2592 PART 10 Disorders of the Gastrointestinal System

designations were believed to have prognostic implications, which

were not corroborated by subsequent observations. Categorization

of chronic hepatitis based primarily on histopathologic features

has been replaced by a more informative classification based on a

combination of clinical, serologic, and histologic variables. Classification of chronic hepatitis is based on (1) its cause; (2) its histologic

activity, or grade; and (3) its degree of progression based on level of

fibrosis, or stage. Thus, neither clinical features alone nor histologic

features—requiring liver biopsy or noninvasive markers of fibrosis—

alone are sufficient to characterize and distinguish among the several

categories of chronic hepatitis.

■ CLASSIFICATION BY CAUSE

Clinical and serologic features allow the establishment of a diagnosis

of chronic viral hepatitis, caused by hepatitis B, hepatitis B plus D, or

hepatitis C; autoimmune hepatitis, including several subcategories, I

and II, based on serologic distinctions; drug-associated chronic hepatitis; and a category of unknown cause, or cryptogenic chronic hepatitis

(Table 341-1). These are addressed in more detail below.

■ CLASSIFICATION BY GRADE

Grade, a histologic assessment of necroinflammatory activity, is based on

examination of the liver biopsy. An assessment of important histologic

features includes the degree of periportal necrosis and the disruption

of the limiting plate of periportal hepatocytes by inflammatory cells

(so-called piecemeal necrosis or interface hepatitis); the degree of confluent necrosis that links or forms bridges between vascular structures—

between portal tract and portal tract or even more important bridges

between portal tract and central vein—referred to as bridging necrosis;

the degree of hepatocyte degeneration and focal necrosis within the

lobule; and the degree of portal inflammation. Several scoring systems

that take these histologic features into account have been devised, and

the most popular are the histologic activity index (HAI), used commonly in the United States, and the METAVIR score, used in Europe

(Table 341-2). Based on the presence and degree of these features of

histologic activity, chronic hepatitis can be graded as mild, moderate,

or severe.

■ CLASSIFICATION BY STAGE

The stage of chronic hepatitis, which reflects the level of progression

of the disease, is based on the degree of hepatic fibrosis. When fibrosis

is so extensive that fibrous septa surround parenchymal nodules and

alter the normal architecture of the liver lobule, the histologic lesion is

defined as cirrhosis. Staging is based on the degree of fibrosis as categorized

on a numerical scale 0−6 (HAI) or 0−4 (METAVIR) (Table 341-2). Several

TABLE 341-1 Clinical and Laboratory Features of Chronic Hepatitis

TYPE OF HEPATITIS DIAGNOSTIC TEST(S) AUTOANTIBODIES THERAPY

Chronic hepatitis B HBsAg, IgG anti-HBc, HBeAg, HBV DNA Uncommon IFN-α, PEG IFN-α

Oral agents:

First-line: entecavir, tenofovir

Second-line: lamivudine, adefovir, telbivudine

Chronic hepatitis C Anti-HCV, HCV RNA Anti-LKM1a PEG IFN-α plus ribavirinb

Direct-acting oral agents:

sofosbuvir, ledipasvir, velpatasvir

ritonavir-boosted paritaprevir, ombitasvir, dasabuvir, elbasvir,

grazoprevir, daclatasvir, simeprevir

Chronic hepatitis D Anti-HDV, HDV RNA, HBsAg, IgG anti-HBc Anti-LKM3 IFN-α, PEG IFN-αc

Autoimmune hepatitis ANAd

 (homogeneous), anti-LKM1 (±)

Hyperglobulinemia

ANA, anti-LKM1 anti-SLAe Prednisone, azathioprine

Drug-associated — Uncommon Withdraw drug

Cryptogenic All negative None Prednisone (?), azathioprine (?)

a

Antibodies to liver-kidney microsomes type 1 (autoimmune hepatitis type II and some cases of hepatitis C). b

Supplanted in almost all cases by combinations of the directacting antiviral agents listed (see www.hcvguidelines.org). c

Early clinical trials suggested benefit of IFN-α therapy; PEG IFN-α is as effective, if not more so, and has

supplanted standard IFN-α. d

Antinuclear antibody (autoimmune hepatitis type I). e

Antibodies to soluble liver antigen (autoimmune hepatitis type III).

Abbreviations: HBc, hepatitis B core; HBeAg, hepatitis B e antigen; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; HCV, hepatitis C virus; HDV, hepatitis D virus;

IFN-α, interferon α; IgG, immunoglobulin G; LKM, liver-kidney microsome; PEG IFN-α, pegylated interferon α; SLA, soluble liver antigen.

noninvasive approaches have been introduced to provide approximations of hepatic histologic stage, including serum biomarkers of

fibrosis; fibrosis scores such as FIB-4, a validated algorithm based on

such routine lab tests as aspartate and alanine aminotransferase (AST

and ALT) levels and platelet counts (PLT) (age [years] × AST/PLT ×

ALT1/2); and imaging determinations of liver elasticity.

CHRONIC VIRAL HEPATITIS

Both of the enterically transmitted forms of viral hepatitis, hepatitis A

and E, are self-limited and do not cause chronic hepatitis (rare reports

notwithstanding in which acute hepatitis A serves as a trigger for the

onset of autoimmune hepatitis in genetically susceptible patients or

in which hepatitis E [Chap. 339] can cause chronic liver disease in

immunosuppressed hosts, for example, after liver transplantation). In

contrast, the entire clinicopathologic spectrum of chronic hepatitis

occurs in patients with chronic viral hepatitis B and C as well as in

patients with chronic hepatitis D superimposed on chronic hepatitis B.

■ CHRONIC HEPATITIS B

The likelihood of chronicity after acute hepatitis B varies as a function

of age. Infection at birth is associated with clinically silent acute infection but a 90% chance of chronic infection, whereas infection in young

adulthood in immunocompetent persons is typically associated with

clinically apparent acute hepatitis but a risk of chronicity of only ~1%.

Most cases of chronic hepatitis B among adults, however, are recognized

in patients who never had a recognized episode of clinically apparent

acute viral hepatitis. The degree of liver injury (grade) in patients with

chronic hepatitis B is variable, ranging from none in inactive carriers

to mild to moderate to severe. Among adults with chronic hepatitis B,

histologic features are of prognostic importance. In one long-term

study of patients with chronic hepatitis B, investigators found a 5-year

survival rate of 97% for patients with mild chronic hepatitis, 86%

for patients with moderate to severe chronic hepatitis, and only 55%

for patients with chronic hepatitis and postnecrotic cirrhosis. The

15-year survival in these cohorts was 77%, 66%, and 40%, respectively.

