2599Chronic Hepatitis CHAPTER 341

toxicity; however, among patients treated with tenofovir, instances

of acute renal failure and of low blood phosphate levels have been

reported. Thus, in patients receiving tenofovir, monitoring bone density is not recommended, but periodic (at least annual) monitoring

for renal injury is recommended (serum creatinine and phosphate,

urine glucose and protein). Frequency of tenofovir administration

should be reduced for patients with impaired creatinine clearance.

Tenofovir alafenamide (TAF), a second-generation tenofovir

approved in 2016, is a prodrug of tenofovir that requires activation

to tenofovir in hepatocytes. This targeted delivery to hepatocytes

allows a lower dose to suffice and reduces systemic exposure by

90%, thereby minimizing TDF-associated proximal tubular renal

injury, its associated phosphate wasting, and the potential consequent loss of bone mineral density. The dose of TAF is 25 mg,

which is equivalent in antiviral potency to 300 mg of TDF; both

formulations have the same high barrier to resistance, and clinical resistance has not been encountered. Randomized, controlled,

double-blind, phase 3 noninferiority trials, one in HBeAg-positive

patients and the other in HBeAg-negative patients, provided the

safety and efficacy data to support TAF approval.

In 873 HBeAg-positive patients treated for 48 weeks, TAF versus

TDF achieved (1) HBV DNA reductions to <29 IU/mL in 64%

versus 67%; (2) ALT normalization in 72% versus 67% (an unexplained TAF biochemical advantage confirmed in other trials); (3)

HBeAg loss in 14% versus 12%; (4) HBeAg seroconversion in 10%

versus 8%; and (5) a negligible loss of HBsAg in 1% versus 0.3%.

Compared to TDF, TAF was associated with reduced impairment of

renal function (median reduction in estimated glomerular filtration

rate of –0.6 mL/min for TAF vs –5.4 mL/min for TDF) and of bone

density (in hip measurements, mean reduction of –0.10% for TAF

vs –1.72% for TDF; adjusted difference, 1.62%).

In the parallel trial among 426 HBeAg-negative patients treated

for 48 weeks, reductions in HBV DNA to <29 IU/mL occurred in

94% versus 93% of individuals treated with TAF versus TDF, respectively; normalization of ALT occurred in 83% versus 75%, but no

HBsAg loss occurred in either group. Similar TAF advantages in

maintaining renal function and bone density were reported: reduction in median estimated glomerular filtration rate (–1.8 mL/min

for TAF vs –4.8 mL/min for TDF) and in median bone density (in

hip measurements, mean reduction of –0.29% for TAF vs –2.16%

for TDF; adjusted percentage difference, 1.87%).

At week 96, TAF and TDF HBV DNA and ALT reductions

(including the TAF advantage observed at 48 weeks) were maintained. In the original TDF group, when TDF was switched to TAF

after week 96, all differences observed during the first 96 weeks (in

normalization of ALT and reductions in renal function and bone

density) had resolved at week 120. Resistance did not emerge to

either TAF or TDF throughout the trial.

Based on these trial outcomes, TAF joined the list of recommended first-line antiviral agents for chronic hepatitis B. This

drug is recommended over TDF by the American Association for

the Study of Liver Diseases (AASLD) and the European Association for the Study of the Liver (EASL) for patients with reduced

renal function (creatinine clearance <50 mL/min), reduced bone

density, and risk factors for renal injury (including, according

to EASL guidelines, decompensated cirrhosis, creatinine clearance

<60 mL/min, poorly controlled hypertension or diabetes, proteinuria, active glomerulonephritis, concomitant nephrotoxic

medications, or solid-organ transplantation); the EASL recommendation extends to persons >60 years, who are at increased

risk of TDF nephrotoxicity. In patients with creatinine clearances

<15 mL/min, neither TDF nor TAF is recommended.

A comparison of antiviral therapies for chronic hepatitis B

appears in Table 341-3; their relative potencies in suppressing

HBV DNA are shown in Fig. 341-1.

COMBINATION THERAPY

Although the combination of lamivudine and PEG IFN suppresses HBV DNA more profoundly during therapy than does

monotherapy with either drug alone (and is much less likely to be

associated with lamivudine resistance), this combination used for

a year is no better than a year of PEG IFN in achieving sustained

responses. To date, combinations of oral nucleoside/nucleotide

agents have not achieved an enhancement in virologic, serologic, or

biochemical efficacy over that achieved by the more potent of the

combined drugs given individually. In a 2-year trial of combination

entecavir and tenofovir versus entecavir monotherapy, for a small

subgroup of patients with very high HBV DNA levels (≥108

 IU/

mL), a reduction in HBV DNA to <50 IU/mL was higher in the

combination group (79 vs 62%); however, no differences in HBeAg

responses or any other endpoint were observed between the combination-therapy and monotherapy groups, even in the high-HBV

DNA subgroup. For resistance to lamivudine or adefovir, adding a second, non-cross-resistant agent was the chosen approach.

Whereas, initially, in clinical studies of adefovir as rescue therapy

for lamivudine resistance, adding adefovir to lamivudine (combination therapy) was considered a better strategy than replacing

lamivudine with adefovir monotherapy (to minimize ALT flares

and to avoid adefovir resistance), according to current treatment

recommendations of the AASLD and the EASL, switching from the

resistant drug to the new drug is preferred. Because the current

generation of antivirals is so potent and has such a high barrier to

resistance, monotherapy with the rescue drug (e.g., tenofovir for

lamivudine resistance) is as effective (as demonstrated in observational reports for up to 5 years) in maintaining viral suppression

without the emergence of resistance as combination therapy with

the resistant drug and the rescue drug. Generally, in patients treated

with entecavir and tenofovir preparations, antiviral drug resistance

is no longer encountered. For currently rare patients who already

have acquired multidrug resistance (to both nucleoside analogues

[lamivudine, entecavir, telbivudine] and nucleotide analogues [adefovir, tenofovir]), treatment with a combination of entecavir and

tenofovir has been shown to be highly effective in suppressing HBV

DNA and overcoming drug resistance.

NOVEL ANTIVIRALS AND STRATEGIES

In addition to the eight approved antiviral drugs for hepatitis

B, emtricitabine, a fluorinated cytosine analogue very similar to

lamivudine in structure, efficacy, and resistance profile, offers no

advantage over lamivudine. A combination of emtricitabine and

tenofovir is approved for the treatment of HIV infection and is

–3

–2

–1

0

–7

–6

–5

–4

ADV PEG IFN LAM

–3.5

–4.5

–5.5

Log10 HBV DNA

TDF TBV ETV

–6.2 –6.4

–6.9

FIGURE 341-1 Relative potency of antiviral drugs for hepatitis B, as reflected

by median log10 hepatitis B virus (HBV) DNA reduction in HBeAg-positive chronic

hepatitis B. These data are from individual reports of large, randomized controlled

registration trials that were the basis for approval of the drugs. In most instances,

these data do not represent direct comparisons among the drugs, because study

populations were different, baseline patient variables were not always uniform,

and the sensitivity and dynamic range of the HBV DNA assays used in the trials

varied. ADV, adefovir dipivoxil; ETV, entecavir; LAM, lamivudine; PEG IFN, pegylated

interferon α2a; TBV, telbivudine; TDF, tenofovir disoproxil fumarate. Because

of potency and a high barrier to resistance, ETV and tenofovir (either TDF or the

second-generation tenofovir alafenamide) are recommended as first-line therapy.

While PEG IFN remains a first-line agent, the oral agents developed earlier, LAM,

ADV, and TBV, are no longer preferred agents.

