2607Chronic Hepatitis CHAPTER 341

prior null responders, and lowest in cirrhotic prior null responders,

for whom no benefit accrued over PEG IFN–ribavirin treatment.

Responses to protease inhibitor triple-drug regimens were higher

in patients with IL28B (IFNL3) C than non-C genotypes, HCV

genotype 1b than genotype 1a, less advanced than more advanced

fibrosis stage, whites than blacks, lower body mass index (BMI)

than elevated BMI, and, for boceprevir, achievement of a >1 log10

HCV RNA reduction during 4 weeks of PEG IFN–ribavirin lead-in

therapy. Age and HCV RNA level were less influential and insulin

resistance was noninfluential on response to these antiviral agents.

Both protease inhibitors had substantial toxicities. Telaprevir was

associated with a severe, generalized (trunk and extremities), often

confluent, maculopapular, pruritic rash in ~6% of treated patients

(that required careful dermatologic monitoring in all patients and

systemic corticosteroid therapy in the most severely affected).

Other common side effects included pruritus, rectal burning, nausea, diarrhea, fatigue, dysgeusia (altered or unpleasant taste), and

anemia, which required close monitoring, could be relatively refractory, and occasionally required transfusion and even hospitalization

(especially in cirrhotic prior nonresponders). Anemia occurred

in half of boceprevir-treated patients, neutropenia in up to 30%,

and thrombocytopenia in 3–4%. Other side effects of boceprevir

included fatigue, nausea, headache, dysgeusia, dry mouth, vomiting, and diarrhea.

Both drugs came with an inconveniently high pill burden and

had to be administered every 8 h with food (telaprevir with a 20-g

fat meal). Use of protease inhibitors was further complicated by

numerous drug-drug interactions. As telaprevir and boceprevir are

both eliminated by and inhibit CYP3A4, these agents could not

be administered with other medications that induce CYP3A4 or

are dependent on CYP3A4 for elimination. Care had to be taken

to examine for any potential interactions between these protease

inhibitors and other medications the patient was taking, and a

convenient website became available to check for such drug-drug

interactions (www.hep-druginteractions.org).

Despite the improvement in SVRs with protease-inhibitor-based

regimens for genotype 1 compared to PEG IFN–ribavirin (e.g., in

treatment-naïve patients 66–79% vs 38–44%), triple-drug protease

inhibitor therapy was hampered by amplified intolerability, the

complexity of response-guided regimens and futility stopping rules,

the inconvenience of thrice-daily dosing with meals and a high

pill burden, the need for PEG IFN injections and ribavirin with all

their intolerability, and multiple drug-drug interactions. Moreover,

side effects appeared to be more severe and burdensome once these

drugs entered practice, especially in cirrhotic nonresponders, in

whom studies reported from Europe showed serious adverse events

in up to 45% and deaths in up to 3%. All these issues, as well as

rapidly accelerating progress on next-generation and all-oral DAA

therapy (see below), conspired to temper enthusiasm for these new

antivirals; after a brief stint as recommended therapy (2011–2013),

these drugs became obsolete and are no longer recommended or

available.

DIRECT-ACTING ANTIVIRAL COMBINATIONS OF SECONDGENERATION PROTEASE INHIBITORS, FIRST-GENERATION

POLYMERASE INHIBITORS, AND FIRST-GENERATION NS5A

INHIBITORS (2014–2015)

Since late 2013, the number of new antiviral agents for hepatitis C has expanded substantially, and currently, PEG IFN–based

treatments have been supplanted by five remaining therapeutic

regimens, which are all oral, IFN-free, highly efficacious (>95%

SVR), and well tolerated, with high barriers to resistance, simple

dosing, low pill burdens, treatment durations as brief as 8–12 weeks,

and pangenotypic efficacy (Table 341-6). These drugs are distributed among three classes of DAAs: NS3/4 protease inhibitors

(which cleave the single HCV polyprotein into constituent structural and nonstructural proteins [drug name ending in “-previr”]),

NS5B nucleoside and nonnucleoside polymerase inhibitors (which

interfere with the RNA-dependent RNA polymerase [a replicase]

involved in synthesis of viral RNA [drug name ending in “-buvir”]),

and NS5A inhibitors (which interfere with a membrane-associated

phosphoprotein essential to the HVC RNA replication complex

[drug name ending in “-asvir”]).

The first of the new DAA agents (approved in November 2013)

was simeprevir, a second-generation protease inhibitor for genotype

1, followed shortly thereafter (December 2013) by sofosbuvir, a

pangenotypic nucleoside polymerase inhibitor. For genotype 1,

both of these agents had to be combined with PEG IFN and

ribavirin; for genotypes 2 and 3, sofosbuvir was administered with

ribavirin, without PEG IFN; however, these treatment regimens

have been supplanted by combinations of all-oral, IFN-free DAAs,

and ribavirin is rarely needed and retained only for very limited

indications.

Simeprevir: When simeprevir was used with PEG IFN, its efficacy (genotype 1b > 1a) was similar to that of first-generation

protease inhibitors but required only once-a-day dosing without

the complexity of response-guided therapy. Similar to first-generation protease inhibitors, simeprevir was hampered by many

drug-drug interactions and side effects (including photosensitivity, rash, and mild hyperbilirubinemia); moreover, patients, with

HCV NS3 polymorphism Q80K had markedly reduced drug efficacy, necessitating pretreatment genetic testing and disqualifying

approximately a third of potential treatment candidates. Little about

simeprevir supported its adoption in combination with PEG IFN

and ribavirin. On the other hand, the combination of simeprevir

(150 mg) along with sofosbuvir (400 mg) for 12 weeks was found to

be effective in treatment-naïve (97% SVR12) or treatment-experienced

(95% SVR12) patients without cirrhosis and in treatment-naïve (88%

SVR12) or treatment-refractory (79% SVR12) patients with cirrhosis.

Like first-generation protease inhibitors, however, simeprevir was

limited to genotype 1, required pretreatment genotyping that disqualified a third of recipients, usually required concomitant PEG

IFN and ribavirin, had multiple drug-drug interactions and side

effects, and was not competitive with the improved combinations

that followed; therefore, simeprevir is no longer recommended.

Sofosbuvir: Sofosbuvir, the first nonprotease inhibitor DAA to

be approved, has an excellent profile—high potency, high barrier

to resistance, pangenotypic activity, very well tolerated with limited

adverse effects (most commonly mild fatigue, insomnia, headache,

and nausea), once-daily oral administration, and relative freedom

from major drug-drug interactions. Sofosbuvir has efficacy in all

genotypes (1–6); in treatment-naïve subjects and prior nonresponders to PEG IFN–based and protease-inhibitor-based therapy;

with PEG IFN–ribavirin or in IFN-free regimens; in combination

with ribavirin or with NS5A inhibitors (see below); and for treatment periods as brief as 8–12 weeks. Currently, sofosbuvir is used

in combination with one of two NS5A inhibitors and is a component of three of the five currently recommended DAA regimens

(Table 341-6).

