinc-binding phosphoprotein that is integral for

HCV RNA replication. Treatment duration varies, usually from 8 to

24 weeks. The goal of HCV treatment is to suppress the level of viral

replication; if levels of HCV RNA in the plasma remain undetectable

when assessed 12 weeks after the end of treatment, an SVR has been

achieved. The SVR is considered synonymous with cure, as it is associated with durable suppression of HCV replication, lower all-cause and

liver-related mortality, and a reduced risk of hepatocellular carcinoma.

These benefits have been confirmed in patients with and without

advanced liver disease and cirrhosis who received IFN-sparing, combination DAA–based regimens.

In general, first-line DAA-based regimens for chronic HCV infection are so effective that cure rates exceed 90%. An SVR is not obtained

in a small subset of patients: up to 6% for genotype 1 (the most

common genotype) and >10% for genotype 3 (historically the most

difficult to treat). Two pangenotypic regimens are approved specifically for re-treatment of chronic HCV infection after treatment failure: glecaprevir/pibrentasvir and sofosbuvir/velpatasvir/voxilaprevir.

While some amino acid substitutions and polymorphisms can impact

the efficacy of HCV treatment with combination DAA–based regimens, the clinical significance of this reduced susceptibility varies

greatly between regimens and by genotype/subtype. In the setting of

unfavorable viral genetics (viral subgenotypes or viral variants with

resistance-associated polymorphisms) or advanced fibrosis, treatment efficacy can frequently be improved by extension of the treatment course or the addition of ribavirin. Review of the online joint

American Association for the Study of Liver Diseases/Infectious Diseases Society of America’s HCV Guidelines is useful. In addition, for all

DAA-based treatments, checking for drug–drug interactions before the

initiation of therapy is recommended.

Most regimens are well tolerated, but all DAAs carry a black-box

warning about reactivation of HBV following HCV suppression. In

some cases, fulminant hepatitis, hepatic flare, and death have occurred

in patients with untreated HBV infection who underwent treatment for

chronic HBV infection. These risks are rare and can be safely managed

with routine monitoring; treatment of HCV should not be deferred

because of HBV co-infection.

■ SOFOSBUVIR AND SOFOSBUVIR-CONTAINING

REGIMENS

Sofosbuvir Sofosbuvir is the prodrug of a uridine inhibitor of the

HCV NS5B RNA-dependent RNA polymerase. The active uridine

nucleoside triphosphate results in termination of viral RNA replication. Sofosbuvir is approved by the FDA for the treatment of HCV

genotypes 1–4 and is active against genotypes 1–6. Resistance to sofosbuvir is conferred by an S282T substitution in the NS5B protein, but

clinically significant resistance to sofosbuvir treatment has rarely been

encountered and virologic breakthrough during sofosbuvir treatment

is exceedingly rare. Sofosbuvir is approved for use with other DAAs

and is available both individually and as part of three fixed-dose

combination regimens: as two-drug regimens with the NS5A protein

inhibitors ledipasvir and velpatasvir, respectively, and as a three-drug

regimen with velpatasvir and the protease inhibitor voxilaprevir. Both

sofosbuvir and its active metabolite are renally cleared, and while

the FDA has approved this drug only for patients with an estimated

GFR of ≥30 mL/min, several studies have demonstrated its safety and

efficacy even in end-stage renal disease and for patients undergoing

dialysis. Sofosbuvir has not been associated with significant toxicity or

drug interactions with one notable exception: sofosbuvir potentiates

amiodarone and may cause severe bradycardia, especially if coadministered with amiodarone and a β-blocker.