2600 PART 10 Disorders of the Gastrointestinal System

TABLE 341-4 Recommendations for Treatment of Chronic Hepatitis Ba

HBeAg STATUS CLINICAL HBV DNA (IU/mL) ALT RECOMMENDATION

HBeAg-reactive b

Chronic hepatitis

Cirrhosis compensated

Cirrhosis decompensated

>2 × 104

>2 × 104d

>2 × 103

<2 × 103

Detectable

Undetectable

≤2 × ULNc,d

>2 × ULNd

< or > ULN

>ULN

< or > ULN

< or > ULN

No treatment; monitor, except in patients >40, with family history of cirrhosis

or hepatocellular carcinoma, with extrahepatic manifestations, with a history

of previous treatment, and/or with liver biopsy (or noninvasive fibrosis

determination) evidence for moderate to severe inflammation or fibrosis

Treate

Treate

 with oral agents, not PEG IFN

Treatment suggestedf

Treate

 with oral agentsg

, not PEG IFN; refer for liver transplantation

Observe; refer for liver transplantation

HBeAg-negative b

Chronic hepatitis

Chronic hepatitis

Cirrhosis compensated

Cirrhosis decompensated

≤2 × 103

>2 × 103

>2 × 103

>2 × 103

<2 × 103

Detectable

Undetectable

≤ULN

1 to >2 × ULNd

>2 × ULNd

< or > ULN

>ULN

< or > ULN

< or > ULN

Inactive carrier; treatment not necessary

No treatment; monitor, except in patients >40, with family history of cirrhosis

or hepatocellular carcinoma, with extrahepatic manifestations, with a history

of previous treatment, and/or with liver biopsy (or noninvasive fibrosis

determination) evidence for moderate to severe inflammation or fibrosis

Treath,i

Treate

 with oral agents, not PEG IFN

Treatment suggestedf

Treath

 with oral agentsg

, not PEG IFN; refer for liver transplantation

Observe; refer for liver transplantation

a

Based on practice guidelines of the American Association for the Study of Liver Diseases (AASLD). Except as indicated in footnotes, these guidelines are similar to those

issued by the European Association for the Study of the Liver (EASL). b

Liver disease tends to be mild or inactive clinically; most such patients do not undergo liver biopsy. c

This pattern is common during early decades of life in Asian patients infected at birth. d

According to the EASL guidelines, treat if HBV DNA is >2 × 103

 IU/mL and ALT >ULN. e

One of the potent oral drugs with a high barrier to resistance (entecavir or tenofovir) or PEG IFN can be used as first-line therapy (see text). These oral agents, but not

PEG IFN, should be used for interferon-refractory/intolerant and immunocompromised patients. PEG IFN is administered weekly by subcutaneous injection for a year; the oral

agents are administered daily for at least a year and continued indefinitely or until at least 6 months after HBeAg seroconversion. f

According to EASL guidelines, patients

with compensated cirrhosis and detectable HBV DNA at any level, even with normal ALT, are candidates for therapy. Most authorities would treat indefinitely, even in HBeAgpositive disease after HBeAg seroconversion. g

Because the emergence of resistance can lead to loss of antiviral benefit and further deterioration in decompensated cirrhosis,

a low-resistance regimen is recommended—entecavir or tenofovir monotherapy or combination therapy with the more resistance-prone lamivudine (or telbivudine) plus

adefovir. Therapy should be instituted urgently. h

Because HBeAg seroconversion is not an option, the goal of therapy is to suppress HBV DNA and maintain a normal ALT.

PEG IFN is administered by subcutaneous injection weekly for a year; caution is warranted in relying on a 6-month posttreatment interval to define a sustained response,

because the majority of such responses are lost thereafter. Oral agents, entecavir or tenofovir, are administered daily, usually indefinitely or until, as very rarely occurs,

virologic and biochemical responses are accompanied by HBsAg seroconversion. i

For older patients and those with advanced fibrosis, consider lowering the HBV DNA

threshold to >2 × 103

 IU/mL.

Abbreviations: ALT, alanine aminotransferase; HBeAg, hepatitis B e antigen; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; PEG IFN, pegylated interferon; ULN,

upper limit of normal.

an appealing combination therapy for hepatitis B, especially for

lamivudine-resistant disease; however, neither emtricitabine nor

the combination is approved for hepatitis B. Several initially promising antiviral agents have been abandoned because of toxicity (e.g.,

clevudine, which was linked to myopathy during its clinical development). The current generation of oral antivirals have been very

successful in the management of chronic hepatitis B; however, most

patients require long-duration, usually indefinite, therapy. Ideally,

an approach to achieving “cure” (eradication of HBV infection)

with finite-duration therapy would be welcome. Currently, innovative approaches being investigated focus on viral-targeting strategies or immunomodulatory strategies. The direct viral approaches

include viral entry inhibitors, nucleocapsid assembly inhibitors,

HBV secretion (HBsAg release) inhibitors, covalently closed circular

(ccc) DNA silencing/inhibition/cleavage, RNA interference, HBx

inhibitors, and CRISPR/Cas9 gene editing. Immunomodulators

being studied have included Toll receptor agonists, T-cell vaccines,

programmed cell death 1 (PD-1) blockade, reconstitution of innate

and adaptive immune responses, and HBV mRNA recognition and

activation of innate immune signaling by retinoic acid–inducible

gene-I (RIG-I). While data supporting several of these unconventional approaches have begun to appear, some have been abandoned

for lack of efficacy or for toxicity (e.g., RIG-I and some of the capsid

inhibitors). Even after almost a decade of early clinical trials, none

has been shown to “cure” hepatitis B, and none is likely to be competitive, unless it can be shown to go beyond current antivirals in

achieving recovery (HBsAg seroconversion) from HBV infection.

TREATMENT RECOMMENDATIONS

Several learned societies and groups of expert physicians have issued

treatment recommendations for patients with chronic hepatitis B;

the most authoritative and updated are those of the AASLD and the

EASL. Although the recommendations differ slightly, a consensus

has emerged on most of the important points (Table 341-4). No

treatment is recommended or available for inactive “nonreplicative”

hepatitis B carriers (undetectable HBeAg with normal ALT and

HBV DNA ≤103

 IU/mL documented serially over time). In patients

with detectable HBeAg and HBV DNA levels >2 × 104

 IU/mL, treatment is recommended by the AASLD for those with ALT levels >2×

the upper limit of normal. (The EASL recommends treatment in

HBeAg-positive patients for HBV DNA levels >2 × 103

 IU/mL and

ALT above the upper limit of normal.) For HBeAg-positive patients

with ALT ≤2× the upper limit of normal, in whom sustained

responses are not likely and who would require multiyear therapy,

antiviral therapy is not recommended currently. This pattern is

common during the early decades of life among Asian patients

infected at birth; even in this group, therapy would be considered

for those >40 years of age, patients with extrahepatic manifestations

of HBV infection, patients with a family history of cirrhosis or

HCC, if the liver biopsy or noninvasive testing shows moderate to

severe necroinflammatory activity or fibrosis, or if the patient has a

history of previous treatment. In this group, when, eventually, ALT

becomes elevated later in life, antiviral therapy should be instituted.

For patients with HBeAg-negative chronic hepatitis B, ALT >2×

the upper limit of normal (above the upper limit of normal according to EASL), and HBV DNA >2 × 103

 IU/mL, antiviral therapy

is recommended. If HBV DNA is >2 × 103

 IU/mL and ALT is 1

to >2× the upper limit of normal, the same considerations apply

as for HBeAg-positive patients with borderline ALT levels—for

those >40 years of age, patients with extrahepatic manifestations

of HBV infection, patients with a family history of cirrhosis or

HCC, if the liver biopsy or noninvasive testing shows moderate to

severe necroinflammatory activity or fibrosis, or if the patient has

a history of previous treatment (treatment in this subset would be

2601Chronic Hepatitis CHAPTER 341

recommended according to EASL guidelines, because ALT is elevated). Per current AASLD recommendations, antiviral treatment

with oral agents can be stopped after HBeAg seroconversion in

noncirrhotics, and the suggested period of consolidation therapy is

12 months with close monitoring for recurrent viremia (monthly × 6,

then every 3 months for the rest of a year) after cessation of therapy.