Sofosbuvir-ledipasvir: The DAA combination that has had a

dominant role in the treatment of hepatitis C is sofosbuvir (400 mg)

plus the NS5A inhibitor ledipasvir (90 mg) in a once-a-day, fixeddose, single pill, approved in October 2014 for genotype 1 and in

November 2015 for genotypes 4, 5, and 6. Phase 3 trials were conducted in treatment-naïve noncirrhotic patients, in treatment-naïve

cirrhotic and noncirrhotic patients, and in treatment-experienced

cirrhotic and noncirrhotic patients treated for 8, 12, or 24 weeks,

both with and without ribavirin. In treatment-naïve noncirrhotics,

an SVR12 was achieved in 97–99% of subjects, and no benefit was

observed by extending therapy from 12 to 24 weeks or by adding ribavirin. Moreover, for treatment-naïve, noncirrhotic patients

with baseline HCV RNA <6 × 106

 IU/mL, a treatment duration of

8 weeks was as effective as one of 12 weeks (94–95% SVR12), which

may be a consideration for a proportion of patients. In cirrhotic

patients, SVR12 was achieved in 97–100% of treatment-naïve subjects (no advantage of extending therapy from 12 to 24 weeks or

of adding ribavirin); however, for cirrhotic prior nonresponders to

IFN-based therapy, 12 weeks of therapy was inferior (86% SVR12)

2608 PART 10 Disorders of the Gastrointestinal System

TABLE 341-6 Indications and Recommendations for Antiviral Therapy of Chronic Hepatitis Ca

Standard Indications for Therapy

All patients with chronic HCV infection (detectable HCV RNA, with or without

elevated ALT) except for those with short life expectancies owing to comorbid

conditions.

Any stage of fibrosis; pretreatment biopsy is no longer embraced and has

been supplanted by noninvasive measures of fibrosis, e.g., imaging to

determine liver elasticity.

Responsiveness in groups previously refractory to interferon-based

therapy (HIV-HCV co-infection, renal insufficiency, African-American and

Latino ethnicity, IL28B non-C haplotype, obesity, insulin resistance, hepatic

decompensation, etc.) is not diminished to contemporary direct-acting oral

combination regimens.

Retreatment Recommended

Relapsers, partial responders, or nonresponders after a previous course

of interferon-based therapy or prior direct-acting antiviral therapy (see

genotype-specific recommendations below).

Antiviral Therapy Not Recommended

Pregnancy: No clinical studies of direct-acting antivirals during pregnancy

are available. Ribavirin is contraindicated during pregnancy; therefore, any

regimen including ribavirin should not be used. Sofosbuvir; sofosbuvir +

ledipasvir; and paritaprevir-ritonavir + ombitasvir + dasabuvir are classified

as pregnancy category B, but the other direct-acting antivirals do not have

a pregnancy classification. Therefore, these therapies are not indicated

routinely in pregnancy and should be used, with caution, only if the benefit of

treatment outweighs the potential for fetal risk.

Therapeutic Regimens (based on AASLD-IDSA recommendations,

www.hcvguidelines.org)

b

The European Association for the Study of the Liver (EASL) recommendations

diverge slightly from AASLD-IDSA recommendations.c

TREATMENT-NAÏVE OR RELAPSED AFTER PRIOR PEG

IFN–RIBAVIRIN THERAPY

FAILED PRIOR PEG IFN/RIBAVIRIN THERAPY, NO CIRRHOSISd

Genotype 1a and 1b

sofosbuvir + velpatasvir 12 weeks

glecaprevir + pibrentasvir 8 weeks

ledipasvir + sofosbuvir 12 weeks

grazoprevir + elbasvir 12 weeks (without ELB NS5A RASs)

Genotype 2

sofosbuvir + velpatasvir 12 weeks

glecaprevir + pibrentasvir 8 weeks

Genotype 3

sofosbuvir + velpatasvir 12 weeks (for patients without baseline NS5A RAS Y93H for

velpatasvir)

glecaprevir + pibrentasvir 16 weeks

sofosbuvir + velpatasvir + voxilaprevir 12 weeks for patients with baseline NS5A RAS

Y93H for velpatasvir

Genotype 4

sofosbuvir + velpatasvir 12 weeks

glecaprevir + pibrentasvir 8 weeks

grazoprevir + elbasvir 12 weeks (for prior relapse)

ledipasvir + sofosbuvir 12 weeks

Genotypes 5, 6

sofosbuvir + velpatasvir 12 weeks

glecaprevir + pibrentasvir 8 weeks

ledipasvir + sofosbuvir 12 weeks

FAILED PRIOR PEG IFN–RIBAVIRIN THERAPY, COMPENSATED CIRRHOSISd

Genotype 1a and 1b

sofosbuvir + velpatasvir 12 weeks

glecaprevir + pibrentasvir 8 weeks

ledipasvir + sofosbuvir 12 weeks (consider 8 weeks for noncirrhotic

HIV-negative patients with HCV RNA <6 × 106

 IU/mL)

grazoprevir + elbasvir 12 weeks (no cirrhosis or cirrhosis sans ELB NS5A

RASs)

Genotype 2

sofosbuvir + velpatasvir 12 weeks

glecaprevir + pibrentasvir 8 weeks

Genotype 3

sofosbuvir + velpatasvir 12 weeks (in cirrhotics, recommended only if

without baseline NS5A RAS Y93H for velpatasvir)

glecaprevir + pibrentasvir 8 weeks

sofosbuvir + velpatasvir 12 weeks + weight-based ribavirin (in cirrhotics with

baseline NS5A RAS Y93H for velpatasvir)

sofosbuvir + velpatasvir + voxilaprevir 12 weeks (in cirrhotics with baseline

NS5A RAS Y93H for velpatasvir)

Genotype 4

sofosbuvir + velpatasvir 12 weeks

glecaprevir + pibrentasvir 8 weeks (12 weeks for HIV co-infection)

ledipasvir + sofosbuvir 12 weeks (consider 8 weeks for noncirrhotic HIVnegative patients with HCV RNA <6 × 10 6

 IU/mL)

grazoprevir + elbasvir 12 weeks

Genotypes 5, 6

sofosbuvir + velpatasvir 12 weeks

glecaprevir + pibrentasvir 8 weeks

ledipasvir + sofosbuvir 12 weeks (except for genotype 6e)