On the other hand, more recent observations do not allow us to be so

sanguine about the prognosis in patients with mild chronic hepatitis;

among such patients followed for 1−13 years, progression to more

severe chronic hepatitis and cirrhosis has been observed in more than

a quarter of cases.

More important to consider than histology alone in patients with

chronic hepatitis B is the degree of hepatitis B virus (HBV) replication. As reviewed in Chap. 339, chronic HBV infection can occur in

the presence or absence of serum hepatitis B e antigen (HBeAg), and

2593Chronic Hepatitis CHAPTER 341

generally, for both HBeAg-reactive and HBeAg-negative chronic hepatitis B, the level of HBV DNA correlates with the level of liver injury

and risk of progression. In HBeAg-reactive chronic hepatitis B, two

phases have been recognized based on the relative level of HBV replication. The relatively replicative phase is characterized by the presence

in the serum of HBeAg and HBV DNA levels well in excess of 103

−104

IU/mL, sometimes exceeding 109

 IU/mL; by the presence in the liver of

detectable intrahepatocyte nucleocapsid antigens (primarily hepatitis B

core antigen [HBcAg]); by high infectivity; and by accompanying liver

injury. In contrast, the relatively nonreplicative phase is characterized

by the absence of the conventional serum marker of HBV replication

(HBeAg), the appearance of anti-HBe, levels of HBV DNA below a

threshold of ~103

 IU/mL, the absence of intrahepatocytic HBcAg,

limited infectivity, and minimal liver injury. Patients in the relatively

replicative phase tend to have more severe chronic hepatitis, whereas

those in the relatively nonreplicative phase tend to have minimal or

mild chronic hepatitis or to be inactive hepatitis B carriers. The likelihood in a patient with HBeAg-reactive chronic hepatitis B of converting spontaneously from relatively replicative to nonreplicative infection

is ~10% per year. Distinctions in HBV replication and in histologic

category, however, do not always coincide. In patients with HBeAgreactive chronic HBV infection, especially when acquired at birth or in

TABLE 341-2 Histologic Grading and Staging of Chronic Hepatitis

HISTOLOGIC ACTIVITY INDEX (HAI)a METAVIRb

HISTOLOGIC FEATURE SEVERITY SCORE SEVERITY SCORE

Necroinflammatory Activity (grade)

Periportal necrosis, including piecemeal

necrosis and/or bridging necrosis (BN)

None

Mild

Mild/moderate

Moderate

Severe

0

1

2

3

4

None

Mild

Moderate

Severe

Bridging necrosis

0

1

2

3

Yes

No

Intralobular necrosis Confluent —None

—Focal

—Zone 3 some

—Zone 3 most

—Zone 3 + BN few

—Zone 3 + BN multiple

—Panacinar/multiacinar

0

1

2

3

4

5

6

None or mild

Moderate

Severe

0

1

2

Focal —None

—≤1 focus/10× field

—2–4 foci/10× field

—5–10 foci/10× field

—>10 foci/10× field

0

1

2

3

4

Portal Inflammation None

Mild

Moderate

Moderate/marked

Marked

Total

0

1

2

3

4

0–18 A0–A3c

Fibrosis (stage)

None

Portal fibrosis—some

Portal fibrosis—most

Bridging fibrosis—few

Bridging fibrosis—many

Incomplete cirrhosis

Cirrhosis

Total

0

1

2

3

4

5

6

6

F0

F1

F1

F2

F3

F4

F4

4

a

Ishak K, Baptista A, Bianchi L, et al: Histologic grading and staging of chronic hepatitis. J Hepatol 22:696, 1995.

b

Bedossa P, Poynard T, French METAVIR Cooperative Study Group: An algorithm for grading activity in chronic

hepatitis C. Hepatology 24:289, 1996. c

Necroinflammatory grade: A0 = none; A1 = mild; A2 = moderate; A3 = severe.

early childhood, as recognized commonly

in Asian countries, a dichotomy is common between very high levels of HBV

replication during the early decades of life

(when the level of apparent host immunologic tolerance of HBV is relatively high)

and negligible levels of liver injury; during this phase of chronic hepatitis B, the

level of viral replication does not correlate

with liver injury or late complications. Yet

despite the relatively immediate, apparently benign nature of liver disease for

many decades in this population, in the

middle decades, activation of liver injury

emerges as what appears to be the relative

tolerance of the host to HBV declines, and

these patients with childhood-acquired

HBV infection are ultimately at increased

risk later in life for cirrhosis, hepatocellular carcinoma (HCC) (Chap. 82),

and liver-related death; the link between

high-level HBV replication and these late

liver complications has been demonstrated

convincingly in, and confined mostly to,

persons in their middle decades, especially

age ≥40. A discussion of the pathogenesis

of liver injury in patients with chronic

hepatitis B appears in Chap. 339.

HBeAg-negative chronic hepatitis B

(i.e., chronic HBV infection with active

virus replication and readily detectable HBV DNA but without HBeAg

[anti-HBe-reactive]) is more common

than HBeAg-reactive chronic hepatitis B

in Mediterranean and European countries and in Asia (and, correspondingly, in

HBV genotypes other than A). Compared

to patients with HBeAg-reactive chronic

hepatitis B, patients with HBeAg-negative chronic hepatitis B have HBV DNA

levels several orders of magnitude lower

(usually no more than 105

−106

 IU/mL)

than those observed in the HBeAgreactive subset. Most such cases represent

precore or core-promoter mutations

acquired late in the natural history of the

disease (mostly early-life onset; age range

40−55 years, older than that for HBeAg-reactive chronic hepatitis B);

these mutations prevent translation of HBeAg from the precore component of the HBV genome (precore mutants) or are characterized

by downregulated transcription of precore mRNA (core-promoter

mutants; Chap. 339). Although their levels of HBV DNA tend to be

lower than among patients with HBeAg-reactive chronic hepatitis B,

patients with HBeAg-negative chronic hepatitis B can have progressive liver injury (complicated by cirrhosis and HCC) and experience

episodic reactivation of liver disease reflected in fluctuating levels of

aminotransferase activity (“flares”). The biochemical and histologic

activity of HBeAg-negative disease tends to correlate closely with

levels of HBV replication, unlike the case mentioned above of Asian

patients with HBeAg-reactive chronic hepatitis B during the early

decades of their HBV infection. Worth reiterating, the level of HBV

replication is the most important risk factor for the ultimate development of cirrhosis and HCC in both HBeAg-reactive (beyond the early

decades of “relatively nonreplicative” infection) and HBeAg-negative

patients. Although levels of HBV DNA are lower and more readily

suppressed by therapy to undetectable levels in HBeAg-negative (compared to HBeAg-reactive) chronic hepatitis B, achieving sustained

responses that permit discontinuation of antiviral therapy is less likely

in HBeAg-negative patients (see below). Inactive carriers are patients

2594 PART 10 Disorders of the Gastrointestinal System

with circulating hepatitis B surface antigen (HBsAg), normal serum

aminotransferase levels, minimal or no histologic evidence of liver

injury, undetectable HBeAg, and levels of HBV DNA that are either

undetectable or present at a threshold of ≤103

 IU/mL. This serologic

profile occurs not only in inactive carriers but also in patients with

HBeAg-negative chronic hepatitis B during periods of relative inactivity; distinguishing between the two requires sequential biochemical

and virologic monitoring over many months.