For patients with HBeAg-negative chronic hepatitis, the current

recommendation with oral agents is for indefinite therapy; stopping

therapy in this group can be considered after HBsAg loss.

The potential for stopping antiviral therapy in noncirrhotic

HBeAg-negative patients after protracted (≥2–5 years) antiviral

therapy has been the subject of several studies. After such prolonged courses of entecavir or tenofovir, in one study (DARING-B),

18-month virologic relapse rates (HBV DNA >2000 IU/mL) in

57 patients were high (in 72%), but only 26% met study criteria for

resumption of therapy (ALT >10× upper limit of normal, ALT >5×

upper limit of normal with bilirubin >2 mg/mL, ALT >3× upper

limit of normal with HBV DNA >105

 IU/mL, or ALT >2× upper

limit of normal and HBV DNA >2 × 103

 IU/mL on three sequential

visits). Moreover, 25% underwent HBsAg loss. In a similar study

(FINITE), virologic relapse rates were high, but 62% did not meet

criteria for retreatment, and 19% lost HBsAg. In contrast, in a

study among Asian patients, only ~30% had sustained responses

for which resumption of therapy was not introduced, and HBsAg

responses were negligible. In other reports, including on patients

with 8 years of TDF treatment prior to stopping, only 35–60% had

sustained treatment-free outcomes, and only 5–13% lost HBsAg.

In the only randomized, controlled trial of stopping therapy versus

continuing therapy in HBeAg-negative patients after prolonged

antiviral therapy (Toronto STOP study), only 33% had sustained

responses after cessation of therapy, and HBsAg loss occurred with

equal, small frequencies in both the stop-treatment group (4%)

and the continue-treatment group (5%). Generally, then, although

HBsAg loss can be achieved in a small fraction and although a subgroup may not require reintroduction of therapy in the short run,

enthusiasm for this approach is limited, and for most HBeAg-negative patients, recommendations support indefinite treatment, unless

they experience HBsAg loss.

For patients with compensated cirrhosis, because antiviral therapy has been shown to retard clinical progression, treatment is

recommended regardless of HBeAg status and ALT as long as

HBV DNA is detectable at >2 × 103

 IU/mL (detectable at any level

according to the EASL); therapy is suggested, however, even for

those with HBV DNA <2 × 103

 IU/mL, regardless of ALT level. For

patients with decompensated cirrhosis, treatment is recommended

regardless of serologic and biochemical status, as long as HBV DNA

is detectable. Patients with decompensated cirrhosis should be

evaluated as candidates for liver transplantation. Cirrhotics should

be treated indefinitely (see considerations for stopping antiviral

therapy in noncirrhotics, above).

Among the eight available drugs for hepatitis B, PEG IFN has

supplanted standard IFN, entecavir has supplanted lamivudine, and

tenofovir has supplanted adefovir. PEG IFN, entecavir, or tenofovir

(TDF or TAF) is recommended as first-line therapy (Table 341-3).

PEG IFN requires finite-duration therapy, achieves the highest rate

of HBeAg responses after a year of therapy, and does not support

viral mutations, but it requires subcutaneous injections and is associated with inconvenience, more intensive clinical and laboratory

monitoring, and intolerability. Oral nucleoside analogues require

long-term therapy in most patients, and when used alone, lamivudine and telbivudine foster the emergence of viral mutations,

adefovir somewhat less so, and entecavir (except in lamivudineexperienced patients) and tenofovir rarely at all. Oral agents do not

require injections or cumbersome laboratory monitoring, are very

well tolerated, lead to improved histology in 50−90% of patients,

suppress HBV DNA more profoundly than PEG IFN, and are

effective even in patients who fail to respond to IFN-based therapy.

Although oral agents are less likely to result in HBeAg responses

during the first year of therapy, as compared to PEG IFN, treatment

with oral agents is usually extended beyond the first year and, by the

end of the second year (of the current generation of potent agents

entecavir and tenofovir), yields HBeAg responses (and even HBsAg

responses) comparable in frequency to those achieved after 1 year

of PEG IFN (and without the associated side effects) (Table 341-5).

In a 2016 systematic review of 1716 patients involved in 25 clinical

trials, responses after oral-agent therapy were found to be durable.

Among patients with HBeAg-reactive chronic hepatitis B, the

pooled rates of durable HBeAg seroconversions maintained after

cessation of nucleoside/nucleotide analogue therapy (including all

the oral agents) were 92% and 88% at posttreatment months 12 and

24, respectively, unaffected by the duration of post-HBeAg-response

consolidation therapy (>6 months in all studies evaluated); the

pooled rate of durable biochemical remission after therapy in this

population was 76%. Even for HBeAg-negative chronic hepatitis B,

for which most authorities recommend indefinite therapy, pooled

rates of virologic remissions maintained after cessation of oralagent therapy were 44%, 31%, and 30% at posttreatment months 12,

24, and 36, and the pooled rate of durable biochemical remission in

this population was 57%.

Although adefovir and tenofovir (TDF) are safe, renal monitoring (e.g., serum creatinine and phosphate, urine glucose and

protein) is recommended (not for TAF). Substantial experience

with lamivudine during pregnancy (see above) has identified no

teratogenicity; although widely used during pregnancy, lamivudine

remains classified as pregnancy category C. Although IFNs do not

TABLE 341-5 Pegylated Interferon Versus Oral Nucleoside Analogues

for the Treatment of Chronic Hepatitis B

PEG IFN

NUCLEOSIDE

ANALOGUES

Administration Weekly injection Daily, orally

Tolerability Poorly tolerated,

intensive monitoring

Well tolerated, limited

monitoring

Duration of therapy Finite 48 weeks ≥1 year, indefinite in most

patients

Maximum mean HBV DNA

suppression

4.5 log10 6.9 log10

Effective in high-level HBV

DNA (≥109

 IU/mL)

No Yes

HBeAg seroconversion

During 1 year of therapy

During >1 year of therapy

~30%

Not applicable

~20%

30% (year 2) to up to 50%

(year 5)

HBeAg-negative

posttreatment HBV DNA

suppression

17% at 5 years 7% at 4 years

(lamivudine)

HBsAg loss

During 1 year of therapy

During >1 year of therapy

 After 1 year of

therapy–HBeAg-negative

3–4%

Not applicable

12% at 5 years

0–3%

3–8% at 5 years of

therapy

3.5% at 5 years

Antiviral resistance None Lamivudine: ~30% year 1,

~70% year 5

Adefovir: 0% year 1,

~30% year 5

Telbivudine: up to 4%

year 1, 22% year 2

Entecavir: ≤1.2% through

year 6

Tenofovir: 0% through

year 8

Use in cirrhosis,

transplantation,

immunosuppressed

No Yes

Cost, 1 year of therapy ++++ + to ++

Abbreviations: HBV, hepatitis B virus; HBeAg, hepatitis B e antigen; HBsAg,

hepatitis B surface antigen; PEG IFN, pegylated interferon.

2602 PART 10 Disorders of the Gastrointestinal System

appear to cause congenital anomalies, these have antiproliferative

properties and should be avoided during pregnancy. Adefovir during pregnancy has not been associated with birth defects; however,

the risk of spontaneous abortion may be increased, and adefovir is

categorized as pregnancy category C. Data on the safety of entecavir

during pregnancy have not been published (pregnancy category C).

Sufficient data in animals and limited data in humans suggest that

telbivudine and tenofovir (both pregnancy category B) can be used

safely during pregnancy; however, telbivudine is not an acceptable

first-line drug. In general, then, except for lamivudine and tenofovir, and until additional data become available, the other antivirals

for hepatitis B should be avoided or used with extreme caution during pregnancy. Tenofovir is the current drug of choice in pregnancy.