Genotype 1a

sofosbuvir + velpatasvir 12 weeks

glecaprevir + pibrentasvir 12 weeks

grazoprevir + elbasvir 12 weeks (without ELB NS5A RASs)

ledipasvir + sofosbuvir + RBV 12 weeks

Genotype 1b

sofosbuvir + velpatasvir 12 weeks

glecaprevir + pibrentasvir 12 weeks

grazoprevir + elbasvir 12 weeks

ledipasvir + sofosbuvir + RBV 12 weeks

Genotype 2

sofosbuvir + velpatasvir 12 weeks

glecaprevir + pibrentasvir 12 weeks

Genotype 3

sofosbuvir + velpatasvir + voxilaprevir 12 weeks

glecaprevir + pibrentasvir 16 weeks

grazoprevir + elbasvir 12 weeks

sofosbuvir + velpatasvir + RBV 12 weeks

Genotype 4

sofosbuvir + velpatasvir 12 weeks

glecaprevir + pibrentasvir 12 weeks

grazoprevir + elbasvir 12 weeks (for prior relapse)

ledipasvir + sofosbuvir 12 weeks

Genotypes 5, 6

sofosbuvir + velpatasvir 12 weeks

glecaprevir + pibrentasvir 12 weeks

ledipasvir + sofosbuvir 12 weeks

FEATURES ASSOCIATED WITH REDUCED RESPONSIVENESS TO DIRECT-ACTING

ANTIVIRAL COMBINATION THERAPY

Genotype and subtype (genotype 1a less responsive than genotype 1b for several drugs)

Treatment experience

Advanced fibrosis (bridging fibrosis, cirrhosis)

Reduced adherence

(Continued)

2609Chronic Hepatitis CHAPTER 341

to 24 weeks of therapy (100% SVR12). This combination, which is

equally effective in patients with HIV-HCV co-infection and in

African-American patients, has been shown to be highly effective

in patients with decompensated cirrhosis and in patients with

hepatitis C after liver transplantation and after kidney transplantation. Initially, sofosbuvir-ledipasvir was not recommended

in patients with advanced renal failure; however, subsequently,

the safety and efficacy of sofosbuvir-ledipasvir in patients with

advanced renal failure were established, and the DAA was approved

for this indication (November 2019). All sofosbuvir-containing regimens can be associated with severe bradycardia in patients taking

the antiarrhythmic agent amiodarone, especially along with beta

blockers; sofosbuvir-containing combinations are contraindicated

with amiodarone. Drug-drug interactions are few, but P-glycoprotein

inducers, such as St. John’s wort and rifampin, and proton pump

gastric acid inhibitors, such as omeprazole, may reduce sofosbuvir-ledipasvir concentrations. Generally, responsiveness to sofosbuvir-ledipasvir is not reduced in patients with baseline RASs to these

agents, with the exception of treatment-experienced patients who

have baseline NS5A RASs (see Table 341-6).

Paritaprevir-ritonavir, ombitasvir, and dasabuvir: The combination of ritonavir (100 mg)–boosted paritaprevir (150 mg), a

protease inhibitor; ombitasvir (25 mg), an NS5A inhibitor; and

dasabuvir (250 mg), a nonnucleoside polymerase inhibitor, with or

without weight-based ribavirin (total of five drugs), was approved

in December 2014 for genotypes 1 and 4. Paritaprevir-ritonavir and

ombitasvir, formulated in a single tablet, are taken once daily, and

both dasabuvir (a separate pill) and weight-based ribavirin (when

included in the regimen) are taken twice daily. In clinical trials, this

combination achieved SVR12 rates of 87–100% in treatment-naïve

and treatment-experienced patients with genotype 1; without

ribavirin, this combination in genotype 1a was ~7% less responsive

than in genotype 1b. Therefore, in treatment-naïve patients with

genotype 1a, this combination was administered with ribavirin for

12 weeks in the absence of cirrhosis (95–97% SVR12) or for 24 weeks

in the presence of compensated cirrhosis (94% SVR12), whereas

in patients with genotype 1b, the combination did not require

ribavirin, and the duration of therapy was 12 weeks for both noncirrhotics and cirrhotics (99–100% SVR12). In prior nonresponders

without cirrhosis, the combination was administered for 12 weeks,

with ribavirin in genotype 1a (96% SVR12) and without ribavirin in

genotype 1b (100% SVR12). In prior nonresponders with cirrhosis,

the combination was administered for 24 weeks with ribavirin in

genotype 1a (SVR12 100% in prior relapsers and partial responders,

95% in prior null responders [in whom treatment without ribavirin

was associated with an 80% SVR12]), but only for 12 weeks and without ribavirin in genotype 1b (100% SVR12). For genotype 4, the regimen was given for 12 weeks with ribavirin but without dasabuvir in

treatment-naïve and treatment-experienced patients (100% SVR12),

including those with compensated cirrhosis. In July 2016, the FDA

approved a long-acting formulation of dasabuvir, allowing once-aday instead of twice-a-day treatment; for genotype 1a, twice-daily

ribavirin dosing remained.

This combination was well tolerated with generally mild side

effects, for example, fatigue, asthenia, insomnia, headache, and

pruritus. Hyperbilirubinemia (primarily unconjugated) and elevations in alanine aminotransferase activity could occur but resolved

during or shortly after treatment. Because of occasional hyperbilirubinemia and potential hepatotoxicity (FDA warning letter issued

October 2015 regarding hepatic failure/decompensation reported

in treated cirrhotic patients), this combination (and all subsequently

introduced protease-inhibitor-containing combinations) was contraindicated in patients with decompensated cirrhosis, and treated

cirrhotic patients had be monitored closely for decompensation;

however, the safety and efficacy of this combination was demonstrated for patients with advanced renal insufficiency. Similar to

other regimens containing protease inhibitors, drug-drug interactions are common with other drugs that induce CYP3A4 or are

dependent on CYP3A4 for elimination. Checking for potential

drug-drug interactions was important prior to initiating therapy with this drug combination (www.hep-druginteractions.org).

Responsiveness to this multidrug regimen was not reduced in

patients with baseline RASs to these agents.

Compared to sofosbuvir-ledipasvir, this regimen had the disadvantage of requiring twice-a-day ribavirin therapy for genotype 1a

and of being contraindicated in decompensated cirrhosis; however,

it had the advantage of offering a 12-week, ribavirin-free regimen

for prior null responders with cirrhosis and providing an option for

patients with renal failure. Based on regimen simplicity and superiority, subsequent-generation, ribavirin-free combination DAAs

have supplanted paritaprevir-ritonavir, ombitasvir, and dasabuvir;

this regimen is no longer recommended at all by the AASLD;

however, it is retained in EASL recommendations as an alternative

regimen for genotype 1b only.

Sofosbuvir and daclatasvir: Daclatasvir, an NS5A inhibitor, along

with the polymerase inhibitor sofosbuvir, was approved by the FDA

in July 2015 for genotype 3 and in February 2016 for genotype 1.

At the time of its approval for genotype 3, daclatasvir filled a need

inadequately met by other available combination DAAs; however, eventually, recommendation of this combination regimen was

extended to genotypes 1–4 in the United States and to all genotypes

(1–6) in Europe. Daclatasvir, a 60-mg tablet, and sofosbuvir, a separate 400-mg tablet, were taken once a day for 12–24 weeks.