Sofosbuvir/Ledipasvir Ledipasvir is an NS5A protein inhibitor that

is available only in combination with sofosbuvir. The fixed-dose combination of ledipasvir and sofosbuvir is effective against genotypes 1,

4, and 6. The standard duration of treatment is 12 weeks for genotype

1 (all subgenotypes), genotype 4, and genotype 6; however, treatment

duration may be reduced to 8 weeks in treatment-naïve, genotype 1–

infected noncirrhotic patients with baseline HCV RNA levels below

6 million copies/mL. Treatment should be extended to 24 weeks or

ribavirin should be added in patients who have decompensated cirrhosis or previous DAA exposure. Ledipasvir is excreted via the biliary

route, and no adjustment is needed for mild or moderate renal impairment. Several studies have shown that sofosbuvir/ledipasvir is safe in

end-stage renal disease, but it remains FDA-approved only for patients

with a CrCl of >30 mL/min. No dose reduction is required for decompensated cirrhosis (Child–Turcotte–Pugh class B or C). Ledipasvir

absorption is improved with food intake and is inhibited by antacids or

proton-pump inhibitors. Ledipasvir is an inhibitor of P-glycoprotein and

may increase levels of tenofovir; renal function should be monitored

in patients receiving both medications, although clinically significant

interactions are unlikely during the relatively short period of treatment.

Ledipasvir is generally well tolerated, and clinical trials have shown

only a small increase in side effects, including headache and fatigue,

over those occurring with placebo.

Sofosbuvir/Velpatasvir While chemically similar to ledipasvir, velpatasvir has an expanded spectrum of activity and exhibits improved

efficacy over ledipasvir against HCV genotypes 2 and 3. Velpatasvir

is available only in combination with sofosbuvir for the treatment of

naïve patients with genotype 1–6 infection and all stages of fibrosis,

including decompensated cirrhosis. In contrast to sofosbuvir/ledipasvir

treatment, shortening of the duration of sofosbuvir/velpatasvir therapy

in these patients is not indicated. Similar to ledipasvir, velpatasvir

should be taken with food, and coadministration with antacids or

1468 PART 5 Infectious Diseases

proton-pump inhibitors should be avoided. Velpatasvir is in general

well tolerated, and reported side effects are minimal.

Sofosbuvir/Velpatasvir/Voxilaprevir Available in a triple-drug

combination with sofosbuvir and velpatasvir, voxilaprevir is a NS3/

NS4A protease inhibitor that is active against HCV genotypes 1–6.

The fixed-dose combination is recommended for the re-treatment of

patients with genotype 1–6 infection in whom an SVR has not been

attained after previous combination DAA treatment and for the treatment of naïve genotype 3–infected patients with cirrhosis. In patients

with NS5A protein inhibitor–experienced genotype 3 infection, SVR

rates are lower in response to sofosbuvir/velpatasvir/voxilaprevir; thus

the addition of ribavirin is recommended in these patients. A 12-week

course is recommended for most patients, including those with compensated cirrhosis. Voxilaprevir is not recommended for patients

with decompensated cirrhosis (see “Protease Inhibitors and Protease

Inhibitor–Containing Regimens,” below) or those with significant

renal impairment and a CrCl of <30 mL/min. Voxilaprevir, like other

protease inhibitors, is metabolized by the CYP3A system, and the effect

of voxilaprevir may be reduced in the presence of other CYP inducers.

Sofosbuvir/Daclatasvir The combination of sofosbuvir with

daclatasvir—the only NS5A protein inhibitor available individually

rather than coformulated with other DAAs—is approved for the treatment of HCV genotypes 1 and 3. Daclatasvir binds the N terminus of

the NS5A protein, both inhibiting viral RNA replication and blocking

virion assembly. It is given in combination with sofosbuvir for 12 weeks

and is safe for the treatment of patients with decompensated cirrhosis.

Daclatasvir is a substrate of CYP3A, and the dose should be adjusted

when given with other CYP3A substrates; i.e., the dose should be

TABLE 191-4 Antiviral Drugs for Hepatitis C Treatment in Adultsa

DRUG FORMULATION ROUTE, DOSE, DURATION

MECHANISM(S) OF

ACTION

SPECTRUM OF

ACTIVITY COMMON SIDE EFFECTS COMMENTS

Sofosbuvir Oral; 400 mg daily;

duration varies (12–24 w)

Nucleoside analogue Genotypes 1–6 Headache, fatigue Should be combined with at least one

other DAA from a different class.