For children aged 2 to <18 years old with HBeAg-reactive

hepatitis B (most children will be HBeAg-reactive; no studies have

been done in children with HBeAg-negative chronic hepatitis B),

treatment is recommended if HBV DNA is detectable and ALT

levels are elevated, but not if ALT levels are normal. Each of the

available drugs, except telbivudine, is approved for different childhood age groups (standard IFN α2b age ≥1 year; PEG IFN α2a

age ≥5 years [approved for hepatitis C, not B, but can be used in

hepatitis B]; lamivudine and entecavir age ≥2 years; adefovir and

tenofovir age ≥12 years). Package inserts should be consulted for

childhood doses.

As noted above, some physicians prefer to begin with PEG IFN,

while other physicians and patients prefer oral agents as first-line

therapy. For patients with decompensated cirrhosis, the emergence

of resistance can result in further deterioration and loss of antiviral

effectiveness. Therefore, in this patient subset, therapy with a very

favorable resistance profile (e.g., entecavir or tenofovir) should be

used. PEG IFN should not be used in patients with compensated or

decompensated cirrhosis.

Several observational studies have suggested that TDF is superior to entecavir in reducing the risk of HCC. Such studies, however,

sophisticated statistical analyses notwithstanding, are subject to

confounding influences that could favor TDF; in addition, while

several studies confirm a differential effect of TDF on long-term

HCC risk, many others do not. Therefore, currently, the preponderance of data is insufficient to support this benefit of TDF over

entecavir.

For patients with end-stage chronic hepatitis B who undergo

liver transplantation, reinfection of the new liver is almost universal

in the absence of antiviral therapy. The majority of patients become

high-level viremic carriers with minimal liver injury. Before the

availability of antiviral therapy, an unpredictable proportion

experienced severe hepatitis B−related liver injury, sometimes a

fulminant-like hepatitis and sometimes a rapid recapitulation of

the original severe chronic hepatitis B (Chap. 339). Currently,

however, prevention of recurrent hepatitis B after liver transplantation has been achieved definitively by combining short-term

(5–7 days) intravenous hepatitis B immune globulin (HBIG) with

lifelong low-resistance oral entecavir or TDF or TAF (Chap. 345);

in some patients, especially those with a low risk for recurrence,

the newer, more potent, and less resistance-prone oral agents

may be used instead of HBIG for posttransplantation therapy. For

patients at high risk for recurrence and progressive disease (e.g.,

patients with HDV-HBV or HIV-HBV co-infection as well as

for nonadherent patients, lifelong combination HBIG-oral agent

therapy should be considered. For patients receiving livers from

anti-HBc-positive donors, lifelong oral-agent therapy is recommended (without HBIG).

Patients with HBV-HIV co-infection can have progressive

HBV-associated liver disease and, occasionally, a severe exacerbation of hepatitis B resulting from immunologic reconstitution following ART. Lamivudine should never be used as monotherapy in

patients with HBV-HIV infection because HIV resistance emerges

rapidly to both viruses. Adefovir was used successfully in the past to

treat chronic hepatitis B in HBV-HIV co-infected patients but is no

longer considered a first-line agent for HBV. Entecavir has low-level

activity against HIV and can result in selection of HIV resistance;

therefore, it is not preferable in HBV-HIV co-infection. Tenofovir

and the combination of tenofovir and emtricitabine in one pill are

approved therapies for HIV and represent excellent choices for

treating HBV infection in HBV-HIV co-infected patients. Generally, even for HBV-HIV co-infected patients who do not yet meet

treatment criteria for HIV infection, treating for both HBV and

HIV is recommended. In HIV-HBV co-infection, TAF is preferable

to TDF because of its better safety profile.

Patients with chronic hepatitis B who undergo cytotoxic chemotherapy for treatment of malignancies as well as patients treated

with immunosuppressive, anticytokine, or anti–tumor necrosis

factor (TNF) therapies (the risk varies, from highest [e.g., B cell–

depleting agents, anthracycline derivatives, moderate-/high-dose

corticosteroids for ≥4 weeks] to moderate [e.g., TNF-α inhibitors,

cytokine or integrin inhibitors, tyrosine kinase inhibitors, low-dose

corticosteroids for ≥4 weeks] to lowest [e.g., immunosuppressive

agents like methotrexate and azathioprine, intraarticular corticosteroids, any dose of corticosteroids for ≤1 week]) experience

enhanced HBV replication and viral expression on hepatocyte

membranes during chemotherapy coupled with suppression of cellular immunity. When chemotherapy is withdrawn, such patients

are at risk for reactivation of hepatitis B, often severe and occasionally fatal. Such rebound reactivation represents restoration of

cytolytic T-cell function against a target organ enriched in HBV

expression. Preemptive treatment with the first of the oral HBV

antivirals, lamivudine, prior to the initiation of chemotherapy was

shown to reduce the risk of such reactivation substantially; treating

after reactivation has occurred is less effective. The newer, more

potent oral antiviral agents, entecavir and tenofovir, which are even

more effective in preventing hepatitis B reactivation and with a

lower risk of antiviral drug resistance, are preferred. The optimal

duration of antiviral therapy after completion of chemotherapy is

not known, but a suggested approach is 6 months (12 months for

B cell–depleting agents) for inactive hepatitis B carriers and longerduration therapy in patients with baseline HBV DNA levels >2 ×

103

 IU/mL, until standard clinical endpoints are met (Table 341-4).

Such chemotherapy-associated reactivation of hepatitis B is common (4–68%, median 25%, in a meta-analysis) in persons with

ongoing HBV infection (HBsAg-reactive); however, such reactivation can occur, albeit less commonly, in persons who have cleared

HBsAg but express anti-HBc (moderate risk, <10%) and rarely

(<5%) even in persons with serologic evidence of recovery from

HBV infection (anti-HBs-reactive, anti-HBc-reactive). Therefore,

most authorities (e.g., Centers for Disease Control and Prevention;

AASLD; American Gastroenterological Association; EASL) recommend HBsAg and anti-HBc (± anti-HBs) screening of all patients

undergoing such chemotherapy and preemptive antiviral prophylaxis for HBsAg-reactive persons and anti-HBc-reactive persons

treated with the most potent immunomodulatory agents (especially

B cell–depleting agents like rituximab) and close on-therapy monitoring of other anti-HBc-reactive/anti-HBs-reactive persons with

treatment if and when reactivation occurs.

CHRONIC HEPATITIS D (DELTA HEPATITIS)

Chronic hepatitis D virus (HDV) may follow acute co-infection

with HBV but at a rate no higher than the rate of chronicity of acute

hepatitis B. That is, although HDV co-infection can increase the

severity of acute hepatitis B, HDV does not increase the likelihood

of progression to chronic hepatitis B. When, however, HDV superinfection occurs in a person who is already chronically infected

with HBV, long-term HDV infection is the rule, and a worsening

of the liver disease is the expected consequence. Except for severity,

chronic hepatitis B plus D has similar clinical and laboratory features to those seen in chronic hepatitis B alone. Relatively severe

and progressive chronic hepatitis, with or without cirrhosis, is the

rule, and mild chronic hepatitis is the exception. Occasionally,

however, mild hepatitis or even, rarely, inactive carriage occurs

in patients with chronic hepatitis B plus D, and the disease may

2603Chronic Hepatitis CHAPTER 341

become indolent after several years of infection. A distinguishing serologic feature of chronic hepatitis D is the presence in the

circulation of antibodies to liver-kidney microsomes (anti-LKM);

however, the anti-LKM seen in hepatitis D, anti-LKM3, are directed

against uridine diphosphate glucuronosyltransferase and are distinct from anti-LKM1 seen in patients with autoimmune hepatitis

and in a subset of patients with chronic hepatitis C (see below). The

clinical and laboratory features of chronic HDV infection are

summarized in Chap. 339.