In clinical trials among treatment-naïve or treatment-experienced

patients, SVR12 rates for 12 weeks of daclatasvir plus sofosbuvir were

98% for genotype 1 (comparable results in genotypes 1a and 1b),

a

Rapidly evolving new recommendations continue to be issued; for up-to-date treatment recommendations, please see www.hcvguidelines.org. b

For treatment-naïve

patients, simplified treatment regimen recommendations are in bold font (based on broad applicability, pangenotypic coverage, and simplicity). For treatment-experienced

patients, recommended regimens are in bold font, and alternative regimens are in standard font. c

The following EASL recommendations differ from those of AASLD-IDSA:

Genotype 1

For genotype 1a, noncirrhotic, prior IFN/RBV nonresponders, sofosbuvir + ledipasvir is not recommended.

For genotype 1b, treatment-naïve or -experienced patients, EASL retains paritaprevir/ritonavir + ombitasvir + dasabuvir for 12 weeks (for 8 weeks in patients with stage

F0–F2 fibrosis).

For genotype 1b, noncirrhotic, treatment-naïve or -experienced patients with stage F0–F2 fibrosis, the recommended duration of grazoprevir + elbasvir is 8 weeks.

Genotype 3

For cirrhotic, treatment-naïve or -experienced patients (IFN-based regimen failures), sofosbuvir + velpatasvir is not recommended. For noncirrhotic patients with genotype 3,

sofosbuvir + ledipasvir + voxilaprevir is not recommended.

Genotype 4

For genotype 4, prior IFN/RBV nonresponders, sofosbuvir + ledipasvir is not recommended. In treatment-naïve noncirrhotics, shorter duration (8 weeks) is not recommended

for patients with HCV RNA ≤6 × 106

 IU/mL.

d

For nonresponders to prior direct-acting antiviral therapy (protease, polymerase, or NS5A inhibitors) and for decompensated cirrhosis, please consult www.hcvguidelines

.org.

Abbreviations: AASLD, American Association for the Study of Liver Diseases; ALT, alanine aminotransferase; ELB NS5A RASs, elbasvir NS5A resistance-associated

substitutions; HCV, hepatitis C virus; IFN, interferon; IDSA, Infectious Diseases Society of America; PEG IFN, pegylated interferon; IU, international units (1 IU/mL is

equivalent to ~2.5 copies/mL); RASs, resistance-associated substitutions; RBV, ribavirin.

TABLE 341-6 Indications and Recommendations for Antiviral Therapy of Chronic Hepatitis Ca (Continued)

2610 PART 10 Disorders of the Gastrointestinal System

92% for genotype 2, and 89% for genotype 3. For noncirrhotic

patients, the addition of ribavirin or the extension of therapy to

24 weeks did not improve efficacy. In patients with compensated

cirrhosis, limited prospective data and data from observational

cohorts suggested that extending therapy to 24 weeks, with or without ribavirin, improved efficacy. In cirrhotics, SVR12 was achieved

in 93% with Child-Pugh class A and B but in only 56% with class C

decompensated cirrhosis. For patients with genotype 3 and cirrhosis,

the combination was effective in treatment-naïve patients (94% SVR12)

but less so in prior nonresponders (69% SVR12). Outcomes in

patients with HIV-HCV co-infection were comparable.

Like other sofosbuvir–NS5A inhibitor combinations, daclatasvir

plus sofosbuvir was well tolerated (mild fatigue, headache, nausea,

or diarrhea in 5–14%) but could cause severe bradycardia when

administered with amiodarone (contraindicated), especially along

with beta blockers. Because daclatasvir is a substrate for CYP3A,

CYP3A inducers can reduce daclatasvir levels, and CYP3A inhibitors reduce daclatasvir levels. Similarly, daclatasvir, an inhibitor

of P-glycoprotein, OATP1B1 and OATP1B3, and breast cancer

resistance protein (BCRP), can increase the levels of drugs that

are substrates of these transporters. Responsiveness to daclatasvircontaining drug combination therapy was reduced in cirrhotic

patients with genotype 1a and in both cirrhotic and noncirrhotic

patients with genotype 3 who had baseline daclatasvir-associated

NS5A RASs.

As new combination DAAs were introduced, however,

daclatasvir-sofosbuvir was less competitive and no longer filled a

niche; it has been supplanted by better, later-generation combination DAAs and is no longer recommended.

DIRECT-ACTING ANTIVIRAL COMBINATIONS OF THIRDGENERATION PROTEASE INHIBITORS AND SECONDGENERATION NS5A INHIBITORS (2016)

Elbasvir-grazoprevir: Elbasvir (50 mg), an NS5A inhibitor, combined in a single, fixed-dose pill with grazoprevir (100 mg), an

NS3/4 protease inhibitor, was approved in January 2016 as a

once-a-day (with or without food) treatment for genotypes 1

and 4. In clinical trials, a 12-week course was effective in treatment-naïve and treatment-experienced patients without cirrhosis

or with compensated cirrhosis. In treatment-naïve patients, this

combination yielded an SVR12 in 92% of patients with genotype

1a, 99% with genotype 1b, and 100% with genotype 4 (very small

numbers, however); 10 patients with genotype 6 were included,

but only 80% achieved SVR12. Cirrhotic and noncirrhotic patients

had comparable rates of SVR12, 97% and 94%, respectively. For this

drug combination, however, ~11% of patients with genotype 1a

harbor NS5A polymorphisms, that is, RASs, at baseline. If present,

these NS5A RASs reduce efficacy of elbasvir-grazoprevir (unlike

baseline RASs to most of the other combination DAA regimens

described above and below) from 99 to 58% in treatment-naïve

patients. Therefore, all patients with genotype 1a require baseline

RAS testing; when these RASs were present, treatment extension to

16 weeks and the addition of weight-based ribavirin were documented to bring SVR12 rates up to expected levels of close to 100%.

In treatment-experienced patients, both extending treatment to

16 weeks and adding ribavirin were studied; however, generally, in

the absence of baseline NS5A RASs, SVR12 rates were not increased

over those without ribavirin for 12 weeks (94–97%). For genotype

1a, among prior nonresponders to PEG IFN–ribavirin, 12 weeks of

elbasvir-grazoprevir sufficed without ribavirin except for patients

with baseline NS5A RASs, who required 16 weeks of therapy and

ribavirin. Among nonresponders to prior protease inhibitor therapy, even in the absence of baseline NS5A RASs, ribavirin had to

be added to a 12-week regimen; in the presence of baseline NS5A

RASs, treatment was extended to 16 weeks and ribavirin added. For

genotype 1b, NS5A RASs are not an issue, and the only subgroup

requiring modification of a 12-week course of therapy were prior

nonresponders to protease inhibitor regimens, for whom ribavirin

was added. For genotype 4, the recommended regimen for all prior

nonresponders (whether to PEG IFN–ribavirin or protease inhibitor regimens) was 16 weeks of elbasvir-grazoprevir plus ribavirin.

Now that simpler, improved combination regimens are available,

for patients with NS5A RASs, extending the duration of elbasvirgrazoprevir and adding ribavirin have been abandoned (Table 341-6);

however, elbasvir-grazoprevir is one of the currently recommended

DAA combinations (Table 341-6).