The spectrum of clinical features of chronic hepatitis B is broad,

ranging from asymptomatic infection to debilitating disease or even

end-stage, fatal hepatic failure. As noted above, the onset of the disease tends to be insidious in most patients, apart from the very few in

whom chronic disease follows failure of resolution of clinically apparent acute hepatitis B. The clinical and laboratory features associated

with progression from acute to chronic hepatitis B are discussed in

Chap. 339.

Fatigue is a common symptom, and persistent or intermittent jaundice

is a common feature in severe or advanced cases. Intermittent deepening of jaundice and recurrence of malaise and anorexia, as well as

worsening fatigue, are reminiscent of acute hepatitis; such exacerbations may occur spontaneously, often coinciding with evidence of

virologic reactivation; may lead to progressive liver injury; and, when

superimposed on well-established cirrhosis, may cause hepatic decompensation. Complications of cirrhosis occur in end-stage chronic

hepatitis and include ascites, edema, bleeding gastroesophageal varices,

hepatic encephalopathy, coagulopathy, and hypersplenism. Occasionally, these complications bring the patient to initial clinical attention.

Extrahepatic complications of chronic hepatitis B, similar to those seen

during the prodromal phase of acute hepatitis B, are associated with

tissue deposition of circulating hepatitis B antigen–antibody immune

complexes. These include arthralgias and arthritis, which are common,

and the rarer purpuric cutaneous lesions (leukocytoclastic vasculitis), immune-complex glomerulonephritis, and generalized vasculitis

(polyarteritis nodosa) (Chap. 363).

Laboratory features of chronic hepatitis B do not distinguish

adequately between histologically mild and severe hepatitis.

Aminotransferase elevations tend to be modest for chronic hepatitis

B but may fluctuate in the range of 100−1000 units. As is true for

acute viral hepatitis B, ALT tends to be more elevated than AST;

however, once cirrhosis is established, AST tends to exceed ALT.

Levels of alkaline phosphatase activity tend to be normal or only

marginally elevated. In severe cases, moderate elevations in serum

bilirubin (51.3−171 μmol/L [3−10 mg/dL]) occur. Hypoalbuminemia and prolongation of the prothrombin time occur in severe or

end-stage cases. Hyperglobulinemia and detectable circulating autoantibodies are distinctly absent in chronic hepatitis B (in contrast to

autoimmune hepatitis). Viral markers of chronic HBV infection

are discussed in Chap. 339.

TREATMENT

Chronic Hepatitis B

Although progression to cirrhosis is more likely in severe than in

mild or moderate chronic hepatitis B, all forms of chronic hepatitis B

can be progressive, and progression occurs primarily in patients

with active HBV replication. Moreover, in populations of patients

with chronic hepatitis B who are at risk for HCC (Chap. 82), the

risk is highest for those with continued, high-level HBV replication and lower for persons in whom initially high-level HBV DNA

falls spontaneously over time. Therefore, management of chronic

hepatitis B is directed at suppressing the level of virus replication.

Although clinical trials tend to focus on clinical endpoints achieved

over 1−2 years (e.g., suppression of HBV DNA to undetectable

levels, loss of HBeAg/HBsAg, improvement in histology, normalization of ALT), these short-term gains translate into reductions in the risk of clinical progression, hepatic decompensation,

HCC, liver transplantation, and death; regression of cirrhosis and

of esophageal varices has been documented to follow long-term

pharmacologic suppression of HBV replication. In addition, restoration of impaired HBV-specific T-cell function has been shown

following successful suppression of HBV replication with antiviral

therapy. To date, eight drugs have been approved for treatment of

chronic hepatitis B: injectable interferon (IFN) α and pegylated

interferon (long-acting IFN bound to polyethylene glycol, PEG

[PEG IFN]) and the oral agents lamivudine, adefovir dipivoxil,

entecavir, telbivudine, tenofovir disoproxil fumarate (TDF), and

tenofovir alafenamide (TAF).

Antiviral therapy for hepatitis B has evolved rapidly since the

mid-1990s, as has the sensitivity of tests for HBV DNA. When IFN

and the first oral antiviral lamivudine were evaluated in clinical

trials, HBV DNA was measured by insensitive hybridization assays

with detection thresholds of 105

−106

 virions/mL; when subsequent

treatments were studied in clinical trials, HBV DNA was measured by sensitive amplification assays (polymerase chain reaction

[PCR]) with detection thresholds of 101

−103

 viral copies/mL or

IU/mL. Recognition of these distinctions is helpful when comparing results of clinical trials that established the efficacy of these

therapies (reviewed below in chronologic order of publication of

these efficacy trials). Of the eight approved treatments, PEG IFN,

entecavir, and the two tenofovir preparations (TDF and TAF) are

recommended as first-line agents, and generally, the oral agents are

favored over injectable PEG IFN.

INTERFERON

IFN-α was the first approved therapy (1992) for chronic hepatitis B.

Although it is no longer used to treat hepatitis B, standard IFN is

important historically, having provided important lessons about

antiviral therapy in general. For immunocompetent adults with

HBeAg-reactive chronic hepatitis B (who tend to have high-level

HBV DNA [>105

−106

 virions/mL] and histologic evidence of

chronic hepatitis on liver biopsy), a 16-week course of subcutaneous IFN, 5 million units daily or 10 million units thrice weekly,

resulted in a loss of HBeAg and hybridization-detectable HBV

DNA (i.e., a reduction to levels below 105

−106

 virions/mL) in ~30%

of patients, with a concomitant improvement in liver histology.