Sofosbuvir/ledipasvir Oral; 400 mg/90 mg daily;

8, 12, or 24 w

Nucleoside analogue/

NS5A inhibitor

Genotypes 1,

4, and 6

Headache, fatigue Avoid coadministration with antacid

medications.

Sofosbuvir/velpatasvir Oral; 400 mg/100 mg daily;

12 w

Nucleoside analogue/

NS5A inhibitor

Genotypes 1–6 Headache, fatigue Avoid coadministration with antacid

medications.

Sofosbuvir/velpatasvir/

voxilaprevir

Oral; 400 mg/100 mg/100

mg once daily; 12 w

Nucleoside analogue/

NS5A inhibitor/protease

inhibitor

Genotypes 1–6 Headache, fatigue,

diarrhea, nausea

Approved for re-treatment of patients

with previous DAA experience.

Avoid coadministration with antacid

medications.

Paritaprevir/ritonavir/

ombitasvir + dasabuvir

Oral; 2 75-mg tablets/50

mg/12.5 mg once daily + 1

250-mg tablet (dasabuvir)

bid; 12 or 24 w

Protease inhibitor/

boosting agent/NS5A

inhibitor + nonnucleoside

polymerase inhibitor

Genotypes 1a

and 1b

Fatigue, nausea, pruritis,

insomnia, and asthenia

Should be combined with ribavirin in

patients with genotype 1a infection.

Monitor hepatic function monthly

during treatment.

Elbasvir/grazoprevir Oral; 50 mg/100 mg once

daily; 12 or 16 w

NS5A inhibitor/protease

inhibitor

Genotypes 1

and 4

Fatigue, anemia,

headache, nausea

Pretreatment testing for resistanceassociated substitutions

recommended in patients infected

with genotype 1a.

Monitor hepatic function panel at

8 w and again at 12 w if patient is

receiving 16 w of treatment.

Glecaprevir/pibrentasvir Oral; 3 100-mg tablets/

40 mg once daily; 8, 12,

or 16 w

NS5A inhibitor/protease

inhibitor

Genotypes 1–6 Headache, fatigue —

Simeprevir Oral; 150-mg capsule

once daily; 12 w

Protease inhibitor Genotypes 1a,

1b, and 4

Rash, pruritus, nausea Recommended only in combination

with sofosbuvir; no longer considered

a first- or second-line regimen.

Baseline testing for resistanceassociated polymorphism Q80K

recommended.

Daclatasvir Oral; 60-mg tablet once

daily; 12 w

Dose reduced to 30 mg

once daily when taken

with a strong CYP3A

inhibitor

Dose increased to 90 mg

once daily when taken

with moderate CYP3A

inducers

NS5A inhibitor Genotypes 1

and 3

Headache, fatigue Use recommended only along

with sofosbuvir—with or without

ribavirin—for genotype 1 or 3

infection; no longer considered a

first- or second-line regimen.

Ribavirin Oral; 3–6 200-mg capsules

once daily or in divided

doses, based on weight,

history of cardiovascular

disease, and renal

function

Nucleoside analogue,

also unknown

mechanisms

Unknown,

used for all

genotypes

Anemia, nausea,

teratogenic in pregnancy

Used only as combined therapy with

DAAs or interferon.

Complete blood counts should be

monitored after 2 w of treatment and

as clinically indicated thereafter.

Dose may be adjusted based on

anemia and renal function.

a

While these drugs are approved by the FDA for chronic, but not acute HCV, they have been recommended for acute HCV by both the Infectious Diseases Society of

America and the American Association for the Study of Liver Diseases.

Abbreviation: DAA, directly acting antiviral agent.