This combination is just as effective in patients with HIV-HCV

co-infection and in patients with advanced renal failure (including

those requiring hemodialysis), but like all protease-inhibitorincluding DAA combinations, it is contraindicated in decompensated

cirrhosis. In this vein, like other protease inhibitor regimens, elbasvirgrazoprevir can be associated with aminotransferase elevations

and potential hepatotoxicity; because these drugs are excreted by

the liver, plasma drug concentrations may become elevated substantially in the presence of impaired hepatic function. Therefore,

all treated patients should have ALT screening periodically during

therapy, and the drug should be stopped for elevations exceeding

tenfold or for elevations of conjugated bilirubin, alkaline phosphatase, or prothrombin time.

Elbasvir-grazoprevir is well tolerated, with only low levels of

mild adverse effects (fatigue, headache, or nausea in 5–11%) seen

just as frequently in placebo recipients. Both elbasvir and grazoprevir are substrates for CYP3A and are subject to multiple potential

drug-drug interactions. Therefore, this combination should not

be used with potent CYP3A inducers; conversely, CYP3A and

OATP1B1 inhibitors can lead to untoward elevations of plasma

elbasvir-grazoprevir concentrations. Checking for potential drugdrug interactions is advisable prior to initiating therapy (www

.hep-druginteractions.org).

Compared to other available regimens for genotypes 1 and 4,

elbasvir-grazoprevir has the disadvantage/inconvenience of requiring baseline NS5A RAS testing but the advantages of a comparable

regimen for cirrhotics and noncirrhotics, for treatment-naïve and

treatment-experienced patients, and for patients with normal renal

function and with renal failure.

Sofosbuvir-velpatasvir: The combination in a single, fixed-dose

pill of velpatasvir (100 mg), a highly potent, pangenotypic NS5A

inhibitor, and the polymerase inhibitor sofosbuvir (400 mg) was

approved in June 2016 for genotypes 1–6 in treatment-naïve and

treatment-experienced noncirrhotics and cirrhotics. In August

2017, approval was extended to include patients with HCV-HIV

co-infection. Ribavirin is not required, including in patients with

genotypes 2 and 3, except in patients with decompensated cirrhosis.

In a series of clinical trials, this combination for 12 weeks in

the absence of ribavirin was shown to yield a 99% SVR12 (range

97–100%) in genotypes 1, 2, 4, 5, and 6 and 95% in genotype 3.

Baseline NS5A RASs had no impact on responsiveness.

Prior to the availability of this drug combination, patients with

genotype 3, especially those with cirrhosis and prior null response

to other therapies, proved to be the most refractory subset of

patients. In treatment-naïve patients with genotype 3, 12 weeks

of sofosbuvir-velpatasvir (95% SVR12) was superior to 24 weeks

of sofosbuvir plus ribavirin (80% SVR12). In patients with genotype 3, the combination of sofosbuvir-velpatasvir for 12 weeks

was comparable in noncirrhotics (97% SVR12) and cirrhotics

(91% SVR12) and in treatment-naïve (97% SVR12) and treatmentexperienced (90% SVR12) patients and was superior in all these

categories to 24 weeks of sofosbuvir plus ribavirin (87%, 66%, 86%,

and 63%, respectively). In cirrhotic null responders, most available IFN-free regimens for genotype 3 (including daclatasvir plus

sofosbuvir, which had been approved specifically for this genotype)

achieved SVR12 rates in the range of ~60–75%, while the combination of PEG IFN, ribavirin, and sofosbuvir could boost SVR12 to the

mid-80% range. For treatment-experienced patients with genotype

3, sofosbuvir-velpatasvir in noncirrhotics and cirrhotics had similarly high efficacy (91% and 89% SVR12, respectively); this was the

highest recorded SVR12 for genotype 3 cirrhotic null responders

treated with IFN-free DAA regimens. Finally, in patients with

2611Chronic Hepatitis CHAPTER 341

genotypes 1–4 and 6 and with decompensated, class B cirrhosis

(55% treatment-experienced), sofosbuvir-velpatasvir plus ribavirin

for 12 weeks yielded an SVR12 in 94%; this result was better than

sofosbuvir-velpatasvir without ribavirin for 12 weeks (83% SVR12)

or 24 weeks (86% SVR12).

Like other all-oral DAAs, sofosbuvir-velpatasvir was very well

tolerated; in noncirrhotic and compensated cirrhotic patients, mild

headache and fatigue were seen in >10% (this occurred in a comparable proportion of placebo recipients), and in patients with

decompensated cirrhosis, mild fatigue, headache, nausea, insomnia, diarrhea, and anemia (ribavirin was part of the regimen) were

seen in >10%. Like other sofosbuvir-containing regimens, sofosbuvir-velpatasvir should not be administered along with amiodarone

(potential serious bradycardia); in addition, P-glycoprotein inducers

and moderate-to-potent CYP3A inducers can reduce plasma levels

of sofosbuvir and/or velpatasvir. Checking for drug-drug interactions prior to therapy is advisable (www.hep-druginteractions.org).

Baseline RASs do not influence responsiveness to this combination.

Sofosbuvir-velpatasvir is one of the currently recommended DAA

combinations for hepatitis C (Table 341-6). Because it is so simple

and broadly effective across patient subgroups, sofosbuvir-velpatasvir

is one of the two combination DAA regimens recommended by the

AASLD and EASL as a preferred, simplified treatment algorithm

(Table 341-6).

DIRECT-ACTING ANTIVIRAL COMBINATIONS OF

THIRD-GENERATION NS5A INHIBITORS AND FOURTHGENERATION PROTEASE INHIBITORS—CURRENT

STANDARD OF CARE (SINCE 2017)

Sofosbuvir-velpatasvir-voxilaprevir: Approved in July 2017, the

pangenotypic, high-barrier-to-resistance protease inhibitor voxilaprevir (100 mg) added to the polymerase inhibitor–NS5A

inhibitor combination of sofosbuvir-velpatasvir yields a very

well-tolerated triple-drug combination with ~97% SVR12 across all

HCV genotypes and patient subgroups. These include the small

percentage of patients with genotype 1 and genotype 3 refractory

to previously approved DAA combinations as well as noncirrhotic/

cirrhotic, treatment-naïve/treatment-experienced groups, including those who had or who had not received prior NS5A treatment.

Efficacy was independent of the number of prior DAA drug classes

received, and no effects of baseline NS5A RASs were noted.

The potential for abbreviated (8-week) treatment with this

triple combination was explored in a clinical trial involving

treatment-naïve patients; however, the shortened duration was

inferior to a full 12-week course. The side effect profile for sofosbuvir-velpatasvir-voxilaprevir was similar to that in the placebo arm of

clinical trial patients and included mild and uncommon headache,

fatigue, nausea, and diarrhea.

