1465CHAPTER 191 Antiviral Chemotherapy, Excluding Antiretroviral Drugs

reverse transcriptase; the other class, the exogenous IFNs, mimics

and augments the role of endogenous interferons (Table 191-3). The

goal of therapy for chronic hepatitis B is to reduce the risk of hepatic

inflammation, which can cause liver fibrosis progressing to cirrhosis, liver failure, and hepatocellular carcinoma. Virologic responses

(defined by suppression of HBV replication), biochemical responses

(improvement or normalization of liver function values), and histologic responses (the degree of hepatic fibrosis visualized on liver

biopsy) are often achievable with current treatments. However, loss of

hepatitis B e antigen (HBeAg), viral clearance with loss of hepatitis B

TABLE 191-3 Antiviral Drugs for Chronic Hepatitis B Treatment in Adults

DRUG ROUTE AND DOSE

DEVELOPMENT OF

RESISTANCE COMMON SIDE EFFECTSa TREATMENT MONITORING COMMENTS

Interferons

Pegylated α2a

Pegylated α2b

SC injection;

180 μg/w for 48 w

SC injection; 1.5 μg/

kg/w for 48 w

Not described in long

term studies.

Side effects are

common and include

fevers, chills, myalgia,

fatigue, neurotoxicity,

and leukopenia.

Autoantibodies can

develop, particularly

antithyroid antibodies.

Complete blood counts should be

performed biweekly for the first

month and then monthly, renal

and liver function testing monthly,

thyroid function testing every

3 months.

Best treatment response seen

among patients with HBV

genotype A infection

While pegylated interferon

α2b is approved for HCV, it is

used for HBV.

Nucelos(t)ide Analogues

Lamivudine Oral; 100 mg daily 30% after 1 year; 70%

after 5 years

Malaise or fatigue, GI

symptoms (nausea/

vomiting, abdominal pain,

diarrhea), headache,

upper respiratory tract

infection

Renal and liver function testing

every 3–6 months

Assessment of lactic acid level

HBV DNA and serologic testing

every 3–6 months

Monotherapy recommended

if duration of therapy is to

be <1 year, as in prophylaxis

against HBV reactivation

with immunosuppression or

chemotherapy

Adefovir Oral; 10 mg daily 20–29% after 5 years

Adefovir is usually active

against lamivudineresistant HBV strains.

Headache, asthenia, GI

symptoms (abdominal

pain, nausea)

Renal and liver function testing

every 6 months

Assessment of lactic acid level

HBV DNA and serologic testing

every 3–6 months

—

Telbivudine Oral; 600 mg daily 11–25% after 2 years

Cross-resistance is

common between

lamivudine- and

telbivudine-resistant HBV

strains.

Headache, fatigue, GI

symptoms (abdominal

pain)

Measurement of creatine kinase

level if there is concern about

myopathy

Renal and liver function testing

every 3–6 months

Assessment of lactic acid level

HBV DNA and serologic testing

every 3–6 months

—

Entecavir Oral; 0.5–1 mg daily 1–2% after 5 years in

nucleos(t)ide-naïve

patients;