1469CHAPTER 191 Antiviral Chemotherapy, Excluding Antiretroviral Drugs

reduced if daclatasvir is given with a strong CYP3A inhibitor and

increased if it is given with moderate CYP3A4 inducers. Daclatasvir

absorption is not affected by food, and daclatasvir is highly protein

bound. The dose does not need to be adjusted for renal impairment,

and side effects are uncommon.

■ PROTEASE INHIBITORS AND PROTEASE

INHIBITOR–CONTAINING REGIMENS

Protease inhibitors are specifically designed to inhibit the HCV NS3/4A

protease by mimicking the HCV polypeptide and, when bound by the

viral protease, form a covalent bond with the catalytic NS3 serine

residues, blocking further activity and preventing proteolytic cleavage

of the HCV polyprotein into NS4A, NS4B, NS5A, and NS5B proteins.

As a class, the protease inhibitors are hepatically metabolized and

therefore should not be administered to patients with decompensated

(Child–Turcotte–Pugh class B or C) cirrhosis. For patients receiving

protease inhibitors, the current recommendation is that liver function

tests should be monitored monthly.

Simeprevir Simeprevir inhibits the HCV NS3/4A protease and is

active against HCV genotype 1 (subgenotype 1b > 1a) and genotype 4.

About one-third of patients infected with HCV genotype 1b have a

polymorphism (Q80K) in the NS3 protein that results in resistance

of the virus to the drug; thus, if simeprevir is used, the infecting virus

should be tested for this polymorphism. Simeprevir absorption is

increased when it is taken with food. The drug is nearly all protein

bound, and it is excreted through the biliary tract. Dose adjustment

is not required for renal dysfunction. Simeprevir is metabolized by

the CYP3A system and should not be given to patients with decompensated cirrhosis. In the past simeprevir was usually combined with

sofosbuvir for 12 weeks, but with newer options this drug combination

is no longer recommended as either a first- or second-line regimen.

Paritaprevir/Ritonavir/Ombitasvir/Dasabuvir The combination

of paritaprevir (boosted with ritonavir), ombitasvir, and dasabuvir

is a fixed-dose regimen for the treatment of HCV. Paritaprevir is

an NS3/NS4A protease inhibitor with activity against genotypes 1a

and 1b, 4, and 6. Paritaprevir is coformulated with the HIV protease

inhibitor ritonavir, not for antiviral activity, but as a CYP3A inhibitor;

ritonavir coformulation boosts paritaprevir levels, allowing once-daily

dosing. Ombitasvir is an NS5A protein inhibitor with activity against

genotypes 1a and 1b as well as genotypes 2, 3, and 5. Dasabuvir is a

nonnucleoside polymerase inhibitor of the HCV NS5B polymerase;

its allosteric inhibition of the polymerase effectively prevents the

interaction of the polymerase with its binding site. The combination

is approved for the treatment of HCV genotype 1b infection and can

be used with the addition of ribavirin for the treatment of genotype 1a

infection. Treatment duration is 12 weeks for patients without cirrhosis

and 24 weeks for patients with compensated cirrhosis. The medications in the combination are metabolized by the CYP2C and CYP3A

systems. The coadministration of paritaprevir with ritonavir results

in clinically significant CYP3A4 interactions. Caution regarding drug

interactions should be taken in the treatment of patients co-infected

with HIV and HCV who are receiving antiretroviral therapy. No dose

adjustment is required in renal insufficiency or end-stage renal disease

requiring dialysis, but use of this drug combination is contraindicated

in decompensated cirrhosis. Rarely, hepatic decompensation has been

reported in patients receiving the combination, and patients should

have liver function monitored monthly during this treatment.

