[Harrisons] Chronic Viral Hepatitis.pdf

2592 designations were believed to have prognostic implications, which noninvasive approaches have been introduced to provide approxi- were not corroborated by subsequent observations. Categoriz...

2592 designations were believed to have prognostic implications, which noninvasive approaches have been introduced to provide approxi- were not corroborated by subsequent observations. Categorization mations of hepatic histologic stage, including serum biomarkers of of chronic hepatitis based primarily on histopathologic features fibrosis; fibrosis scores such as FIB-4, a validated algorithm based on has been replaced by a more informative classification based on a such routine lab tests as aspartate and alanine aminotransferase (AST combination of clinical, serologic, and histologic variables. Classifi- and ALT) levels and platelet counts (PLT) (age [years] × AST/PLT × cation of chronic hepatitis is based on (1) its cause; (2) its histologic ALT1/2); and imaging determinations of liver elasticity. activity, or grade; and (3) its degree of progression based on level of fibrosis, or stage. Thus, neither clinical features alone nor histologic CHRONIC VIRAL HEPATITIS features—requiring liver biopsy or noninvasive markers of fibrosis— Both of the enterically transmitted forms of viral hepatitis, hepatitis A alone are sufficient to characterize and distinguish among the several and E, are self-limited and do not cause chronic hepatitis (rare reports categories of chronic hepatitis. notwithstanding in which acute hepatitis A serves as a trigger for the onset of autoimmune hepatitis in genetically susceptible patients or CLASSIFICATION BY CAUSE in which hepatitis E [Chap. 339] can cause chronic liver disease in Clinical and serologic features allow the establishment of a diagnosis immunosuppressed hosts, for example, after liver transplantation). In of chronic viral hepatitis, caused by hepatitis B, hepatitis B plus D, or contrast, the entire clinicopathologic spectrum of chronic hepatitis hepatitis C; autoimmune hepatitis, including several subcategories, I occurs in patients with chronic viral hepatitis B and C as well as in and II, based on serologic distinctions; drug-associated chronic hepati- patients with chronic hepatitis D superimposed on chronic hepatitis B. tis; and a category of unknown cause, or cryptogenic chronic hepatitis (Table 341-1). These are addressed in more detail below. CHRONIC HEPATITIS B CLASSIFICATION BY GRADE The likelihood of chronicity after acute hepatitis B varies as a function Grade, a histologic assessment of necroinflammatory activity, is based on of age. Infection at birth is associated with clinically silent acute infec- examination of the liver biopsy. An assessment of important histologic tion but a 90% chance of chronic infection, whereas infection in young features includes the degree of periportal necrosis and the disruption adulthood in immunocompetent persons is typically associated with of the limiting plate of periportal hepatocytes by inflammatory cells clinically apparent acute hepatitis but a risk of chronicity of only ~1%. (so-called piecemeal necrosis or interface hepatitis); the degree of conflu- Most cases of chronic hepatitis B among adults, however, are recognized ent necrosis that links or forms bridges between vascular structures— in patients who never had a recognized episode of clinically apparent between portal tract and portal tract or even more important bridges acute viral hepatitis. The degree of liver injury (grade) in patients with between portal tract and central vein—referred to as bridging necrosis; chronic hepatitis B is variable, ranging from none in inactive carriers the degree of hepatocyte degeneration and focal necrosis within the to mild to moderate to severe. Among adults with chronic hepatitis B, PART 10 lobule; and the degree of portal inflammation. Several scoring systems histologic features are of prognostic importance. In one long-term that take these histologic features into account have been devised, and study of patients with chronic hepatitis B, investigators found a 5-year the most popular are the histologic activity index (HAI), used com- survival rate of 97% for patients with mild chronic hepatitis, 86% monly in the United States, and the METAVIR score, used in Europe for patients with moderate to severe chronic hepatitis, and only 55% for patients with chronic hepatitis and postnecrotic cirrhosis. The Disorders of the Gastrointestinal System (Table 341-2). Based on the presence and degree of these features of