60% in lamivudineresistant patients

Headache, fatigue,

elevated alanine

aminotransferase level

Renal and liver function testing

every 3–6 months

Assessment of lactic acid level

HBV DNA and serologic testing

every 3–6 months

Recommended as first-line

therapy

Dose of 0.5 mg daily in

treatment-naïve patients,

1 mg daily in treatmentexperienced patients

Dose adjusted in renal

dysfunction

Tenofovir

disoproxil

Oral; 300 mg daily No resistance after up to

7 years of treatment

Headache, fatigue,

nasopharyngitis, upper

respiratory tract infection,

nausea

Renal and liver function testing

every 3–6 months

Phosphorus assessment in patients

with chronic kidney disease

Assessment of lactic acid level

HBV DNA and serologic testing

every 3–6 months

Recommended as first-line

therapy

Dosing frequency—but not

dose—reduced in chronic

kidney disease

May be used during

pregnancy; possible risk of

low birth weight

Tenofovir

alafenamide

Oral; 25 mg daily No long-term follow-up

data available

Headache, fatigue,

nasopharyngitis, upper

respiratory tract infection

Renal and liver function testing

every 3–6 months

Phosphorus assessment in patients

with chronic kidney disease

Assessment of lactic acid level

HBV DNA and serologic testing

every 3–6 months

Recommended as first-line

therapy

May be used during

pregnancy; possible risk of

low birth weight

Emtricitabine Oral; 200 mg daily Not defined Headache, GI symptoms

(nausea, diarrhea,

abdominal pain), fatigue,

depression, insomnia,

abnormal dreams, rash,

asthenia, increased

cough, rhinitis

Renal and liver function testing

every 3–6 months

Assessment of lactic acid level

HBV DNA and serologic testing

every 3–6 months

While not approved for

treatment of chronic

HBV infection, used

interchangeably with

lamivudine

Dosing frequency adjusted in

chronic kidney disease

a

For emtricitabine, side effects were assessed only in combination with antiretroviral therapy.

Abbreviation: GI, gastrointestinal.

1466 PART 5 Infectious Diseases

surface antigen (HBsAg), and viral protection (defined by a hepatitis B

surface antibody [HBsAb] titer of >10 IU/mL) are uncommon with

current therapies.

Treatment with a nucleos(t)ide analogue is considered first-line

therapy for chronic HBV infection because of its favorable side effect

profile and ease of administration. All drugs in this class are given by

mouth once daily. While all nucleos(t)ide analogues carry a warning

for lactic acidosis and severe hepatomegaly, these adverse events were

observed in patients taking older nucleoside analogues (such as stavudine and didanosine for the treatment of HIV) and have not occurred

in clinical trials of nucleos(t)ides for chronic HBV infection. The main

risk of nucleos(t)ide therapy for chronic hepatitis B consists of virus

rebound and subsequent hepatitis flare following treatment cessation,

which can occur in up to 20% of patients and rarely may lead to hepatic

failure. Comparative studies of nucleos(t)ide analogues have demonstrated that newer drugs (entecavir and tenofovir) are associated with

lower rates of viral resistance than older agents (lamivudine and adefovir), but, if viral replication is effectively suppressed, histologic and

biochemical improvement will occur in ~60–75% of patients, without

significant differences between antiviral agents or combinations. However, rates of HBsAg clearance remain extremely low (<1–5%).

IFN-based therapies are associated with slightly higher rates of serologic response and lower rates of viral resistance, but also with lower

rates of biochemical and virologic responses (<40% for both). Response

rates are somewhat higher when IFNs are combined with nucleos(t)ide

therapy in naïve patients: overall rates of HBsAg loss after 48 weeks of

combination therapy with pegylated IFN-α2a and tenofovir disoproxil

fumarate (TDF) were low but significantly higher than when either

was given alone: 9.1% versus 0 with TDF alone (p<.001) and 2.8% with

IFN alone (p<.005). However, no significant difference was observed

when IFN was added to the regimen administered to patients already

receiving nucleos(t)ide therapy. IFN-based treatments often are not

tolerated because of side effects and drug interactions and are generally

reserved for patients with favorable HBV genotype A infection with

HBeAg-positive active disease (characterized by viral loads of ≥20,000

IU/mL and aminotransferase levels greater than two times the upper

limit of normal) and those in whom a short course of treatment is preferred (e.g., women who are planning to become pregnant).

■ LAMIVUDINE

Lamivudine is an oral cytidine analogue that competitively inhibits the

viral reverse transcriptase activity of both HIV and HBV, preventing

viral replication. Lamivudine has been used for prophylaxis against

HBV reactivation during immunosuppression following liver transplantation or chemotherapy, particularly when the duration of prophylaxis is expected to be relatively short. Long-term use can be limited by

a low threshold of viral resistance: rates approach 30% among patients

treated for 1 year and reach 70% after 5 years of therapy. Changes in

the YMDD motif of the HBV DNA polymerase are associated with

reduced lamivudine efficacy.

While not approved for the treatment of chronic HBV infection,

emtricitabine is a cytosine analogue similar in structure, activity, and

resistance to lamivudine. It offers no advantage over lamivudine, but

emtricitabine is available in combination tablets coformulated with

tenofovir (both TDF and tenofovir alafenamide fumarate [TAF]).

When appropriate, as in cases of established nucleoside resistance or

in patients with HIV/HBV co-infection requiring lifelong antiviral

therapy, these coformulations can be used with monitoring recommendations and expectations for clinical response similar to those for

lamivudine and tenofovir.

■ ADEFOVIR

Adefovir dipivoxil is the oral prodrug of adefovir—a monophosphate nucleotide analogue of adenosine. This drug is active against

HBV, HIV, some herpesviruses (HSV and CMV), and poxviruses.