TREATMENT

Chronic Hepatitis D

Management is not well defined, and the host cellular RNA polymerase upon which HDV replication depends cannot be targeted

by conventional antiviral agents. Glucocorticoids are ineffective and

are not used. Preliminary experimental trials of IFN-α suggested

that conventional doses and durations of therapy lower levels of

HDV RNA and aminotransferase activity only transiently during

treatment but have no impact on the natural history of the disease.

In contrast, high-dose IFN-α (9 million units three times a week)

for 12 months was reported to be associated with a sustained loss of

HDV replication and clinical improvement in up to 50% of patients.

Moreover, in anecdotal reports, the beneficial impact of treatment

has been observed to persist for 15 years and to be associated with

a reduction in grade of hepatic necrosis and inflammation, reversion of advanced fibrosis (improved stage), and clearance of HDV

RNA in some patients. A suggested approach to therapy has been

high-dose, long-term IFN for at least a year and, in responders,

extension of therapy until HDV RNA and HBsAg clearance; however, extension of therapy to a second year provided no advantage,

and sustained responses after completion of therapy have been rare.

While standard IFN-α is the only approved drug for hepatitis D,

PEG IFN has been shown to be more effective but still of limited

therapeutic value; after 48 weeks of therapy, durable undetectable

HDV RNA for 24 posttreatment weeks has been reported in a quarter to just over a half of patients. Disappointingly, loss of virologic

responses (reappearance of HDV RNA) was observed during longterm (median 4.5 years) monitoring in a majority of 24-week-posttreatment responders, with durable HDV RNA suppression to

undetectable in only 12%. Even extending PEG IFN therapy for

5 years and driving treatment doses up to 270 μg weekly (of PEG

IFN-α2a), as reported in a small trial among 13 patients, while

achieving serologic, virologic, histologic, biochemical, and clinical

improvement, yielded sustained virologic responses (SVRs) in only

3 patients (58–246 weeks of posttreatment observation). None of

the nucleoside analogue antiviral agents for hepatitis B is effective

in hepatitis D, and adding oral nucleoside agents to PEG IFN is no

more effective than PEG IFN monotherapy. While recommended,

12 months of PEG IFN therapy is far from satisfactory.

Preliminary trials have been performed with an oral prenylation

inhibitor, lonafarnib, and with an inhibitor of HBV/HDV viral

entry into hepatocytes, myrcludex B. Prenylation, the posttranslational covalent addition of the prenyl lipid farnesyl to large HDV

antigen, is required for this HDV protein to interact and form

secreted viral particles with HBsAg. In 14 patients treated twice

daily for 28 days with 100 or 200 mg of lonafarnib, HDV RNA

fell by 0.73 log10 IU/mL and 1.54 log10 IU/mL, respectively, before

rebounding after completion of therapy. HBV entry into hepatocytes requires the binding of the myristolated N-terminal pre-S1

peptide of large HBsAg to sodium taurocholate co-transporting

peptide, the functional receptor for HBV into hepatocytes. The

application of myrcludex B, a synthetic homologous myristolated

lipopeptide that competes for binding with HBsAg, was reported

in a study of 24 patients (with a baseline mean of 4.1–4.2 log10

copies/mL of HDV RNA) randomized to 24 weeks of treatment

with myrcludex B (2 mg daily subcutaneously) as monotherapy or

combined with PEG IFN compared to PEG IFN alone. A reduction

in HDV RNA occurred in all three groups, by 1.67 log10 copies/

mL (in two of eight patients RNA became undetectable), 2.59 log10

copies/mL (in five of eight patients RNA became undetectable), and

2.17 log10 copies/mL (in two of eight patients RNA became undetectable), respectively. No change occurred, however, in the level of

HBsAg, which would have been expected. In these two exploratory

brief-duration trials, sustained responses were not achieved, and

toxicities were encountered (e.g., intermittent vomiting and weight

loss [lonafarnib] and transient amylase and lipase elevations

[myrcludex B]); however, from these proof-of-principle trials,

more definitive and larger-scale studies of efficacy are awaited.

Additional experimental approaches to the treatment of hepatitis D include nucleic acid polymer therapy to inhibit HBsAg

release, administered alone or with PEG IFN and/or nucleoside

analogues; so far, these studies have been done in one Eastern

European site, have yielded some promising reductions in HDV

RNA and HBsAg, but have been plagued by adverse effects, including marked ALT elevations. PEG IFN lambda has also been studied

in small numbers of patients with hepatitis D; both IFN-associated

side effects and elevations of aminotransferase and bilirubin levels accompanied modest on-treatment reductions in HDV RNA.

Follow-up studies in larger numbers of patients have been frustratingly slow to materialize.

In patients with end-stage liver disease secondary to chronic

hepatitis D, liver transplantation has been effective. If hepatitis D

recurs in the new liver without the expression of hepatitis B

(an unusual serologic profile in immunocompetent persons but

common in transplant patients), liver injury is limited. In fact,

the outcome of transplantation for chronic hepatitis D is superior to that for chronic hepatitis B; in such patients, combination

HBIG and nucleoside analogue therapy for hepatitis B is indicated

(Chap. 345).

■ CHRONIC HEPATITIS C

Regardless of the epidemiologic mode of acquisition of hepatitis C

virus (HCV) infection, chronic hepatitis follows acute hepatitis C in

50−70% of cases; chronic infection is common even in those with

a return to normal in aminotransferase levels after acute hepatitis

C, adding up to an 85% likelihood of chronic HCV infection after

acute hepatitis C. Few clues had emerged to explain host differences

associated with chronic infection until recently, when variation in a

single nucleotide polymorphism (SNP) on chromosome 19, IL28B

(which codes for IFN-λ3, now renamed IFNL3), was identified that

distinguished between responders and nonresponders to IFN-based

antiviral therapy (see below). The same variants correlated with

spontaneous resolution after acute infection: 53% in genotype C/C,

30% in genotype C/T, but only 23% in genotype T/T. The association

with HCV clearance after acute infection is even stronger when IL28B

(IFNL3) haplotype is combined with haplotype G/G of a SNP near

human leukocyte antigen (HLA) class II DBQ1*

03:01.

In patients with chronic hepatitis C followed for 20 years, progression to cirrhosis occurs in ~20−25%. Such is the case even for patients

with relatively clinically mild chronic hepatitis, including those without

symptoms, with only modest elevations of aminotransferase activity,

and with mild chronic hepatitis on liver biopsy. Even in cohorts of

well-compensated patients with chronic hepatitis C referred for clinical research trials (no complications of chronic liver disease and with

normal hepatic synthetic function), the prevalence of cirrhosis may

be as high as 50%. Most cases of hepatitis C are identified initially in

asymptomatic patients who have no history of acute hepatitis C (e.g.,

those discovered while attempting to donate blood, while undergoing

lab testing as part of an application for life insurance, or as a result

of routine laboratory tests). The source of HCV infection in many

of these cases is not defined, although a long-forgotten percutaneous

exposure (e.g., injection drug use) in the remote past can be elicited

in a substantial proportion and probably accounts for most infections;

most of these infections were acquired in the 1960s and 1970s among

persons in the 1945–1965 birth cohort (Chap. 339), coming to clinical

attention decades later.

2604 PART 10 Disorders of the Gastrointestinal System

Approximately one-third of patients with chronic hepatitis C have

normal or near-normal aminotransferase activity; although one-third to

one-half of these patients have chronic hepatitis on liver biopsy, the grade

of liver injury and stage of fibrosis tend to be mild in the vast majority.

In some cases, more severe liver injury has been reported—even, rarely,

cirrhosis, most likely the result of previous histologic activity. Among

patients with persistent normal aminotransferase activity sustained over

≥5−10 years, histologic progression has been shown to be rare; however,

approximately one-fourth of patients with normal aminotransferase

activity experience subsequent aminotransferase elevations, and histologic injury can be progressive once abnormal biochemical activity

resumes. Therefore, continued clinical monitoring and antiviral therapy

are indicated, even for patients with normal aminotransferase activity.