Seroconversion from HBeAg to anti-HBe occurred in ~20%, and, in

early trials, ~8% lost HBsAg. Successful IFN therapy and seroconversion were often accompanied by an acute hepatitis-like elevation

in aminotransferase activity, postulated to result from enhanced

cytolytic T-cell clearance of HBV-infected hepatocytes. Relapse

after successful therapy was rare (1 or 2%). Responsiveness to IFN

was higher in patients with low-level HBV DNA and substantial

ALT elevations. Therapy with IFN was not effective in immunosuppressed persons, persons with neonatal acquisition of infection and

minimal-to-mild ALT elevations, or patients with decompensated

chronic hepatitis B (in whom such therapy was actually detrimental, sometimes precipitating decompensation, often associated

with severe adverse effects). After HBeAg loss during IFN therapy,

80% experienced eventual loss of HBsAg and ALT normalization

over the ensuing decade. In addition, improved long-term and

complication-free survival as well as a reduction in the frequency

of HCC were documented among IFN responders, supporting the

conclusion that successful antiviral therapy improves the natural

history of chronic hepatitis B.

Brief-duration IFN therapy in patients with HBeAg-negative

chronic hepatitis B was disappointing, suppressing HBV replication

transiently during therapy but almost never resulting in sustained

antiviral responses; however, more protracted courses for up to 1.5

years resulted in sustained virologic/biochemical remissions documented to last for several years in ~20%.

Complications of IFN therapy include systemic “flu-like” symptoms;

marrow suppression; emotional lability (irritability, depression,

anxiety); autoimmune reactions (especially autoimmune thyroiditis);

and miscellaneous side effects such as alopecia, rashes, diarrhea,

and numbness and tingling of the extremities. With the possible

exception of autoimmune thyroiditis, all these side effects are

reversible upon dose lowering or cessation of therapy.

2595Chronic Hepatitis CHAPTER 341

Although no longer competitive with the newer generation of

antivirals, IFN did represent the first successful antiviral approach,

set a standard against which to measure efficacy of subsequent

drugs, and demonstrated the benefit of antiviral therapy on the

natural history of chronic hepatitis B. Standard IFN has been supplanted by long-acting PEG IFN (see below), and IFN nonresponders are now treated with one of the newer oral nucleoside analogues.

LAMIVUDINE

The first of the nucleoside analogues to be approved (in 1998)

for hepatitis B, the dideoxynucleoside lamivudine inhibits reverse

transcriptase activity of both HIV and HBV and is an effective

agent for chronic hepatitis B; however, it is now superseded by

newer, more potent, less resistance-prone agents. For a summary

of its virologic, serologic, biochemical, and histologic efficacy,

as well as its resistance profile, please refer to Table 341-3. In

clinical trials, lamivudine therapy at daily doses of 100 mg for

48−52 weeks suppressed HBV DNA, as measured by sensitive

PCR amplification assays, by a median of ~5.5 log10 copies/mL in

HBeAg-positive chronic hepatitis B and ~4.5 log10 copies/mL in

HBeAg-negative chronic hepatitis B (baseline HBV DNA levels

TABLE 341-3 Comparison of Pegylated Interferon (PEG IFN), Lamivudine, Adefovir, Entecavir, Telbivudine, and Tenofovir Therapy for Chronic

Hepatitis Ba

FEATURE PEG IFNb LAMIVUDINE ADEFOVIR ENTECAVIR TELBIVUDINE

TENOFOVIR

(TDF) TENOFOVIR (TAF)

Route of administration Subcutaneous

injection (180 μg/

week)

Oral

(100 mg/d)

Oral (10 mg/d) Oral (0.5 mg/d) Oral (600 mg/d) Oral (300 mg/d) Oral 25 mg/d)

Status First-line No longer

preferred

No longer

preferred

First-line No longer

preferred,

withdrawn

First-line First-line

Duration of therapyc 48–52 weeks ≥52 weeks ≥48 weeks ≥48 weeks ≥52 weeks ≥48 weeks 48 weeks

Tolerability Poorly tolerated Well tolerated Well tolerated;

creatinine

monitoring

recommended

Well tolerated Well tolerated Well tolerated;

creatinine

monitoring

recommended

Well tolerated

HBeAg seroconversion

1 yr Rx

>1 yr Rx

18–20%

NA

16–21%

up to 50% at

5 yrs

12%

43% at 3 yrsd

21%

31% at 2 yrs

44% at 6 yrs

22%

30% at 2 yrs

21%

40% at 5 yrs

10% (14% HBeAg loss)

18% at yr 2 (HBeAg

loss 22%)

Log10 HBV DNA reduction

(mean copies/mL)

HBeAg-reactive

HBeAg-negative

4.5

4.1

5.5

4.4–4.7

Median 3.5–5

Median 3.5–3.9

6.9

5.0

6.4

5.2

6.2

4.6

Not reported in clinical

trials, likely same as

TDF

HBV DNA PCR negative

(at then current PCR

sensitivitya

) at end of yr 1

HBeAg-reactive

HBeAg-negative

10–25%

63%

36–44%

60–73%

13–21%

48–77%

67% (91% at 4 yrs)

90%

60%

88%

76%

93%

64%

94%

ALT normalization at end

of yr 1

HBeAg-reactive

HBeAg-negative

39%

34–38%

41–75%

62–79%

48–61%

48–77%

68%

78%

77%

74%

68%

76%

72%

83%

HBsAg loss, yr 1

>yr 1

3–4%

12% 5 yr after

1 yr of Rx

≤1%

No data

0%

5% at yr 5

2%

6% at yr 6

<1%

No data

3%

8% at yr 5

1%

 1%

Histologic improvement

(≥2 point reduction in HAI)

at yr 1

HBeAg-reactive

HBeAg-negative

38% 6 months

after

48% 6 months

after

49–62%

61–66%

53–68%

64%

72%

70%

65%

67%

74%

72%

Not included in clinical

trials

Viral resistance None 15–30% at 1 yr

70% at 5 yrs

None at 1 yr

29% at 5 yrs

≤1% at 1 yre

1.2% at 6 yrse

Up to 5% at yr 1

Up to 22% at

yr 2

0% at yr 1

0% through yr 8

0% at yr 1

 0% through yr 2

Pregnancy category C Cf C C B B B

a

Generally, these comparisons are based on data on each drug tested individually versus placebo in registration clinical trials; with rare exception, these comparisons are

not based on head-to-head testing of these drugs. In addition, the sensitivity of HBV DNA assays increased in sensitivity over the two decades between the introduction

of the earliest and latest of these approved drugs. Therefore, relative advantages and disadvantages should be interpreted cautiously. b

Although standard interferon

α administered daily or three times a week is approved as therapy for chronic hepatitis B, it has been supplanted by PEG IFN, which is administered once a week and

is more effective. Standard interferon has no advantages over PEG IFN. c

Duration of therapy in clinical efficacy trials; use in clinical practice may vary. d

Because of a

computer-generated randomization error that resulted in misallocation of drug versus placebo during the second year of clinical trial treatment, the frequency of HBeAg

seroconversion beyond the first year is an estimate (Kaplan-Meier analysis) based on the small subset in whom adefovir was administered correctly. e

7% during a year of

therapy (43% at year 4) in lamivudine-resistant patients. f

Despite its category C designation, lamivudine has an extensive pregnancy safety record in women with HIV/AIDS.