histologic activity, chronic hepatitis can be graded as mild, moderate, 15-year survival in these cohorts was 77%, 66%, and 40%, respectively. or severe. On the other hand, more recent observations do not allow us to be so sanguine about the prognosis in patients with mild chronic hepatitis; CLASSIFICATION BY STAGE among such patients followed for 1−13 years, progression to more The stage of chronic hepatitis, which reflects the level of progression severe chronic hepatitis and cirrhosis has been observed in more than of the disease, is based on the degree of hepatic fibrosis. When fibrosis a quarter of cases. is so extensive that fibrous septa surround parenchymal nodules and More important to consider than histology alone in patients with alter the normal architecture of the liver lobule, the histologic lesion is chronic hepatitis B is the degree of hepatitis B virus (HBV) replica- defined as cirrhosis. Staging is based on the degree of fibrosis as categorized tion. As reviewed in Chap. 339, chronic HBV infection can occur in on a numerical scale 0−6 (HAI) or 0−4 (METAVIR) (Table 341-2). Several the presence or absence of serum hepatitis B e antigen (HBeAg), and 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 (±) ANA, anti-LKM1 anti-SLAe Prednisone, azathioprine Hyperglobulinemia 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). bSupplanted in almost all cases by combinations of the direct- acting antiviral agents listed (see www.hcvguidelines.org). cEarly clinical trials suggested benefit of IFN-α therapy; PEG IFN-α is as effective, if not more so, and has supplanted standard IFN-α. dAntinuclear antibody (autoimmune hepatitis type I). eAntibodies 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.  TABLE 341-2 Histologic Grading and Staging of Chronic Hepatitis early childhood, as recognized commonly 2593 in Asian countries, a dichotomy is com- HISTOLOGIC ACTIVITY INDEX (HAI) a b METAVIR mon between very high levels of HBV HISTOLOGIC FEATURE SEVERITY SCORE SEVERITY SCORE replication during the early decades of life Necroinflammatory Activity (grade) (when the level of apparent host immuno- Periportal necrosis, including piecemeal None 0 None 0 logic tolerance of HBV is relatively high) necrosis and/or bridging necrosis (BN) Mild 1 Mild 1 and negligible levels of liver injury; dur- ing this phase of chronic hepatitis B, the Mild/moderate 2 Moderate 2 level of viral replication does not correlate Moderate 3 Severe 3 with liver injury or late complications. Yet Severe 4 Bridging necrosis Yes despite the relatively immediate, appar- No ently benign nature of liver disease for many decades in this population, in the Intralobular necrosis Confluent —None 0 None or mild 0 middle decades, activation of liver injury —Focal 1 Moderate 1 emerges as what appears to be the relative —Zone 3 some 2 Severe 2 tolerance of the host to HBV declines, and —Zone 3 most 3 these patients with childhood-acquired —Zone 3 + BN few 4 HBV infection are ultimately at increased —Zone 3 + BN multiple 5 risk later in life for cirrhosis, hepato- cellular carcinoma (HCC) (Chap. 82), —Panacinar/multiacinar 6 and liver-related death; the link between Focal —None 0 high-level HBV replication and these late —≤1 focus/10× field 1 liver complications has been demonstrated —2–4 foci/10× field 2 convincingly in, and confined mostly to, —5–10 foci/10× field 3 persons in their middle decades, especially —>10 foci/10× field 4 age ≥40. A discussion of the pathogenesis Portal Inflammation None 0 of liver injury in patients with chronic Mild 1 hepatitis B appears in Chap. 339. CHAPTER 341 Chronic Hepatitis Moderate 2 HBeAg-negative chronic hepatitis B Moderate/marked 3 (i.e., chronic HBV infection with active virus replication and readily detect- Marked 4 able HBV DNA but without HBeAg Total 0–18 A0–A3c [anti-HBe-reactive]) is more common Fibrosis (stage) than HBeAg-reactive chronic hepatitis B None 0 F0 in Mediterranean and European coun- Portal fibrosis—some 1 F1 tries and in Asia (and, correspondingly, in Portal fibrosis—most 2 F1 HBV genotypes other than A). Compared Bridging fibrosis—few 3 F2 to patients with HBeAg-reactive chronic hepatitis B, patients with HBeAg-nega- Bridging fibrosis—many 4 F3 tive chronic hepatitis B have HBV DNA Incomplete cirrhosis 5 F4 levels several orders of magnitude lower Cirrhosis 6 F4 (usually no more than 105−106 IU/mL) Total 6 4 than those observed in the HBeAg- a Ishak K, Baptista A, Bianchi L, et al: Histologic grading and staging of chronic hepatitis. J Hepatol 22:696, 1995. reactive subset. Most such cases represent b