Elbasvir/Grazoprevir The coformulation of elbasvir, an NS5A

replication complex inhibitor, and grazoprevir, an NS3/NS4A protease

inhibitor, is active against HCV genotypes 1 and 4. However, its efficacy in the treatment of HCV genotype 1a is reduced in the presence

of baseline resistance–associated polymorphisms in the NS5A protein

at positions M28, Q30, L31, and Y93; thus, in patients infected with

genotype 1a, baseline resistance testing should be performed and, if

the result is positive, ribavirin should be added and the combination

therapy should be extended to improve response rates. Susceptibility

to grazoprevir is reduced with NS5A protein D168 substitutions, but

few resistant isolates have been noted in cases of virologic failure; thus,

testing for these substitutions before therapy is not recommended.

Treatment duration is 12 weeks (genotype 1b or genotype 1a without baseline resistance–associated polymorphisms) or 16 weeks (in

combination with ribavirin in patients with baseline NS5A protein

polymorphisms and in genotype 4–infected patients with previous

IFN exposure). Absorption of grazoprevir and elbasvir is unaffected

by food, and the dose does not need to be adjusted in patients with

chronic kidney disease or those who are undergoing dialysis. Elbasvir,

like grazoprevir, is a substrate of the CYP3A system; coadministration

with moderate or strong CYP3A inducers or with strong inhibitors is

not recommended. Both components are well tolerated, and few side

effects have been reported. The use of this drug combination, as with

all those containing protease inhibitors, is contraindicated in decompensated cirrhosis.

Glecaprevir/Pibrentasvir The newest approved DAA-combination

treatment consists of glecaprevir, a pangenotypic NS3/NS4A protease

inhibitor, and pibrentasvir, a pangenotypic NS5A protein inhibitor.

Each medication individually has a high genetic barrier to resistance

and is active against HCV genotypes 1–6. In patients infected with

genotypes other than genotype 3, baseline resistance has no influence

on glecaprevir treatment efficacy, and NS3/NS4A baseline polymorphisms have not been noted to correlate with virologic failure. Treatment duration varies with fibrosis and treatment experience: an 8-week

course of therapy is recommended for treatment-naïve patients who

are infected with any genotype and have any degree of fibrosis up to

compensated cirrhosis, including patients with genotype 3 infection,

while treatment-experienced cirrhotic patients should receive 12 weeks

of treatment, and patients with prior NS5A protein inhibitor exposure

with or without compensated cirrhosis should receive 16 weeks of therapy. The combination of glecaprevir/pibrentasvir should be taken with

food. Clearance is via biliary excretion; therefore, no dose adjustment

is required in end-stage renal disease. Because of the protease component, the combination of glecaprevir/pibrentasvir is not appropriate for

patients with decompensated cirrhosis. Glecaprevir and pibrentasvir

are only weak CYP3A inducers, but they inhibit the P glycoprotein,

breast cancer resistance protein (BCRP), and organo anion transporter

P1 (OATP1) drug transporters. When taken with other drugs that are

substrates for these transporters, concentrations of both drugs may be

increased. The combination regimen is generally well tolerated; mild

headache, fatigue, diarrhea, and nausea have been reported.

■ RIBAVIRIN

Ribavirin, a synthetic oral triazole guanosine analogue, weakly inhibits

both DNA and RNA polymerases, but its primary mechanism in HCV

treatment is not well understood. It may promote infidelity of RNA

viral replication, giving rise to unfit or less fit viral mutations, and

also appears to stimulate IFN-response genes and modulate adaptive

immune responses. The role of ribavirin in HCV therapy has changed

over time. Ribavirin played an integral role in HCV treatment during the IFN era and, combined with sofosbuvir, was required as part

of IFN-sparing regimens before other DAAs were available. However, adverse drug effects associated with higher doses (in heavier

patients)—including hemolytic anemia, which is increased with renal

failure—are frequently treatment-limiting. Other side effects include

rash, myalgia, and fatigue. Ribavirin is teratogenic, and its use in

women with child-bearing potential is therefore limited.