Abbreviations: ALT, alanine aminotransferase; HAI, histologic activity index; HBeAg, hepatitis B e antigen; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; NA, not

applicable; PEG IFN, pegylated interferon; PCR, polymerase chain reaction; Rx, therapy; yr, year; TAF, tenofovir alafenamide; TDF, tenofovir disoproxil fumarate.

2596 PART 10 Disorders of the Gastrointestinal System

are lower in HBeAg-negative than in HBeAg-positive chronic

hepatitis B) and to undetectable levels in ~40% and ~70%, respectively. Lamivudine, which was shown to improve histology, retard

hepatic fibrosis, and prevent progression to cirrhosis, was effective

in patients resistant to IFN (e.g., those with high-level HBV DNA)

or who had failed prior IFN therapy. As was true for IFN therapy of

chronic hepatitis B, lamivudine-associated HBeAg seroconversion

occurred in ~20%; patients with near-normal ALT activity tended

not to experience HBeAg responses (despite suppression of HBV

DNA), while patients with ALT levels ≥5× the upper limit of normal could expect 1-year HBeAg seroconversion rates of 50−60%.

Generally, HBeAg seroconversions were confined to patients who

achieved suppression of HBV DNA to <104

 copies/mL (equivalent

to ~103

 IU/mL). Lamivudine-associated HBeAg responses were

accompanied by a delayed posttreatment HBsAg seroconversion

rate comparable to that seen after IFN. Among Western patients

who experienced HBeAg responses during a year-long course of

therapy and in whom the response was sustained for 4−6 months

after cessation of therapy, the response was durable thereafter in

the vast majority (>80%); therefore, the achievement of an HBeAg

response represented a viable stopping point in therapy. Reduced

durability, however, was reported in Asian patients; therefore, to

support the durability of HBeAg responses, a period of consolidation therapy of ≥6 months in Western patients and ≥1 year in

Asian patients was recommended after HBeAg seroconversion (see

treatment guidelines below; a full 12-month consolidation period

is recommended currently for treatment extension after oral-agentinduced HBeAg seroconversion). Close posttreatment monitoring

was recommended to identify HBV reactivation promptly and to

resume therapy. If HBeAg was unaffected by lamivudine therapy,

lamivudine was continued until an HBeAg response occurred, but

long-term therapy was required to suppress HBV replication and, in

turn, limit liver injury; HBeAg seroconversions increased to a level

of 50% after 5 years of therapy. After a cumulative course of 3 years

of lamivudine therapy, necroinflammatory activity was reduced in

the majority of patients, and even cirrhosis was shown to regress to

precirrhotic stages in as many as three-quarters of patients.

Losses of HBsAg were few during the first year of lamivudine

therapy, and this observation had been cited as an advantage of

IFN-based therapy over lamivudine therapy; however, in head-tohead comparisons between standard IFN and lamivudine monotherapy, HBsAg losses were rare in both groups. Trials in which

lamivudine and IFN were administered in combination failed to

show a benefit of combination therapy over lamivudine monotherapy for either treatment-naïve patients or prior IFN nonresponders.

Patients with HBeAg-negative chronic hepatitis B (i.e., in those

with precore and core-promoter HBV mutations and who lack

HBeAg) cannot achieve an HBeAg response to nucleoside analogue

therapy—a stopping point in HBeAg-reactive patients; almost

invariably, when therapy was discontinued, reactivation was the rule.

Therefore, these patients required long-term lamivudine therapy.

Clinical and laboratory side effects of lamivudine were negligible

and indistinguishable from those observed in placebo recipients;

however, lamivudine doses were reduced in patients with reduced

creatinine clearance. During lamivudine therapy, transient ALT

elevations, resembling those seen during IFN therapy and during spontaneous HBeAg-to-anti-HBe seroconversions, occurred

in one-fourth of patients. These ALT elevations may result from

restored cytolytic T-cell activation permitted by suppression of

HBV replication. Similar ALT elevations, however, occurred at

an identical frequency in placebo recipients; however, ALT elevations associated temporally with HBeAg seroconversion in

clinical trials were confined to lamivudine-treated patients. When

therapy was stopped after a year of therapy, two- to threefold ALT

elevations occurred in 20−30% of lamivudine-treated patients,

representing renewed liver-cell injury as HBV replication returned.

Although these posttreatment flares were almost always transient

and mild, rare severe exacerbations, especially in cirrhotic patients,

were observed, mandating close and careful clinical and virologic

monitoring after discontinuation of treatment. Many authorities

cautioned against discontinuing therapy in patients with cirrhosis,

in whom posttreatment flares could precipitate decompensation.

Long-term monotherapy with lamivudine was associated

with methionine-to-valine (M204V) or methionine-to-isoleucine

(M204I) mutations, primarily at amino acid 204 in the tyrosine-methionine-aspartate-aspartate (YMDD) motif of the C domain of

HBV DNA polymerase, analogous to mutations that occur in

HIV-infected patients treated with this drug. During a year of

therapy, YMDD mutations occurred in 15−30% of patients; the frequency increased with each year of therapy, reaching 70% at year 5.

Ultimately, patients with YMDD mutants experienced degradation

of clinical, biochemical, and histologic responses; therefore, if treatment was begun with lamivudine monotherapy, the emergence of

lamivudine resistance, reflected clinically by a breakthrough from

suppressed levels of HBV DNA and ALT, was managed by adding

another antiviral to which YMDD variants are sensitive (e.g., adefovir, tenofovir; see below).

Currently, lamivudine has been eclipsed by more potent antivirals that have superior resistance profiles (see below); it is

no longer recommended as first-line therapy. Still, as the first

successful oral antiviral agent for use in hepatitis B, lamivudine

provided proof of principle that polymerase inhibitors can achieve

virologic, serologic, biochemical, and histologic benefits, including retardation and reversal of fibrosis and even of cirrhosis. In

addition, lamivudine was shown to be effective in the treatment

of patients with decompensated hepatitis B (for whom IFN is contraindicated), in some of whom decompensation can be reversed.