Bedossa P, Poynard T, French METAVIR Cooperative Study Group: An algorithm for grading activity in chronic precore or core-promoter mutations hepatitis C. Hepatology 24:289, 1996. Necroinflammatory grade: A0 = none; A1 = mild; A2 = moderate; A3 = severe. c acquired late in the natural history of the disease (mostly early-life onset; age range generally, for both HBeAg-reactive and HBeAg-negative chronic hep- 40−55 years, older than that for HBeAg-reactive chronic hepatitis B); atitis B, the level of HBV DNA correlates with the level of liver injury these mutations prevent translation of HBeAg from the precore com- and risk of progression. In HBeAg-reactive chronic hepatitis B, two ponent of the HBV genome (precore mutants) or are characterized phases have been recognized based on the relative level of HBV repli- by downregulated transcription of precore mRNA (core-promoter cation. The relatively replicative phase is characterized by the presence mutants; Chap. 339). Although their levels of HBV DNA tend to be in the serum of HBeAg and HBV DNA levels well in excess of 103−104 lower than among patients with HBeAg-reactive chronic hepatitis B, IU/mL, sometimes exceeding 109 IU/mL; by the presence in the liver of patients with HBeAg-negative chronic hepatitis B can have progres- detectable intrahepatocyte nucleocapsid antigens (primarily hepatitis B sive liver injury (complicated by cirrhosis and HCC) and experience core antigen [HBcAg]); by high infectivity; and by accompanying liver episodic reactivation of liver disease reflected in fluctuating levels of injury. In contrast, the relatively nonreplicative phase is characterized aminotransferase activity (“flares”). The biochemical and histologic by the absence of the conventional serum marker of HBV replication activity of HBeAg-negative disease tends to correlate closely with (HBeAg), the appearance of anti-HBe, levels of HBV DNA below a levels of HBV replication, unlike the case mentioned above of Asian threshold of ~103 IU/mL, the absence of intrahepatocytic HBcAg, patients with HBeAg-reactive chronic hepatitis B during the early limited infectivity, and minimal liver injury. Patients in the relatively decades of their HBV infection. Worth reiterating, the level of HBV replicative phase tend to have more severe chronic hepatitis, whereas replication is the most important risk factor for the ultimate develop- those in the relatively nonreplicative phase tend to have minimal or ment of cirrhosis and HCC in both HBeAg-reactive (beyond the early mild chronic hepatitis or to be inactive hepatitis B carriers. The likeli- decades of “relatively nonreplicative” infection) and HBeAg-negative hood in a patient with HBeAg-reactive chronic hepatitis B of convert- patients. Although levels of HBV DNA are lower and more readily ing spontaneously from relatively replicative to nonreplicative infection suppressed by therapy to undetectable levels in HBeAg-negative (com- is ~10% per year. Distinctions in HBV replication and in histologic pared to HBeAg-reactive) chronic hepatitis B, achieving sustained category, however, do not always coincide. In patients with HBeAg- responses that permit discontinuation of antiviral therapy is less likely reactive chronic HBV infection, especially when acquired at birth or in in HBeAg-negative patients (see below). Inactive carriers are patients  2594 with circulating hepatitis B surface antigen (HBsAg), normal serum pharmacologic suppression of HBV replication. In addition, res- aminotransferase levels, minimal or no histologic evidence of liver toration of impaired HBV-specific T-cell function has been shown injury, undetectable HBeAg, and levels of HBV DNA that are either following successful suppression of HBV replication with antiviral undetectable or present at a threshold of ≤103 IU/mL. This serologic therapy. To date, eight drugs have been approved for treatment of profile occurs not only in inactive carriers but also in patients with chronic hepatitis B: injectable interferon (IFN) α and pegylated HBeAg-negative chronic hepatitis B during periods of relative inac- interferon (long-acting IFN bound to polyethylene glycol, PEG tivity; distinguishing between the two requires sequential biochemical [PEG IFN]) and the oral agents lamivudine, adefovir dipivoxil, and virologic monitoring over many months. entecavir, telbivudine, tenofovir disoproxil fumarate (TDF), and The spectrum of clinical features of chronic hepatitis B is broad, tenofovir alafenamide (TAF). ranging from asymptomatic infection to debilitating disease or even Antiviral therapy for