Because other DAA regimens are so effective in most patients

with chronic hepatitis C, recommendations for sofosbuvir-velpatasvir-voxilaprevir are limited to a small subset of otherwise refractory

patients: for treatment-naïve cirrhotic patients with genotype 3 and

baseline NS5A velpatasvir RAS Y93H, for treatment-naïve (according

to AASLD, not EASL) or IFN-ribavirin–experienced noncirrhotic or

cirrhosis patients with genotype 3 (Table 341-6), and for patients with

or without compensated cirrhosis and prior, failed NS5A inhibitor–

containing therapy (consult www.hcvguidelines.org).

This triple-drug combination, like all sofosbuvir-containing

combinations, is contraindicated in patients taking amiodarone

and, like all protease inhibitor-containing combinations, in patients

with decompensated cirrhosis. Concomitant omeprazole, 20 mg,

can be taken with this sofosbuvir-containing regimen. Prior to initiating therapy, checking for drug-drug interactions is recommended.

Glecaprevir-pibrentasvir: A regimen of 8 weeks of this single-pill,

fixed-dose combination of the protease inhibitor glecaprevir

(300 mg) and NS5A inhibitor pibrentasvir (120 mg), two pangenotypic, high-potency DAAs with high barriers to resistance (approved

in August 2017), achieves SVR12 in close to 100% of treatment-naïve

patients with all genotypes, with or without cirrhosis: SVR12 of

~99% for genotypes 1, 2, and 4–6 and of 95–98% for genotype 3.

Extended treatment for 12 weeks did not increase efficacy. In trials

among treatment-experienced patients, treatment with 12 weeks of

this DAA combination was just as effective as 16 weeks for all genotypes except genotype 3; however, with increasing numbers of prior

treatment courses, SVR12 rates fell—100% for patients treated with

a protease inhibitor only, 88% for patients treated with an NS5A

inhibitor only, and 79% for patients treated previously with both a

protease inhibitor and an NS5A inhibitor. Similarly, baseline RASs

reduced SVR12 rates—from 100% without RASs (or with RASs

limited to those reflecting protease inhibitor resistance) to 89% for

baseline NS5A RASs.

For retreatment of patients with prior glecaprevir-pibrentasvir

failure, 16 weeks of glecaprevir-pibrentasvir plus sofosbuvir are

recommended (alternatively, sofosbuvir-velpatasvir-voxilaprevir

for 12 weeks [+ ribavirin in cirrhotics]). Glecaprevir-pibrentasvir

for 16 weeks is recommended as well after failure to respond to

the triple-drug combination of sofosbuvir-velpatasvir-voxilaprevir

(see below). For retreatment of patients with sofosbuvirvelpatasvir-voxilaprevir failure, 16 weeks of glecaprevir-pibrentasvir

plus ribavirin is recommended, as is a repeat course of sofosbuvirvelpatasvir-voxilaprevir plus ribavirin for 24 weeks.

As is the case for any DAA combination containing a protease

inhibitor, glecaprevir-pibrentasvir is contraindicated in decompensated cirrhosis; it has been shown to achieve an SVR12 in 98%

of patients with stage 4 or 5 renal disease (in treatment-naïve or

experienced, cirrhotic or noncirrhotic patients) and is a preferred

treatment for patients with severe renal impairment. This DAA

combination should be taken with food, and drug-drug interactions

should be considered prior to initiating treatment. Because it is so

simple and broadly effective across patient subgroups (8 weeks for all

noncirrhotic treatment-naïve patients except patients with HIV co-infection [12 weeks]; 12 weeks for all treatment-experienced cirrhotics

and treatment-naïve cirrhotics with genotype 3 [except treatmentexperienced cirrhotic or noncirrhotic genotype 3 (16 weeks)]),

glecaprevir-pibrentasvir is one of the two combination DAA regimens

recommended by the AASLD and EASL as a preferred, simplified

treatment algorithm (Table 341-6).

Emerging data on the impact of DAAs on the natural history

of chronic hepatitis C indicated that, as was documented for IFNbased therapy, successful DAA therapy is associated with a gradual

reduction in fibrosis progression and a regression of advanced

fibrosis (cirrhosis), improvement in survival among patients with

decompensated cirrhosis, a reduction in HCC, and a decline in

the number of patients with hepatitis C being referred for liver

transplantation. Early observations purported to show an increase

in HCC after a DAA-associated SVR for chronic hepatitis C. On

the contrary, HCC rates are reduced dramatically and consistently

after successful DAA therapy. Ultimately, the initial observation was

attributed to a cohort bias resulting from the application of simpleto-use DAA therapy to an older and sicker population with more

advanced chronic hepatitis C (including decompensated cirrhosis);

this cohort effect explains why the baseline risk for HCC was higher

in DAA-treated patients than it had been when IFN-based therapy

was withheld from such patients. Thus, the increased risk in HCC

cases was not linked to DAA treatment but to more advanced liver

disease at baseline in patients treated with DAAs. The reports of

HCC after DAA therapy drive home the residual HCC risk after

SVR in patients with cirrhosis (advanced hepatic fibrosis) treated

either in the IFN or DAA era; therefore, continued HCC surveillance after therapy is recommended for anyone with baseline

advanced fibrosis prior to therapy.

Based on the known prevalence, natural history, and rate of

progression of chronic hepatitis C and on the efficacy of DAA therapies and their impact on the complications of hepatitis C, modeling

estimates have suggested that the availability and application of these

therapies have the potential to reduce the hepatitis C–associated disease burden, including liver-related death, HCC, decompensated cirrhosis, and liver transplantation, by 50–70% between 2015 and 2050.

2612 PART 10 Disorders of the Gastrointestinal System

TREATMENT RECOMMENDATIONS

Because the pace of new drug development and approval has been

so rapid, the AASLD and the Infectious Diseases Society of America

(IDSA) have been providing a consensus of updated treatment

recommendations for patients with hepatitis C; these recommendations, which continue to be revised regularly based on new

data, are available online at www.hcvguidelines.org and should be

consulted before initiating therapy (Table 341-6). The EASL issues

similar (but not identical) treatment recommendations annually

for hepatitis C (www.easl.eu), most recently in November 2020.

Divergences between AASLD-IDSA and EASL recommendations

are noted in Table 341-6.

Prior to therapy, HCV genotype should be determined, because

the genotype contributes to decisions about which treatment regimens are indicated (Table 341-6). Monitoring of serum HCV RNA

levels before, during, and after treatment is crucial in assessing

response to therapy; moreover, the baseline level may contribute to

determining the duration of therapy (e.g., in noncirrhotic patients

with genotype 1 and HCV RNA <6 × 106

 IU/mL, 8 [instead of the

usual 12] weeks of sofosbuvir-ledipasvir may be a consideration).

The goal of treatment is to eradicate HCV RNA during therapy

and to document that the virus remains undetectable for at least

12 weeks after completion of therapy (SVR12). Several reports have

appeared describing hepatitis B reactivation, often severe, during

and after DAA therapy in patients co-infected with HCV and HBV

who were not being treated for their HBV infections. Therefore,

screening for HBV infection is recommended prior to initiating

DAA therapy for hepatitis C (which should have been done to

determine HBV immunity status as a prelude to recommended

hepatitis B vaccination in patients with chronic hepatitis C), and

therapy for HBV infection (for those meeting HBV treatment criteria, see above) should be initiated prior to or simultaneously with

HCV therapy.