Moreover, among patients with cirrhosis or advanced fibrosis,

lamivudine was shown to be effective in reducing the risk of

progression to hepatic decompensation and, based on subsequent

population studies, the risk of HCC. In the half decade following

the introduction in the United States of lamivudine therapy for

hepatitis B, referral of patients with HBV-associated end-stage liver

disease for liver transplantation fell by ~30%, supporting further

the beneficial impact of oral antiviral therapy on the natural history of chronic hepatitis B.

Because lamivudine monotherapy in persons with HIV infection can result universally in the rapid emergence of YMDD variants, testing for HIV infection was recommended for all patients

with chronic hepatitis B prior to lamivudine therapy; if HIV infection was identified, lamivudine monotherapy at the HBV daily dose

of 100 mg was contraindicated. These patients require treatment for

both HIV and HBV with an HIV drug regimen that includes or is

supplemented by at least two drugs active against HBV; antiretroviral therapy (ART) often contains two drugs with antiviral activity

against HBV (e.g., tenofovir and emtricitabine), but if lamivudine

was part of the regimen, the 300-mg daily dose was required

(Chap. 202). The safety of lamivudine during pregnancy has not

been established; however, the drug is not teratogenic in rodents

and has been used safely in pregnant women with HIV infection

and with HBV infection. As shown for subsequent nucleoside

analogues, administration of lamivudine during the last months of

pregnancy to mothers with high-level hepatitis B viremia reduced

the likelihood of perinatal transmission of hepatitis B.

ADEFOVIR DIPIVOXIL

At an oral daily dose of 10 mg, the acyclic nucleotide analogue adefovir dipivoxil, the prodrug of adefovir (approved for hepatitis B in

2002), reduces HBV DNA by ~3.5−4 log10 copies/mL, i.e., it is less

potent than lamivudine or any of the newer antiviral agents. For

a summary of its virologic, serologic, biochemical, and histologic

efficacy, as well as its resistance profile, please refer to Table 341-3.

Like IFN and lamivudine, adefovir dipivoxil is more likely to

achieve an HBeAg response in patients with high baseline ALT;

HBeAg responses to it are highly durable and can be relied upon as

a treatment stopping point, after a period of consolidation therapy;

and biochemical, serologic, and virologic outcomes improve over

time with continued therapy.

2597Chronic Hepatitis CHAPTER 341

In HBeAg-negative chronic hepatitis B, as was true for lamivudine, because HBeAg responses—a potential stopping point—

cannot be achieved, reactivation is the rule when adefovir therapy

is discontinued, and indefinite, long-term therapy is required.

Reported attempts to stop adefovir after 5 years were followed by a

period of maintained suppression of HBV DNA and ALT; however,

most such patients had persistent hepatitis B viremia, and most

HBeAg-negative patients were treated indefinitely unless HBsAg

loss, albeit very rare, was achieved.

Adefovir contains a flexible acyclic linker instead of the

L-nucleoside ring of lamivudine, avoiding steric hindrance by

mutated amino acids. In addition, the molecular structure of phosphorylated adefovir is very similar to that of its natural substrate;

therefore, mutations to adefovir would also affect binding of the

natural substrate, dATP. Thus, resistance to adefovir was much

less likely than resistance to lamivudine, and no resistance was

encountered in 1 year of clinical trial therapy. In subsequent years,

however, adefovir resistance began to emerge (asparagine to threonine at amino acid 236 [N236T] and alanine to valine or threonine

at amino acid 181 [A181V/T], primarily), occurring in 2.5% after

2 years but in 29% after 5 years of therapy (reported in

HBeAg-negative patients). The primary contribution of adefovir, its

effectiveness in lamivudine-resistant, YMDD-mutant HBV, led to

its adoption for lamivudine-resistant hepatitis B. When lamivudine

resistance occurred, adding adefovir (i.e., maintaining lamivudine

to preempt the emergence of adefovir resistance) was superior to

switching to adefovir. Almost invariably, patients with adefovir-induced HBV mutations respond to lamivudine (or newer agents,

such as entecavir, see below). When, in the past, adefovir had been

evaluated as therapy for HIV infection, doses of 60−120 mg were

required to suppress HIV, and, at these doses, the drug was nephrotoxic. Even at 30 mg/d, creatinine elevations of 44 μmol/L (0.5 mg/

dL) occurred in 10% of patients; however, at the HBV-effective dose

of 10 mg, such creatinine elevations were encountered rarely and

hardly ever before 6−8 months of therapy. Although renal tubular

injury was a rare potential side effect, and although creatinine monitoring was recommended during treatment, the therapeutic index of

adefovir dipivoxil was high, and the nephrotoxicity observed in clinical trials at higher doses was reversible. For patients with underlying renal disease, frequency of administration of adefovir had to be

reduced, and it could be given only once a week for patients undergoing hemodialysis. Adefovir was very well tolerated, and ALT elevations during and after withdrawal of therapy were similar to those

observed and described above in clinical trials of lamivudine. An

advantage of adefovir was its relatively favorable resistance profile;

however, it was not as potent as the other approved oral agents, it did

not suppress HBV DNA as rapidly or as uniformly as the others, it

was the least likely of all agents to result in HBeAg seroconversion,

and 20−50% of patients failed to suppress HBV DNA by 2 log10

(“primary nonresponders”). For these reasons, adefovir, which has

been supplanted in both treatment-naïve and lamivudine-resistant

patients by the more potent, less resistance-prone tenofovir (see

below), is no longer recommended as first-line therapy.

PEGYLATED IFN

After long-acting PEG IFN was shown to be effective in the

treatment of hepatitis C (see below), this more convenient IFN

preparation was evaluated in the treatment of chronic hepatitis B.

Once-a-week PEG IFN is more effective than the more frequently

administered, standard IFN, and several large-scale trials of PEG

IFN versus oral lamivudine were conducted in patients with chronic

hepatitis B.