hepatitis B has evolved rapidly since the end-stage, fatal hepatic failure. As noted above, the onset of the dis- mid-1990s, as has the sensitivity of tests for HBV DNA. When IFN ease tends to be insidious in most patients, apart from the very few in and the first oral antiviral lamivudine were evaluated in clinical whom chronic disease follows failure of resolution of clinically appar- trials, HBV DNA was measured by insensitive hybridization assays ent acute hepatitis B. The clinical and laboratory features associated with detection thresholds of 105−106 virions/mL; when subsequent with progression from acute to chronic hepatitis B are discussed in treatments were studied in clinical trials, HBV DNA was mea- Chap. 339. sured by sensitive amplification assays (polymerase chain reaction Fatigue is a common symptom, and persistent or intermittent jaundice [PCR]) with detection thresholds of 101−103 viral copies/mL or is a common feature in severe or advanced cases. Intermittent deep- IU/mL. Recognition of these distinctions is helpful when compar- ening of jaundice and recurrence of malaise and anorexia, as well as ing results of clinical trials that established the efficacy of these worsening fatigue, are reminiscent of acute hepatitis; such exacer- therapies (reviewed below in chronologic order of publication of bations may occur spontaneously, often coinciding with evidence of these efficacy trials). Of the eight approved treatments, PEG IFN, virologic reactivation; may lead to progressive liver injury; and, when entecavir, and the two tenofovir preparations (TDF and TAF) are superimposed on well-established cirrhosis, may cause hepatic dec- recommended as first-line agents, and generally, the oral agents are ompensation. Complications of cirrhosis occur in end-stage chronic favored over injectable PEG IFN. hepatitis and include ascites, edema, bleeding gastroesophageal varices, hepatic encephalopathy, coagulopathy, and hypersplenism. Occasion- INTERFERON ally, these complications bring the patient to initial clinical attention. IFN-α was the first approved therapy (1992) for chronic hepatitis B. Extrahepatic complications of chronic hepatitis B, similar to those seen Although it is no longer used to treat hepatitis B, standard IFN is during the prodromal phase of acute hepatitis B, are associated with important historically, having provided important lessons about PART 10 tissue deposition of circulating hepatitis B antigen–antibody immune antiviral therapy in general. For immunocompetent adults with complexes. These include arthralgias and arthritis, which are common, HBeAg-reactive chronic hepatitis B (who tend to have high-level and the rarer purpuric cutaneous lesions (leukocytoclastic vasculi- HBV DNA [>105−106 virions/mL] and histologic evidence of tis), immune-complex glomerulonephritis, and generalized vasculitis chronic hepatitis on liver biopsy), a 16-week course of subcuta- (polyarteritis nodosa) (Chap. 363). neous IFN, 5 million units daily or 10 million units thrice weekly, Disorders of the Gastrointestinal System Laboratory features of chronic hepatitis B do not distinguish resulted in a loss of HBeAg and hybridization-detectable HBV adequately between histologically mild and severe hepatitis. DNA (i.e., a reduction to levels below 105−106 virions/mL) in ~30% Aminotransferase elevations tend to be modest for chronic hepatitis of patients, with a concomitant improvement in liver histology. B but may fluctuate in the range of 100−1000 units. As is true for Seroconversion from HBeAg to anti-HBe occurred in ~20%, and, in acute viral hepatitis B, ALT tends to be more elevated than AST; early trials, ~8% lost HBsAg. Successful IFN therapy and serocon- however, once cirrhosis is established, AST tends to exceed ALT. version were often accompanied by an acute hepatitis-like elevation Levels of alkaline phosphatase activity tend to be normal or only in aminotransferase activity, postulated to result from enhanced marginally elevated. In severe cases, moderate elevations in serum cytolytic T-cell clearance of HBV-infected hepatocytes. Relapse bilirubin (51.3−171 μmol/L [3−10 mg/dL]) occur. Hypoalbumine- after successful therapy was rare (1 or 2%). Responsiveness to IFN mia and prolongation of the prothrombin time occur in severe or was higher in patients with low-level HBV DNA and substantial end-stage cases. Hyperglobulinemia and detectable circulating auto- ALT elevations. Therapy with IFN was not effective in immunosup- antibodies are distinctly absent in chronic hepatitis B (in contrast to pressed persons, persons with