With the advent of several combination DAA-only, IFN-sparing

regimens, there are often multiple ribavirin-free options for treatment.

However, there are still several indications for ribavirin augmentation of combination DAA-based therapy. Most importantly, ribavirin

improves the SVR rate by an average of 5% in treatment-naïve and

treatment-experienced patients with genotype 1 infection, particularly

that due to subgenotype 1a. The addition of ribavirin to treatment with

paritaprevir/ritonavir/ombitasvir plus dasabuvir is recommended for

patients with genotype 1a or 4 infection as well as for patients infected

1470 PART 5 Infectious Diseases

with genotype 1a who are receiving elbasvir/grazoprevir with baseline

NS5A protein resistance–associated substitutions to overcome reduced

susceptibility to elbasvir. Ribavirin is frequently included in regimens

for re-treatment of genotype 1–infected, therapy-experienced patients

with cirrhosis in order to preserve SVR rates while shortening re-treatment duration. SVR rates at 12 weeks were comparable in treatmentexperienced cirrhotic patients receiving 24 weeks of ledipasvir/sofosbuvir

and those receiving 12 weeks of ledipasvir/sofosbuvir plus ribavirin.

Ribavirin also improves outcomes in treatment-experienced patients

with genotype 3 infection—an ongoing therapeutic challenge even

in the setting of current pangenotypic regimens. Ribavirin improves

treatment response in other clinical settings as well, specifically in

patients with decompensated cirrhosis for whose treatment protease

inhibitors cannot be used and in patients with genotype 2 infection in

resource-limited settings where ribavirin is more affordable than fixeddose combination DAA regimens. Because of its broad antiviral effects,

ribavirin is not known to select for any particular resistance-associated

amino acid substitutions.

Absorption of ribavirin is improved by administration with food,

and the drug is excreted renally. Lowering the dose of the drug may

reduce toxicity. While determining red blood cell counts and hemoglobin levels after 2 weeks of therapy is recommended to monitor for

hemolytic anemia, ribavirin can be administered safely to most patients

for the relatively short period of DAA-based therapy. In patients with

renal insufficiency and those with end-stage renal disease who are

undergoing dialysis, the dose must be adjusted and the patient closely

monitored for anemia.

In a recent large-scale study, ribavirin was effective in the treatment

of chronic infection with hepatitis E virus, which can cause chronic

inflammatory hepatitis in immunosuppressed patients, particularly

solid-organ transplant recipients.

■ INTERFERON

Pegylated interferon combined with ribavirin is no longer used for the

treatment of hepatitis C, as response rates are inferior and treatment is

less well tolerated than with DAAs.

■ FURTHER READING

Acosta E et al: Advances in the development of therapeutics for

cytomegalovirus infections. J Infect Dis 221(Suppl 1):S32, 2020.

American Association for the Study of Liver Diseases/

Infectious Diseases Society of America: Recommendations for

testing, managing, and treating hepatitis C. Available at http://www

.hcvguidelines.org. Accessed October 18, 2020.

Chou R et al: Screening for hepatitis C virus infection in adolescents

and adults: Updated evidence report and systematic review for the US

Preventive Services Task Force. JAMA 323:976, 2020.

Gnann JW JR, Whitley RJ: Genital herpes. N Engl J Med 375:666,

2016.

Ison MG et al: Early treatment with baloxavir marboxil in high-risk

adolescent and adult outpatients with uncomplicated influenza

(CAPSTONE-2): A randomised, placebo-controlled, phase 3 trial.

Lancet Infect Dis 20:1204, 2020.

Koh C et al: Pathogenesis of and new therapies for hepatitis D. Gastroenterology 156:461, 2019.

Spyrou E et al: Hepatitis B: Current status of therapy and future therapies. Gastroenterol Clin North Am 2020;49:215, 2020.

Tang LE et al: Chronic hepatitis B infection: A review. JAMA 319:1802,

2018.