In HBeAg-reactive chronic hepatitis B, two large-scale studies were

done. In one study, PEG IFN-α2b (100 μg weekly for 32 weeks, then

50 μg weekly for another 20 weeks for a total of 52 weeks) was evaluated against a comparison arm of combination PEG IFN with oral

lamivudine in 307 subjects. The other study involved PEG IFN-α2a

(180 μg weekly for 48 weeks) in 814 primarily Asian patients, threefourths of whom had ALT ≥2× the upper limit of normal, with

comparison arms of lamivudine monotherapy and combination PEG

IFN plus lamivudine. At the end of therapy (48−52 weeks) in the

PEG IFN monotherapy arms, HBeAg loss occurred in ~30%, HBeAg

seroconversion in 22−27%, undetectable HBV DNA (<400 copies/mL

by PCR) in 10−25%, and normal ALT in 34−39%, and a mean reduction in HBV DNA of 2 log10 copies/mL (PEG IFN-α2b) to 4.5 log10

copies/mL (PEG IFN-α2a) was seen. Six months after completing

PEG IFN monotherapy in these trials, HBeAg losses were present

in ~35%, HBeAg seroconversion in ~30%, undetectable HBV DNA

in 7−14%, and normal ALT in 32−41%, and the mean reduction in

HBV DNA was 2−2.4 log10 copies/mL. Although the combination of

PEG IFN and lamivudine was superior at the end of therapy in one

or more serologic, virologic, or biochemical outcomes, neither the

combination arm (in both studies) nor the lamivudine monotherapy

arm (in the PEG IFN-α2a trial) demonstrated any benefit compared

to the PEG IFN monotherapy arms 6 months after therapy. Moreover,

HBsAg seroconversion occurred in 3−7% of PEG IFN recipients

(with or without lamivudine); some of these seroconversions were

identified by the end of therapy, but many were identified during

the posttreatment follow-up period. The likelihood of HBeAg loss

in PEG IFN–treated HBeAg-reactive patients was associated with

HBV genotype A > B > C > D (shown for PEG IFN-α2b but not for

PEG IFN-α2a). PEG IFN-α2a was approved in the United States for

hepatitis B in 2005; PEG IFN-α2b, which is not approved for hepatitis B in the United States, is used in other countries.

Based on these results, some authorities concluded that PEG

IFN monotherapy should be the first-line therapy of choice in

HBeAg-reactive chronic hepatitis B; however, this conclusion has

been challenged. Although a finite, 1-year course of PEG IFN

results in a higher rate of sustained response (6 months after

treatment) than is achieved with oral nucleoside/nucleotide analogue therapy, the comparison is confounded by the fact that oral

agents are not discontinued at the end of 1 year. Instead, taken

orally and free of side effects, therapy with oral agents is extended

indefinitely or until after the occurrence of an HBeAg response.

The rate of HBeAg responses after 2 years of oral-agent nucleoside analogue therapy is at least as high as, if not higher than, that

achieved with PEG IFN after 1 year; favoring oral agents is the

absence of injections, difficult-to-tolerate side effects, and laboratory monitoring as well as lower direct and indirect medical care

costs and inconvenience. The association of HBsAg responses with

PEG IFN therapy occurs in such a small proportion of patients that

subjecting everyone to PEG IFN for the marginal gain of HBsAg

responses during or immediately after therapy in such a very small

minority is questionable. Moreover, HBsAg responses occur in a

comparable proportion of patients treated with early-generation

nucleoside/nucleotide analogues in the years after therapy, and,

with the newer, more potent nucleoside analogues, the frequency

of HBsAg loss during the first year of therapy equals that of

PEG IFN and is exceeded during year 2 and beyond (see below).

Of course, resistance is not an issue during PEG IFN therapy, but

the risk of resistance is much lower with new agents (≤1% up to

3−8 years in previously treatment-naïve, entecavir-treated patients

and 0% in tenofovir-treated patients; see below). Finally, the level of

HBV DNA inhibition that can be achieved with the newer agents,

and even with lamivudine, exceeds that achieved with PEG IFN, in

some cases by several orders of magnitude.

In HBeAg-negative chronic hepatitis B, a trial of PEG IFN-α2a

(180 μg weekly for 48 weeks vs comparison arms of lamivudine

monotherapy and of combination therapy) in 564 patients showed

that PEG IFN monotherapy resulted at the end of therapy in suppression of HBV DNA by a mean of 4.1 log10 copies/mL, undetectable HBV DNA (<400 copies/mL by PCR) in 63%, normal ALT in

38%, and loss of HBsAg in 4%. Although lamivudine monotherapy

and combination lamivudine−PEG IFN therapy were both superior

to PEG IFN at the end of therapy, no advantage of lamivudine

monotherapy or combination therapy was apparent over PEG IFN

monotherapy 6 months after therapy—suppression of HBV DNA

by a mean of 2.3 log10 copies/mL, undetectable HBV DNA in 19%,

2598 PART 10 Disorders of the Gastrointestinal System

and normal ALT in 59%. In patients involved in this trial followed

for up to 5 years, among the two-thirds followed who had been

treated initially with PEG IFN, 17% maintained HBV DNA suppression to <400 copies/mL, but ALT remained normal in only 22%;

HBsAg loss increased gradually to 12%. Among the half followed

who had been treated initially with lamivudine monotherapy, HBV

DNA remained <400 copies/mL in 7% and ALT normal in 16%;

by year 5, 3.5% had lost HBsAg. As was the case for standard IFN

therapy in HBeAg-negative patients, only a small proportion maintained responsiveness after completion of PEG IFN therapy, raising

questions about the relative value of a finite period of PEG IFN

versus a longer course with a potent, low-resistance oral nucleoside

analogue in these patients. Moreover, the value of PEG IFN for

HBeAg-negative chronic hepatitis B has not been confirmed. In the

only other controlled clinical trial of PEG IFN for HBeAg-negative

chronic hepatitis B, the hepatitis C regimen of PEG IFN plus ribavirin was compared to PEG IFN monotherapy. In this trial, HBV

DNA suppression (<400 copies/mL) occurred in only 7.5% of the

two groups combined, and no study subject lost HBsAg.

In patients treated with PEG IFN, HBeAg and HBsAg responses

have been associated with IL28B (now renamed IFN lambda-3,

IFNL3) genotype CC, the favorable genotype identified in trials of

PEG IFN for chronic hepatitis C. Also, reductions in quantitative

HBsAg levels have been shown to correlate with and to be predictive

of responsiveness to PEG IFN in chronic hepatitis B. If HBsAg levels

fail to fall within the first 12–24 weeks or to reach <20,000 IU/mL

by week 24, PEG IFN therapy is unlikely to be effective and should

be discontinued. (Similar observations of HBsAg levels in oralagent-treated patients are of interest but of limited clinical relevance,

given the very high likelihood of virologic responses during such

therapy.) While PEG IFN remains one of the recommended firstline agents for hepatitis B, subsequent-generation, injection-free,

very-well-tolerated, high-barrier-to-resistance, oral agents are used

much more widely.