Despite this substantial rate of progression of chronic hepatitis C and

even though liver failure can result from end-stage chronic hepatitis C,

the long-term prognosis over 1–2 decades for chronic hepatitis C in

most patients is relatively benign. Mortality over 10−20 years among

patients with transfusion-associated chronic hepatitis C has been shown

not to differ from mortality in a matched population of transfused

patients in whom hepatitis C did not develop. Although death in the

hepatitis group is more likely to result from liver failure and although

hepatic decompensation may occur in ~15% of such patients over the

course of a decade, the majority (almost 60%) of patients remain asymptomatic and well compensated, with no clinical sequelae of chronic liver

disease. Overall, chronic hepatitis C tends to be very slowly and insidiously progressive, if at all, in most patients, whereas in approximately

one-fourth of cases, chronic hepatitis C will progress eventually to

end-stage cirrhosis. In fact, because HCV infection is so prevalent, and

because a proportion of patients progress inexorably to end-stage liver

disease, hepatitis C was the most frequent indication for liver transplantation (Chap. 345) in the era prior to the availability of direct-acting antiviral (DAA) therapy (see below). In the United States, hepatitis C accounts

for up to 40% of all chronic liver disease; as of 2007, mortality caused by

hepatitis C surpassed that associated with HIV/AIDS, and as of 2012,

reported deaths caused by hepatitis C surpassed those associated with

all other notifiable infectious diseases (HIV, tuberculosis, hepatitis B,

and 57 other infectious diseases). Moreover, because the prevalence of

HCV infection is so much higher in the “baby boomer” cohort born

between 1945 and 1965, three-quarters of the mortality associated

with hepatitis C occurs in this age cohort. Referral bias may account

for the more severe outcomes described in cohorts of patients reported

from tertiary care centers (20-year progression of ≥20%) versus the

more benign outcomes in cohorts of patients monitored from initial

blood-product-associated acute hepatitis or identified in community

settings (20-year progression of only 4−7%). Still unexplained, however, are the wide ranges in reported progression to cirrhosis, from 2%

over 17 years (eventually 19% over 36 years) in a population of Irish

women with hepatitis C infection acquired from contaminated anti-D

immune globulin to 30% over ≤11 years in recipients of contaminated

intravenous immune globulin.

Progression of liver disease in patients with chronic hepatitis C has

been reported to be more likely in patients with older age, longer duration of infection, advanced histologic stage and grade, more complex

HCV quasispecies diversity, increased hepatic iron, concomitant other

liver disorders (alcoholic liver disease, chronic hepatitis B, hemochromatosis, α1

 antitrypsin deficiency, and steatohepatitis), HIV infection,

and obesity. Among these variables, however, duration of infection

appears to be one of the most important, and some of the others probably reflect disease duration to some extent (e.g., quasispecies diversity, hepatic iron accumulation). No other epidemiologic or clinical

features of chronic hepatitis C (e.g., severity of acute hepatitis, level of

aminotransferase activity, level of HCV RNA, presence or absence of

jaundice during acute hepatitis) are predictive of eventual outcome.

Despite the relatively benign nature of chronic hepatitis C over time

in many patients, cirrhosis following chronic hepatitis C has been

associated with the late development, after several decades, of HCC

(Chap. 82); the annual rate of HCC in cirrhotic patients with hepatitis

C is 1−4%, occurring primarily in patients who have had HCV infection for 30 years or more.

Perhaps the best prognostic indicator in chronic hepatitis C is liver

histology; the rate of hepatic fibrosis may be slow, moderate, or rapid.

Patients with mild necrosis and inflammation as well as those with

limited fibrosis have an excellent prognosis and limited progression to

cirrhosis. In contrast, among patients with moderate to severe necroinflammatory activity or fibrosis, including septal or bridging fibrosis,

progression to cirrhosis is highly likely over the course of 10−20 years.

The pace of fibrosis progression may be accelerated by such factors

as concomitant HIV infection, other causes of liver disease, excessive

alcohol use, and hepatic steatosis. Among patients with compensated

cirrhosis associated with hepatitis C, the 10-year survival rate is close

to 80%; mortality occurs at a rate of 2−6% per year; decompensation

at a rate of 4−5% per year; and, as noted above, HCC at a rate of 1−4%

per year. Estimates of the natural history of chronic hepatitis C have

been made, based on data available on the prevalence of HCV infection in the U.S. population and on the rate of disease progression.

Weighted primarily by the concentration of chronic hepatitis C in the

baby boomer generation, the peak prevalence was estimated to have

occurred in 2015. The calculated frequency of cirrhosis in U.S. patients

with hepatitis C was 5% in 1990 and 25% in 2010 and was projected to

be 37% in 2020. Estimated peak mortality has been predicted to occur

in 2032. A discussion of the pathogenesis of liver injury in patients

with chronic hepatitis C appears in Chap. 339.

Clinical features of chronic hepatitis C are similar to those described

above for chronic hepatitis B. Generally, fatigue is the most common

symptom; jaundice is rare. Immune complex–mediated extrahepatic

complications of chronic hepatitis C are less common than in chronic

hepatitis B (despite the fact that assays for immune complexes are often

positive in patients with chronic hepatitis C), with the exception of essential mixed cryoglobulinemia (Chap. 339), which is linked to cutaneous

vasculitis and membranoproliferative glomerulonephritis as well as

lymphoproliferative disorders such as B-cell lymphoma and unexplained

monoclonal gammopathy. In addition, chronic hepatitis C has been

associated with extrahepatic complications unrelated to immune-complex injury. These include Sjögren’s syndrome, lichen planus, porphyria

cutanea tarda, renal injury, type 2 diabetes mellitus, and the metabolic

syndrome (including insulin resistance and steatohepatitis). In addition,

a link has been observed between HCV infection and cardiovascular/

cerebrovascular disease, rheumatologic/immunologic disorders, mental

health and cognitive disorders, and nonliver malignancies.

Laboratory features of chronic hepatitis C are similar to those in

patients with chronic hepatitis B, but aminotransferase levels tend to

fluctuate more (the characteristic episodic pattern of aminotransferase

activity) and to be lower, especially in patients with long-standing disease. An interesting and occasionally confusing finding in patients with

chronic hepatitis C is the presence of autoantibodies. Rarely, patients

with autoimmune hepatitis (see below) and hyperglobulinemia have

false-positive immunoassays for anti-HCV. On the other hand, some

patients with serologically confirmable chronic hepatitis C have circulating anti-LKM. These antibodies are anti-LKM1, as seen in patients

with autoimmune hepatitis type 2 (see below), and are directed against

a 33-amino-acid sequence of cytochrome P450 IID6. The occurrence

of anti-LKM1 in some patients with chronic hepatitis C may result

from the partial sequence homology between the epitope recognized

by anti-LKM1 and two segments of the HCV polyprotein. In addition, the presence of this autoantibody in some patients with chronic

hepatitis C suggests that autoimmunity may be playing a role in the

pathogenesis of chronic hepatitis C.

Histopathologic features of chronic hepatitis C, especially those that

distinguish hepatitis C from hepatitis B, are described in Chap. 339.

TREATMENT

Chronic Hepatitis C

Therapy for chronic hepatitis C has evolved substantially in the

30 years since IFN-α was introduced for this indication in 1991.

The therapeutic armamentarium grew to include PEG IFN with

ribavirin and, then, in 2011, the introduction of the first protease

2605Chronic Hepatitis CHAPTER 341

inhibitors, telaprevir and boceprevir, used in combination with

PEG IFN and ribavirin in patients with HCV genotype 1. The field

of antiviral therapy for hepatitis C was transformed beginning in

2013, with the approval of the first nucleoside analogue polymerase

inhibitor, sofosbuvir. Although several of these combination regimens have been supplanted by better, later-generation drugs, as of

2020, five all-oral, highly effective (>95%), low-resistance, pangenotypic, well-tolerated, short-duration (primarily 8–12 weeks) combination regimens of DAA drugs are recommended. The remarkable

historical evolution of antiviral therapy for hepatitis C is instructive.