Treatment-limiting side effects (including rare nephrotoxicity) preclude the use of the higher doses required to inhibit HIV (60–120 mg

daily), which are not FDA-approved for this indication. Studies of a

10-mg dose for HBV infection demonstrated an excellent safety and

tolerability profile and led to FDA approval for the treatment of chronic

HBV infection. Adefovir is effective in the treatment of naïve HBV-infected patients and those infected with lamivudine-resistant HBV. Viral

resistance to adefovir is slower to emerge than resistance to lamivudine

but still develops in 20–30% of patients after 5 years of treatment.

Because adefovir dipivoxil is renally cleared, routine monitoring of

renal function (every 6 months) is advised.

■ TELBIVUDINE

A β-L enantiomer of thymidine, telbivudine was approved by the FDA

in 2006 for the treatment of chronic HBV infection. Telbivudine was

shown to result in virologic, biochemical, and histologic improvement

in patients with chronic HBV infection. Telbivudine-resistant HBV is

generally cross-resistant with lamivudine-resistant virus but usually is still

susceptible to adefovir or tenofovir. After 2 years of therapy, strains

resistant to telbivudine were noted in 25% of HBeAg-positive patients

and 11% of HBeAg-negative patients; this resistance has limited its use.

Because telbivudine is rapidly absorbed and renally metabolized, the

dose is reduced in patients with a CrCl of <50 mL/min. Telbivudine is

generally well tolerated, but increases in creatinine kinase and fatigue

and myalgias have been observed.

■ ENTECAVIR

Entecavir is a cyclopentyl guanosine analogue that, once triphosphorylated, blocks HBV polymerase in multiple ways, inhibiting both

reverse transcription of the HBV negative strand and positive-strand

synthesis. Entecavir effectively inhibits HBV replication, with resulting

biochemical and histologic improvement. This drug is active against

some lamivudine-resistant HBV strains, but only at concentrations

20- to 30-fold higher than those obtained with the standard 0.5-mg

dose; thus a higher dose (1 mg daily) of entecavir is recommended

for patients with previous lamivudine exposure. Entecavir resistance

leading to viral rebound is uncommon among patients naïve to HBV

treatment but may occur in up to 60% of patients with prior lamivudine resistance after 4 years of entecavir treatment. Entecavir-resistant

strains retain susceptibility to tenofovir and occasionally adefovir.

Entecavir is generally well tolerated and highly bioavailable but should

be taken on an empty stomach because food interferes with its absorption. The drug is renally cleared, and dosing should be adjusted for a

CrCl of <50 mL/min.

■ TENOFOVIR

Tenofovir is a nucleotide analogue of adenosine monophosphate

with activity against both retroviruses and hepadnaviruses. Tenofovir

potently inhibits HBV replication. Clinically significant resistance to

tenofovir has not been observed with up to 7 years of therapy. It is

available in two prodrug forms, TDF and TAF. Both formulations of

tenofovir are approved by the FDA for the treatment of both HIV infection and HBV infection and are renally excreted. Because of structural

similarities among TDF, adefovir, and cidofovir (the latter two drugs

can cause proximal renal tubular toxicity), TDF carries a warning for

renal toxicity, including Fanconi syndrome and diabetes insipidus, but

these risks have not been found in large clinical trials of hepatitis B

treatment. Rather, a small decline (by ~5 mg/dL) has been noted in the

glomerular filtration rate over 2 years of TDF therapy. A mild decline in

bone mineral density has been observed after 5 years of TDF treatment,

but the clinical significance of this change is unknown and the risk of

fracture remained low. Routine monitoring of renal function during

TDF therapy is indicated, and dose frequency should be reduced in

chronic kidney disease. TAF has greater stability than TDF, with higher

drug concentrations within hepatocytes and less systemic exposure.

A comparative study revealed that, while TAF carries the same risks,

the magnitude of decline in glomerular filtration rate (GFR) and bone

mineral density was 25–30% of that observed with TDF.

■ INTERFERONS

IFNs have a broad spectrum of antiviral activity in addition to modulating the immune system. IFNs are given IM, SC, or IV. Recombinant

α, β, γ, and λ IFNs have been evaluated in a variety of viral infections.

1467CHAPTER 191 Antiviral Chemotherapy, Excluding Antiretroviral Drugs

IFNs may also be pegylated: linkage of INF-α to polyethylene glycol

results 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