Because of their high efficacy and pangenotypic range, two

DAA regimens, glecaprevir-pibrentasvir (8 weeks) and sofosbuvirvelpatasvir (12 weeks), are recommended as simplified treatment

algorithms that can be prescribed for all treatment-naïve patients

with or without cirrhosis (Table 341-6).

INDICATIONS FOR ANTIVIRAL THERAPY

Patients with chronic hepatitis C who have detectable HCV RNA

in serum, whether or not aminotransferase levels are increased,

and chronic hepatitis of any grade and stage are candidates for

antiviral therapy with DAA agents. The only exception would be

patients with short life expectancies, for whom treating hepatitis C

would have no influence on longevity. Certainly, for patients with

advanced liver disease, early treatment merits a high priority.

Although patients with persistently normal aminotransferase activity tend to progress histologically very slowly or not at all, they

respond to antiviral therapy just as well as do patients with elevated

aminotransferase levels; therefore, such patients are candidates for

antiviral therapy. As noted above, antiviral therapy has been shown

to improve survival and complication-free survival and to slow

progression of and to reverse fibrosis.

HCV genotype determines the regimen to be selected

(Table 341-6). Similarly, the absence or presence of cirrhosis or

advanced fibrosis determines the treatment options from which

to select, including the antiviral agents to be used, the duration of

therapy, and the now rare need for ribavirin (Table 341-6). In the

past, a pretreatment liver biopsy was relied upon to assess histologic grade and stage as well as to identify such histologic factors

as steatosis, which can influence responsiveness to therapy. As

therapy has improved for patients with a broad range of histologic

severity and as noninvasive measures of the stage of fibrosis (e.g.,

assessment of liver elasticity by imaging, FIB-4 score [see above])

have gained in accuracy and popularity, noninvasive approaches

have supplanted histology in almost most cases. As noted above, if

cirrhosis or advanced fibrosis is present prior to therapy, the risk

of HCC, although reduced substantially by successful therapy, is

not eliminated, and twice-yearly posttreatment imaging for HCC

surveillance (and endoscopic surveillance for esophageal varices at

intervals of 1–3 years) is indicated even after an SVR. In patients

with low-level fibrosis at baseline, achievement of an SVR allows the

cessation of such surveillance.

Patients who have relapsed after, or failed to respond to, a

course of IFN-based or DAA agent–based therapy are candidates for retreatment with a DAA therapy regimen (Table 341-6).

For patients who have failed to respond to a DAA combination,

options include increasing the duration of therapy with the failed

regimen, adding ribavirin, or changing the drug class (e.g., after

failed protease and polymerase inhibitors, switching to an NS5Acontaining combination). In the presence of cirrhosis or a need

for urgent retreatment, patients who have failed protease inhibitor plus polymerase inhibitor combination therapy or who have

failed an NS5A combination are candidates for RAS testing and

tailored therapy based on such resistance testing. If reliable RAS

testing is not available, adding ribavirin or extending the duration

of therapy are options. For prior nonresponders to IFN-based

therapy, NS5A inhibitor–containing regimens are highly effective;

however, reduced responsiveness can be encountered, especially

in cirrhotic patients. For this relatively refractory group, ideally,

the most potent or effective NS5A regimen should be selected

to give such patients the best chance of responding and to avoid

treatment-emergent NS5A RASs. Noted above (see discussion of

sofosbuvir-velpatasvir-voxilaprevir and of glecaprevir-pibrentasvir)

are potential retreatment approaches after failure of a prior NS5Acontaining regimen. Additional details for treatment of such patient

subgroups can be found at www.hcvguidelines.org. It is worth

reiterating that protease inhibitors are contraindicated for patients

with decompensated cirrhosis, and sofosbuvir-containing regimens

are not recommended for patients taking amiodarone (especially

with beta blockers) for treatment of cardiac arrhythmias. While

sofosbuvir-containing DAA combinations were not recommended

initially for patients with advanced renal failure, subsequent studies

demonstrated safety and efficacy in this subgroup, and sofosbuvircontaining DAA combinations are now approved for advanced

renal failure.

Persons with acute hepatitis C are also candidates for antiviral

therapy (Chap. 339) with the same pangenotypic combination DAA

agents (and the same duration of treatment) approved for chronic

hepatitis C; delaying the initiation of therapy to allow for spontaneous recovery is no longer recommended. According to EASL

recommendations, patients with acute hepatitis C should be treated

ideally with a currently recommended 8-week DAA regimen. In

patients with biochemically and histologically mild chronic hepatitis

C, the rate of progression is slow; however, such patients respond just

as well to antiviral therapy as those with elevated aminotransferase

levels and more histologically severe hepatitis. Because of the high

cost of DAA treatments, in the past, a higher priority was assigned to

patients with advanced fibrosis/cirrhosis; however, this controversial

approach was relied upon by some medical insurers and pharmacy

benefit management organizations to withhold therapy from patients

with low-level fibrosis. Unfortunately, delaying therapy until fibrosis

becomes advanced misses the opportunity to prevent all the dire consequences of chronic hepatitis C (liver failure, death/transplantation,

HCC), which can be reduced, but not eliminated completely, once

advanced fibrosis is established. Therefore, therapy for patients with

mild disease is justified as well as cost-effective.

Patients with compensated cirrhosis can respond to therapy, and

their likelihood of a sustained response with DAAs is comparable to

that in noncirrhotics. Patients with decompensated cirrhosis, who

were not candidates for IFN-based antiviral therapy, respond well

to DAA therapy regimens consisting of combinations of polymerase

inhibitors and NS5A inhibitors (e.g., sofosbuvir-ledipasvir, sofosbuvir-velpatasvir); however, protease-inhibitor-containing combinations have been associated with potential hepatotoxicity and hepatic

decompensation and, as noted above, are contraindicated in this

patient subset. For decompensated cirrhosis, ribavirin should be

2613Chronic Hepatitis CHAPTER 341

added to a 12-week course of sofosbuvir-NS5A therapy; however,

in cases of ribavirin ineligibility, the duration of therapy should

be extended to 24 weeks. In cases of prior failure to respond to

sofosbuvir-NS5A therapy, the sofosbuvir-NS5A regimen should be

repeated but supplemented with ribavirin and extended to 24 weeks

(www.hcvguidelines.org). Patients with decompensated cirrhosis

should be referred to a liver transplantation center. DAAs are highly

effective not only for patients with end-stage liver disease awaiting

liver transplantation but also for patients with recurrent hepatitis C

after liver transplantation. Ideally, patients should be treated prior

to liver transplantation; however, a concern is that eradication of

HCV infection will disqualify such patients from accepting donor

livers from persons with HCV infection, thus contracting the

potential donor pool and limiting accessibility to donor organs and

timely transplantation. In addition, responsiveness to DAA therapy

appears to be reduced in patients with decompensated cirrhosis

and with high Model for End-Stage Liver Disease (MELD) scores;

in this subgroup, responsiveness after liver transplantation would

be substantially better. Therefore, advocacy has been expressed

for postponing DAA therapy in patients with high-MELD-score

(≥18–20), HCV-associated, end-stage liver disease until after liver

transplantation; for patients with MELD scores <18–20, pretransplantation DAA therapy is advised. Still, the decision whether to

treat pretransplantation or posttransplantation should be individualized thoughtfully for each patient, based on such factors as MELD

score, time anticipated prior to availability of a donor organ, relative

clinical stability, and comorbidities (Chap. 345). Because DAA

therapy is so effective, many transplantation centers, to expand

the donor pool, are accepting organs from HCV-infected donors,

transplanting them into HCV-uninfected recipients, and treating

recipients with sofosbuvir-velpatasvir for 12 weeks or glecaprevir-pibrentasvir for 8 weeks after transplantation—with excellent

results.