THE INTERFERON ERA (1991–2011)

IFN-based therapy has been supplanted by DAA agents introduced

in the second decade of the twenty-first century; however, many

important lessons about antiviral therapy for chronic hepatitis C

were learned from the experience with IFN-based treatment, and

many of the limitations of—and disparities in responsiveness to—

IFN-based therapy have been overcome by current-generation

DAA treatments. Mechanistically, HCV proteins inhibit several

steps of the JAK-STAT signal transduction pathway, and by activation of JAK-STAT signaling, exogenous IFN culminates in and

restores intracellular expression of IFN-stimulated genes and their

protein products that have antiviral properties.

When first approved, subcutaneous IFN-α three times a week

for 6 months achieved an SVR (Fig. 341-2) (defined then as a

reduction of HCV RNA to PCR-undetectable levels ≥24 weeks after

completion of therapy) in <10%. Doubling the duration of therapy

increased the SVR rate to ~20%, and addition to the regimen of

daily ribavirin (ineffective when used alone), an oral guanosine

nucleoside, increased the SVR rate to 40% by reducing the likelihood of virologic relapse after completion of treatment (Fig. 341-2).

Although its mechanism of action remains poorly understood,

ribavirin retains a limited role in supporting DAA agents in several

subgroups of otherwise refractory patients (see below).

Treatment with the combination of PEG IFN and ribavirin

increased SVR rates to 55% overall—to >40% in genotypes 1 and 4,

requiring 48 weeks of therapy, and to >80% in genotypes 2 and 3,

requiring only 24 weeks of therapy—and histologic improvement

in approximately three-fourths of patients. After initiation of IFN

treatment, ALT levels fell precipitously, and up to 90% of virologic

responses were achieved within the first 12 weeks of therapy. Failure

to achieve an early virologic response (EVR), a ≥2-log10 reduction in

HCV RNA by week 12, predicted failure to experience a subsequent

SVR. Similarly, patients in whom HCV RNA became undetectable

within 4 weeks (i.e., who achieve a rapid virologic response [RVR])

had a very high likelihood of achieving an SVR (Fig. 341-2). Surprisingly, however, high-dose induction with IFN-based therapy

did not yield higher SVR rates.

Most relapses occurred within the first 12 weeks after treatment,

and absence of HCV RNA 12 weeks after completion of therapy has

become the current standard for SVR (SVR12); relapses are very rare

6 months to a year after SVR and almost unheard of after 2 years.

Of documented durability decades after successful therapy, an SVR

to antiviral therapy for chronic hepatitis C is tantamount to a cure

and is followed by marked improvements in liver-disease outcomes

(see below).

Patient variables that correlated with IFN-based SVRs included

favorable genotype (genotypes 2 and 3 as opposed to genotypes 1

and 4; genotype 1b as opposed to genotype 1a); low baseline HCV

RNA level (<800,000 IU/mL), low HCV quasispecies diversity,

and histologically mild hepatitis and minimal fibrosis, especially

absence of cirrhosis; immunocompetence; low liver iron levels;

age <40; female gender; and absence of obesity, insulin resistance,

type 2 diabetes mellitus, and hepatic steatosis. High levels of HCV

RNA, more histologically advanced liver disease, and high HCV

quasispecies diversity all went hand in hand with advanced duration of infection and reduced IFN responsiveness. Also associated

with poor responses to IFN-based therapy were African-American

ethnicity (contributed to, but not explained entirely by, a higher

proportion with genotype 1, slower early treatment viral kinetics,

impaired HCV-specific immunity, and host genetic differences in

IL28B [IFNL3] alleles, described below), Latino ethnicity, and poor

treatment adherence (<80% of IFN and ribavirin doses and <80% of

prescribed duration of therapy). Ironically, patients whose disease

was least likely to progress were the ones most likely to respond to

IFN and vice versa.

As described above in the discussion of spontaneous recovery

from acute hepatitis C, IFN gene variants discovered in genomewide association studies were shown to have a substantial impact on

IFN responsiveness of patients with genotype 1 to antiviral therapy.

In studies of patients treated with PEG IFN and ribavirin, variants

of the IL28B (now renamed IFNL3) SNP that code for IFN-λ3

(a type III IFN, the receptors for which are more discretely distributed than IFN-α receptors and more concentrated in hepatocytes)

correlated significantly with responsiveness. Homozygotes for the C

allele at this locus (C/C) achieved SVRs of ~80%, heterozygotes (C/T)

SVRs of ~35%, and homozygotes for the T allele (T/T) SVRs of ~25%.

Side effects of IFN therapy are described in the section on treatment of chronic hepatitis B (see above). Besides ribavirin-associated

nasal and chest congestion, pruritus, and precipitation of gout, the

most pronounced ribavirin side effect is hemolysis, often requiring

dose reduction or addition of erythropoietin therapy (not shown,

however, to increase the likelihood of an SVR); therefore, close

monitoring of blood counts is crucial, and ribavirin should be

avoided in patients with anemia, hemoglobinopathies, coronary

artery disease or cerebrovascular disease, or renal insufficiency (the

drug is excreted renally) and in pregnancy (the drug is teratogenic,

mandating contraception during, and for several months after, therapy in women of child-bearing age [because of their antiproliferative properties, IFNs also are contraindicated during pregnancy]).

Overall, combination IFN-ribavirin therapy was more difficult to

tolerate than IFN monotherapy and more likely to lead to dose

reductions and discontinuation of therapy.

Peginterferon and Ribavirin

7

6

5

4

3

2

1

0

HCV RNA log10 IU/ml

–8 –4 –2 048 12

Weeks after start of therapy

16 20 24 32 40 48 52 60 72

Undetectable

RVR EVR ETR SVR

Relapse

Partial

Null

Nonresponse

FIGURE 341-2 Classification of virologic responses based on outcomes during and

after a 48-week course of pegylated interferon (PEG IFN) plus ribavirin antiviral

therapy in patients with hepatitis C, genotype 1 or 4 (for genotype 2 or 3, the

course would be 24 weeks). Nonresponders can be classified as null responders

(hepatitis C virus [HCV] RNA reduction of <2 log10 IU/mL) or partial responders

(HCV RNA reduction ≥2 log10 IU/mL but not suppressed to undetectable) by week 24

of therapy. In responders, HCV RNA can become undetectable, as shown with

sensitive amplification assays, within 4 weeks (rapid virologic response [RVR]);

can be reduced by ≥2 log10 IU/mL within 12 weeks (early virologic response

[EVR]; if HCV RNA is undetectable at 12 weeks, the designation is “complete” EVR);

or can be undetectable at the end of therapy, 48 weeks (end-treatment response

[ETR]). In responders, if HCV RNA remains undetectable for 24 weeks after ETR, week

72, the patient has a sustained virologic response (SVR), but if HCV RNA becomes

detectable again, the patient is considered to have relapsed. The posttreatment

week-24 SVR (SVR24) has been supplanted by an SVR at week 12 (SVR12), which

has been shown to be equivalent to an SVR24. In patients treated with direct-acting

antiviral therapy, RVR and EVR milestones are largely irrelevant, being met by almost

all patients. (Reproduced with permission from Marc G. Ghany, National Institute of

Diabetes and Digestive and Kidney Diseases, National Institutes of Health and the

American Association for the Study of Liver Diseases. Hepatology 49:1335, 2009.)

2606 PART 10 Disorders of the Gastrointestinal System

Beginning in 2011, for the treatment of hepatitis C, standard

IFNs were supplanted by PEG IFNs, which have substantially longer

half-lives, permitting administration once (rather than three times)

a week. Once-a-week PEG IFN monotherapy was twice as effective as IFN monotherapy, approached the efficacy of combination

standard IFN plus ribavirin, and was as well tolerated as standard

IFNs. For most of the decade prior to 2011, when protease inhibitors were introduced for HCV genotype 1 (see below), the standard

of care was a combination of PEG IFN plus ribavirin for all HCV

genotypes.