Uyeki T et al: Clinical practice guidelines by the Infectious Diseases

Society of America: 2018 update on diagnosis, treatment, chemoprophylaxis, and institutional outbreak management of seasonal influenza. Clin Infect Dis 68:e1, 2019.

Venkatesan S et al: Neuraminidase inhibitors and hospital length

of stay: A meta-analysis of individual participant data to determine

treatment effectiveness among patients hospitalized with nonfatal

2009 pandemic influenza A (H1N1) virus infection. J Infect Dis

221:356, 2020.

Section 12 Infections Due to DNA Viruses

192

■ DEFINITION

Herpes simplex viruses (HSV-1, HSV-2; Herpesvirus hominis) produce

a variety of infections involving mucocutaneous surfaces, the peripheral nervous system (PNS), the central nervous system (CNS), and—on

occasion—visceral organs. Prompt recognition and treatment reduce

the morbidity and mortality rates associated with HSV infections.

■ ETIOLOGIC AGENT

The genome of HSV is a 152-kb linear, double-stranded DNA

molecule (molecular weight, ~100 × 106

) that encodes >90 transcription units with 84 identified proteins. The genomic structures of the two HSV subtypes are similar. The overall genomic

sequence homology between HSV-1 and HSV-2 is ~50%, whereas the

proteome homology is >80%. The homologous sequences are distributed over the entire genome map, and most of the polypeptides specified by one viral type are antigenically related to polypeptides of the

other viral type. Many type-specific regions unique to HSV-1 and

HSV-2 proteins do exist, and a number of them appear to be important

in host immunity. These type-specific regions have been used to

develop serologic assays that distinguish between the two viral subtypes. Either restriction endonuclease analysis or sequencing of viral

DNA can be used to distinguish between the two subtypes and among

strains of each subtype. Recombinant viruses (HSV-1/HSV-2) do circulate in nature. The variability of nucleotide sequences from clinical

strains of HSV-1 and HSV-2 is such that HSV isolates obtained from

two individuals can be differentiated by restriction enzyme patterns or

genomic sequences. Moreover, epidemiologically related sources, such

as sexual partners, mother–infant pairs, or persons involved in a commonsource outbreak, can be inferred from such patterns. Deep sequencing

of sequential isolates suggests that more than one variant of HSV-1 or

HSV-2 can be found in a single individual.

The viral genome is packaged in a regular icosahedral protein shell

(capsid) composed of 162 capsomeres (Chap. 190). The outer covering

of the virus is a lipid-containing membrane (envelope) acquired as the

DNA-containing capsid buds through the inner nuclear membrane

of the host cell. Between the capsid and lipid bilayer of the envelope

is the tegument. Viral replication has both nuclear and cytoplasmic

phases. Initial attachment to the cell membrane involves interactions

of viral glycoproteins C and B with several cellular heparan sulfate–like

surface receptors. Subsequently, viral glycoprotein D binds to cellular

co-receptors that belong to the tumor necrosis factor receptor family

of proteins, the immunoglobulin superfamily (nectin family), or both.

The ubiquity of these receptors contributes to the wide host range of

herpesviruses. HSV replication is highly regulated. After fusion and

entry, the nucleocapsid enters the cytoplasm and several viral proteins

are released from the virion. Some of these viral proteins shut off host

protein synthesis (by increasing cellular RNA degradation), whereas

others “turn on” the transcription of immediate early genes of HSV

replication. These immediate early gene products, designated α genes,

are required for synthesis of the subsequent polypeptide group: the

β polypeptides, many of which are regulatory proteins and enzymes

required for DNA replication. Most current antiviral drugs interfere

with β proteins, such as viral thymidine kinase (TK) and DNA polymerase. The third (γ) class of HSV genes encodes viral structural

and tegument proteins and mostly requires viral DNA replication for

expression. New antiviral drugs directed at viral assembly and release

are under development.

Herpes Simplex

Virus Infections

Lawrence Corey