The cutaneous and renal vasculitis of HCV-associated essential

mixed cryoglobulinemia (Chap. 339) may respond to antiviral

therapy, but sustained responses were rare after discontinuation of

therapy in the IFN era, and prolonged, potentially indefinite, therapy was recommended. Now that more effective DAAs are available, a 12-week course of sofosbuvir-based combination therapy has

been shown to yield an SVR12 rate exceeding 80% in cryoglobulinemic vasculitis. Anecdotal reports suggest that IFN-based antiviral

therapy may be effective in porphyria cutanea tarda or lichen planus

associated with hepatitis C; whether the more appealing DAAs are

effective in these groups remains to be documented.

In patients with HCV/HIV co-infection, hepatitis C is more progressive and severe than in HCV-monoinfected patients. Although

patients with HCV/HIV co-infection responded less well to IFNbased antiviral therapy for hepatitis C, they respond as well as

patients with HCV infection alone to DAA combination regimens.

For patients with HCV/HIV co-infection, an abbreviated, 8-week

course of sofosbuvir-ledipasvir for low-level HCV RNA is not recommended, and a full 12 weeks should be given; similarly, for patients

with genotype 4, a 12-week course of glecaprevir-pibrentasvir is

recommended instead of an 8-week course for treatment-naïve or

-experienced patients with or without cirrhosis (Table 341-6). In

HCV/HIV-infected patients, ribavirin can potentiate the toxicity

of didanosine (e.g., lactic acidosis) and the lipoatrophy of stavudine, and zidovudine can exacerbate ribavirin-associated hemolytic

anemia; therefore, these drug combinations should be avoided.

In HCV/HIV co-infected persons, the list of potential drug-drug

interactions is extensive and should be consulted carefully before

beginning DAA treatment (www.hcvguidelines.org).

Patients with a history of injection drug use and alcoholism

can be treated successfully for chronic hepatitis C, preferably in

conjunction with drug and alcohol treatment programs. Moreover,

because injection drug users, as a source of transmission to others,

account disproportionately for perpetuating the spread of HCV

infection in the population, the impact of treating active injection

drug users is amplified by reducing such transmission.

The approved oral DAA combinations are effective in patients

with mild-modest renal failure and require no dose adjustments.

For patients with severe renal impairment (creatinine clearances

<30 mL/min), including those undergoing hemodialysis, recommended combinations are 12 weeks of elbasvir-grazoprevir for

genotypes 1 and 4 or 12 weeks of glecaprevir-pibrentasvir for all

genotypes. Both in severe renal impairment and after renal transplantation, levels of SVR12 in patients treated with these oral DAA

combinations have approached 100%. Initially, in patients with

severe renal impairment, sofosbuvir-containing combinations were

not recommended. Subsequently, however, based on efficacy and

safety in a series of clinical trials, sofosbuvir-containing regimens

were approved by the FDA in November 2019 for patients with

severe renal impairment.

No clinical studies of the use of DAAs during pregnancy are

available. Ribavirin is contraindicated during pregnancy; therefore,

any regimen including ribavirin should not be used. Sofosbuvir;

sofosbuvir-ledipasvir; and paritaprevir-ritonavir, ombitasvir, and

dasabuvir are classified as pregnancy category B; the other DAAs

do not have a pregnancy classification. Therefore, these therapies

are not indicated routinely in pregnancy and should be used, with

caution, only if the benefit of treatment is compelling and justified

compared to the potential for fetal risk. Currently, screening all

pregnant women for HCV infection is recommended. Breast feeding is not contraindicated in women with HCV infection (unless the

mother has a break in the integrity of the nipples or is co-infected

with HIV).

Choosing Among Available Treatment Options Choosing among

the number of all-oral DAA combinations approved since 2013

was daunting to treating clinicians. Currently, however, the number of recommended DAA combinations has narrowed to a

very manageable few. The most popular of the regimens have

been fixed-dose, single-pill, pangenotypic combinations. Although

sofosbuvir-ledipasvir and elbasvir-grazoprevir are among the recommended DAA combinations (Table 341-6), for simplicity, two

“one-size-fits-all” pangenotypic regimens—sofosbuvir-velpatasvir

and glecaprevir-pibrentasvir—can be used, for 8–12 weeks, mostly

without ribavirin, in almost all treatment-naïve, noncirrhotic and

cirrhotic patients, including those with advanced renal failure

and HCV-HIV co-infection. Applicability of the triple-drug combination sofosbuvir-velpatasvir-voxilaprevir is quite limited in

treatment-naïve patients, reserved primarily for cirrhotic patients

with genotype 3. As noted above, protease-inhibitor-containing

DAA regimens (elbasvir-grazoprevir, glecaprevir-pibrentasvir, and

sofosbuvir-velpatasvir-voxilaprevir) are contraindicated in decompensated cirrhosis.

AUTOIMMUNE HEPATITIS

■ DEFINITION

Autoimmune hepatitis is a chronic disorder characterized by continuing hepatocellular necrosis and inflammation, usually with fibrosis,

which can progress to cirrhosis and liver failure. When fulfilling criteria of severity, this type of chronic hepatitis, when untreated, may

have a 6-month mortality of as high as 40%. Based on contemporary

estimates of the natural history of autoimmune hepatitis, the 10-year

survival is 80−98% for treated and 67% for untreated patients. The

prominence of extrahepatic features of autoimmunity and seroimmunologic abnormalities in this disorder supports an autoimmune process

in its pathogenesis; this concept is reflected in the prior labels lupoid

and plasma cell hepatitis. Autoantibodies and other typical features of

autoimmunity, however, do not occur in all cases; among the broader

categories of “idiopathic” or cryptogenic chronic hepatitis, many, perhaps the majority, are probably autoimmune in origin. Cases in which

hepatotropic viruses, metabolic/genetic derangements (including nonalcoholic fatty liver disease), and hepatotoxic drugs have been excluded

represent a spectrum of heterogeneous liver disorders of unknown

cause, a proportion of which are most likely autoimmune hepatitis.