Two PEG IFNs were available: PEG IFN-α2b, a 12-kD, linear

PEG molecule bound to IFN-α2b, and PEG IFN-α2a, a larger,

40-kD, branched PEG molecule bound to IFN-α2a; because of its

larger size and smaller volume of extravascular distribution, PEG

IFN-α2a could be given at a uniform dose independent of weight,

whereas the dose of the smaller PEG IFN-α2b, which has a much

wider volume distribution, had to be weight-based. Between the

two PEG IFNs, PEG IFN-α2a appeared to be slightly better tolerated

and slightly more effective than PEG IFN-α2b in registration trials.

The frequency of an SVR to PEG IFN–ribavirin therapy could be

increased by tailoring therapy according to baseline variables and

on-treatment virologic responsiveness. For example, in patients

with baseline variables weighing against a response (e.g., high HCV

RNA, obesity), raising the dose of PEG IFN and/or of ribavirin or

extending therapy to 72 weeks for patients with genotype 1 and a

slow virologic response, SVR rates could be improved. In contradistinction, in the ≤20% of patients with genotype 1 (and 4) who had

a 4-week RVR and low baseline HCV RNA, treatment could be

abbreviated to 24 weeks and SVR rates of ~90% achieved.

For most of the decade prior to 2011, when protease inhibitors

were introduced for HCV genotype 1 (see below), the standard of

care was a combination of PEG IFN plus ribavirin (unless ribavirin was contraindicated) for all HCV genotypes. Even after the

introduction of protease inhibitors for genotypes 1 and 4, however,

PEG IFN–ribavirin remained the standard of care for patients with

genotypes 2 and 3 until late 2013. Responsiveness to IFN-ribavirin–

based therapy was diminished in immunocompromised patients

and in patients with HIV-HCV co-infection and contraindicated

in patients with decompensated liver disease or end-stage renal

disease. The cumbersome nature of IFN-ribavirin–based therapy

(injections, complicated laboratory monitoring, side effects and

poor tolerability, modest efficacy, variables and patient subsets

associated with poor responsiveness, tailored therapy, futility rules,

etc.) was supplanted eventually (in 2016) by DAAs for all genotypes

(see below). Most of the variables associated with poor responsiveness to IFN-based therapy became irrelevant, and difficult-to-treat

patient subpopulations began to experience responses to DAAs

that were indistinguishable from responses in standard patients

(see below).

Persons with chronic HCV infection suffer increased liverrelated mortality, all-cause mortality, and multiple extrahepatic disorders (see above). On the other hand, successful antiviral therapy

of chronic hepatitis C resulting in an SVR was shown to improve

survival (and to reduce the need for liver transplantation); to lower

the risk of liver failure, liver-related death, and all-cause mortality;

to slow the progression of chronic hepatitis C; to reverse fibrosis and

even cirrhosis; and to improve such HCV-associated extrahepatic

disorders as type 2 diabetes and renal disease. Whereas the 10- and

20-year survival in the absence of an SVR is reduced in cirrhotic

patients with chronic hepatitis C, survival at these intervals after an

SVR has been found to be indistinguishable from that of the general population. In cirrhotic patients (and in those with advanced

fibrosis), although successful treatment reduces mortality and liver

failure (three- to fourfold 10-year reduction) and reduces the need

for liver transplantation and the likelihood of HCC (14-fold 10-year

reduction), the risk of liver-related death and HCC persists, albeit at

a much reduced level, necessitating continued clinical monitoring

and cancer surveillance after SVR in cirrhotics. On the other hand,

in the absence of an SVR, IFN-based therapy does not reduce the

risk of HCC. Fortunately, PEG IFN–ribavirin nonresponders can

now be retreated with DAAs and experience SVR rates comparable

to those in treatment-naïve persons (see below).

FIRST-GENERATION PROTEASE INHIBITORS (2011–2013)

The HCV RNA genome encodes a single polyprotein, which is

cleaved during and after translation by host and viral-encoded

proteases. One protease involved in the cleavage of the viral polyprotein is an NS3/4A viral protein that has serine protease activity.

Telaprevir and boceprevir are serine protease inhibitors that target

NS3/4A. In 2011, telaprevir and boceprevir used in combination

with PEG IFN and ribavirin were approved by the U.S. Food and

Drug Administration (FDA) as the first oral DAA agents for the

treatment of hepatitis C genotype 1 (not other genotypes) in adults

with stable liver disease, both in patients who had not been treated

before and in patients who had failed previous treatment. Although

now replaced by more effective, all-oral regimens, these first-inclass agents represented a breakthrough in the treatment of chronic

hepatitis C and established milestones against which subsequent

therapies could be measured.

Because resistance developed rapidly during monotherapy with

telaprevir and boceprevir, these drugs had to be used in combination with PEG IFN and ribavirin. Ribavirin in particular appeared

to reduce relapse rates significantly in protease-inhibitor-based

regimens, such that those who could not take or were intolerant

to ribavirin were unlikely to benefit from the addition of these

agents. Telaprevir and boceprevir regimens consisted of periods

of triple therapy (protease inhibitor plus PEG IFN plus ribavirin)

and periods of dual therapy (PEG IFN plus ribavirin). Telaprevir regimens began with 12 weeks of triple therapy followed by

dual therapy of a duration based on HCV RNA status at weeks 4

and 12 (“response-guided therapy”) and prior treatment status.

Boceprevir-based regimens consisted of a 4-week lead-in period of

dual (PEG IFN–ribavirin) therapy followed by triple therapy and, in

some instances, a further extension of dual therapy, with duration

of response-guided therapy based on HCV RNA status at weeks 4,

8, and 24 and prior treatment status.

For patients with HCV genotype 1, protease inhibitors improved

the frequency of RVRs and SVRs significantly as compared to PEG

IFN plus ribavirin alone. In treatment-naïve patients, telaprevir-based

SVRs were achieved in up to 79% of patients who received

12 weeks of triple therapy followed by 12–36 weeks of dual therapy,

and among those with EVRs (undetectable HCV RNA at weeks 4

and 12) and response-guided therapy stopped at week 24 (12 weeks

of triple therapy, then 12 weeks of dual therapy), SVRs occurred

in 83–92%. In studies with boceprevir in treatment-naïve patients,

SVRs occurred in 59–66% of patients, and among those with undetectable HCV RNA at 8 weeks, the SVR rate increased to 86–88%.

Adding to the complexity of treatment with these protease inhibitors were absolute stopping rules for futility, that is, absence of HCV

RNA reductions at critical treatment milestones, which were shown

to be invariably predictive of nonresponse (telaprevir: HCV RNA

>1000 IU/mL at weeks 4 or 12, or detectable at week 24; boceprevir:

HCV RNA ≥100 IU/mL at week 12, or detectable at week 24).

In patients previously treated unsuccessfully with PEG IFN plus

ribavirin, telaprevir-based treatment achieved SVRs in 83–88% of

prior relapsers, 54–59% of partial responders (HCV RNA reduced

by ≥2 log10 IU/mL but not to undetectable levels), and 29–33% of

null responders (HCV RNA reduced by <2 log10 IU/mL). With

boceprevir, a similar degradation in SVR rate occurred as a function of prior responsiveness—in 75% of prior relapsers, in 40–52%

of previous partial responders, and in ~30–40% of null responders.

In a substantial proportion of protease inhibitor nonresponders,

resistance-associated substitutions (RASs, previously referred to

as resistance-associated variants [RAVs]) could be identified, but

these variants were not archived, and wild-type HCV reemerged in

almost all cases within 1.5–2 years. SVRs to these protease inhibitors

were highest in prior relapsers and treatment-naïve patients (white

> black ethnicity), lower in prior partial responders, lower still in