ENTECAVIR

Entecavir, an oral cyclopentyl guanosine analogue polymerase

inhibitor (approved in 2005), appears to be the most potent of

the HBV antivirals and is just as well tolerated as lamivudine. In

a 709-subject clinical trial among HBeAg-reactive patients, oral

entecavir, 0.5 mg daily, was compared to lamivudine, 100 mg daily.

At 48 weeks, entecavir was superior to lamivudine in suppression

of HBV DNA (mean 6.9 vs 5.5 log10 copies/mL), percentage with

undetectable HBV DNA (<300 copies/mL by PCR; 67 vs 36%),

histologic improvement (≥2-point improvement in necroinflammatory HAI score; 72 vs 62%), and normal ALT (68 vs 60%). The

two treatments were indistinguishable in percentage with HBeAg

loss (22 vs 20%) and seroconversion (21 vs 18%). Among patients

treated with entecavir for 96 weeks, HBV DNA was undetectable

cumulatively in 80% (vs 39% for lamivudine), and HBeAg seroconversions had occurred in 31% (vs 26% for lamivudine). After

3–6 years of entecavir, HBeAg seroconversions were observed in

39–44% and HBsAg loss in 5–6%. Similarly, in a 638-subject clinical

trial among HBeAg-negative patients, at week 48, oral entecavir,

0.5 mg daily, was superior to lamivudine, 100 mg daily, in suppression of HBV DNA (mean 5.0 vs 4.5 log10 copies/mL) and in

percentage with undetectable HBV DNA (90 vs 72%), histologic

improvement (70 vs 61%), and normal ALT (78 vs 71%). No resistance mutations were encountered in previously treatment-naïve,

entecavir-treated patients during 96 weeks of therapy, and in a

cohort of subjects treated for up to 6 years, resistance emerged

in only 1.2%. Entecavir-induced HBeAg seroconversions are as

durable as those achieved with other antivirals. Its high barrier to

resistance coupled with its high potency renders entecavir a firstline drug for patients with chronic hepatitis B.

Entecavir is also effective against lamivudine-resistant HBV

infection. In a trial of 286 lamivudine-resistant patients, entecavir,

at a higher daily dose of 1 mg, was superior to lamivudine, as measured at week 48, in achieving suppression of HBV DNA (mean

5.1 vs 0.48 log10 copies/mL), undetectable HBV DNA (72 vs 19%),

normal ALT (61 vs 15%), HBeAg loss (10 vs 3%), and HBeAg seroconversion (8 vs 3%). In this population of lamivudine-experienced

patients, however, entecavir resistance emerged in 7% at 48 weeks.

Although entecavir resistance requires both a YMDD mutation

and a second mutation at one of several other sites (e.g., T184A,

S202G/I, or M250V), resistance to entecavir in lamivudine-resistant

chronic hepatitis B was reported to increase progressively to 43%

at 4 years and 57% at 6 years; therefore, entecavir is not as attractive a choice (and is not recommended, despite its approval for

this indication) as adefovir was or as tenofovir is for patients with

lamivudine-resistant hepatitis B.

In clinical trials, entecavir had an excellent safety profile. In

addition, on-treatment and posttreatment ALT flares are relatively

uncommon and relatively mild in entecavir-treated patients. Doses

should be reduced for patients with reduced creatinine clearance.

Entecavir does have low-level antiviral activity against HIV and

cannot be used as monotherapy to treat HBV infection in HIV/

HBV co-infected persons.

TELBIVUDINE

Telbivudine, a cytosine analogue (approved in 2006), is similar in

efficacy to entecavir but slightly less potent in suppressing HBV

DNA (a slightly less profound median 6.4 log10 reduction in HBeAgreactive disease and a similar 5.2 log10 reduction in HBeAg-negative

disease). In its registration trial, telbivudine at an oral daily dose

of 600 mg suppressed HBV DNA to <300 copies/mL in 60% of

HBeAg-positive and 88% of HBeAg-negative patients, reduced ALT

to normal in 77% of HBeAg-positive and 74% of HBeAg-negative

patients, and improved histology in 65% of HBeAg-positive and

67% of HBeAg-negative patients. Although resistance to telbivudine (M204I, not M204V, mutations) was less frequent than resistance to lamivudine at the end of 1 year, resistance mutations after

2 years of treatment occurred in up to 22%. Generally well tolerated,

telbivudine was associated with a low frequency of asymptomatic

creatine kinase elevations and with a very low frequency of peripheral neuropathy; frequency of administration had to be reduced for

patients with impaired creatinine clearance. Its excellent potency

notwithstanding, the inferior resistance and safety profile of telbivudine limited its appeal; telbivudine is neither recommended as

first-line therapy nor widely used.

TENOFOVIR

Tenofovir disoproxil fumarate (TDF), an acyclic nucleotide analogue and potent antiretroviral agent used to treat HIV infection

(approved for hepatitis B in 2008), is similar to adefovir but more

potent in suppressing HBV DNA and inducing HBeAg responses;

it is highly active against both wild-type and lamivudine-resistant

HBV and active in patients whose response to adefovir is slow

and/or limited. At an oral once-daily dose of 300 mg for 48 weeks,

tenofovir suppressed HBV DNA by 6.2 log10 (to undetectable

levels [<400 copies/mL] in 76%) in HBeAg-positive patients and

by 4.6 log10 (to undetectable levels in 93%) in HBeAg-negative

patients; reduced ALT to normal in 68% of HBeAg-positive and

76% of HBeAg-negative patients; and improved histology in

74% of HBeAg-positive and 72% of HBeAg-negative patients. In

HBeAg-positive patients, HBeAg seroconversions occurred in 21%

by the end of year 1, 27% by year 2, 34% by year 3, and 40% by year

5 of tenofovir treatment; HBsAg loss occurred in 3% by the end

of year 1, 6% at year 2, and 8% by year 5. After 5 years of tenofovir therapy, 87% of patients experienced histologic improvement,

including reduction in fibrosis score (51%) and regression of cirrhosis

(71%). The 5-year safety (negligible renal toxicity, in 1%, and mild

reduction in bone density, in ~0.5%) and resistance profiles (none

recorded through 8 years) of tenofovir are very favorable as well;

therefore, tenofovir has supplanted adefovir both as first-line therapy

for chronic hepatitis B and as rescue therapy for lamivudine-resistant

chronic hepatitis B. Studies of tenofovir and entecavir reviewed in

2015 showed no difference in long-term risks of renal and bone