neonatal acquisition of infection and autoimmune hepatitis). Viral markers of chronic HBV infection minimal-to-mild ALT elevations, or patients with decompensated are discussed in Chap. 339. chronic hepatitis B (in whom such therapy was actually detri- mental, sometimes precipitating decompensation, often associated with severe adverse effects). After HBeAg loss during IFN therapy, TREATMENT 80% experienced eventual loss of HBsAg and ALT normalization Chronic Hepatitis B over the ensuing decade. In addition, improved long-term and complication-free survival as well as a reduction in the frequency Although progression to cirrhosis is more likely in severe than in of HCC were documented among IFN responders, supporting the mild or moderate chronic hepatitis B, all forms of chronic hepatitis B conclusion that successful antiviral therapy improves the natural can be progressive, and progression occurs primarily in patients history of chronic hepatitis B. with active HBV replication. Moreover, in populations of patients Brief-duration IFN therapy in patients with HBeAg-negative with chronic hepatitis B who are at risk for HCC (Chap. 82), the chronic hepatitis B was disappointing, suppressing HBV replication risk is highest for those with continued, high-level HBV replica- transiently during therapy but almost never resulting in sustained tion and lower for persons in whom initially high-level HBV DNA antiviral responses; however, more protracted courses for up to 1.5 falls spontaneously over time. Therefore, management of chronic years resulted in sustained virologic/biochemical remissions docu- hepatitis B is directed at suppressing the level of virus replication. mented to last for several years in ~20%. Although clinical trials tend to focus on clinical endpoints achieved Complications of IFN therapy include systemic “flu-like” symptoms; over 1−2 years (e.g., suppression of HBV DNA to undetectable marrow suppression; emotional lability (irritability, depression, levels, loss of HBeAg/HBsAg, improvement in histology, nor- anxiety); autoimmune reactions (especially autoimmune thyroiditis); malization of ALT), these short-term gains translate into reduc- and miscellaneous side effects such as alopecia, rashes, diarrhea, tions in the risk of clinical progression, hepatic decompensation, and numbness and tingling of the extremities. With the possible HCC, liver transplantation, and death; regression of cirrhosis and exception of autoimmune thyroiditis, all these side effects are of esophageal varices has been documented to follow long-term reversible upon dose lowering or cessation of therapy.  Although no longer competitive with the newer generation of transcriptase activity of both HIV and HBV and is an effective 2595 antivirals, IFN did represent the first successful antiviral approach, agent for chronic hepatitis B; however, it is now superseded by set a standard against which to measure efficacy of subsequent newer, more potent, less resistance-prone agents. For a summary drugs, and demonstrated the benefit of antiviral therapy on the of its virologic, serologic, biochemical, and histologic efficacy, natural history of chronic hepatitis B. Standard IFN has been sup- as well as its resistance profile, please refer to Table 341-3. In planted by long-acting PEG IFN (see below), and IFN nonrespond- clinical trials, lamivudine therapy at daily doses of 100 mg for ers are now treated with one of the newer oral nucleoside analogues. 48−52 weeks suppressed HBV DNA, as measured by sensitive LAMIVUDINE 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 The first of the nucleoside analogues to be approved (in 1998) HBeAg-negative chronic hepatitis B (baseline HBV DNA levels for hepatitis B, the dideoxynucleoside lamivudine inhibits reverse TABLE 341-3 Comparison of Pegylated Interferon (PEG IFN), Lamivudine, Adefovir, Entecavir, Telbivudine, and Tenofovir Therapy for Chronic Hepatitis Ba TENOFOVIR FEATURE PEG IFNb LAMIVUDINE ADEFOVIR ENTECAVIR TELBIVUDINE (TDF) TENOFOVIR (TAF) Route of administration Subcutaneous Oral Oral (10 mg/d) Oral (0.5 mg/d) Oral (600 mg/d) Oral (300 mg/d) Oral 25 mg/d) injection (180 μg/ (100 mg/d) week) Status First-line No longer No longer First-line No longer First-line First-line preferred preferred preferred, withdrawn 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; Well tolerated Well tolerated Well tolerated; Well tolerated creatinine creatinine monitoring monitoring recommended recommended HBeAg seroconversion CHAPTER 341 Chronic Hepatitis 1 yr Rx 18–20% 16–21% 12% 21% 22% 21% 10% (14% HBeAg loss) >1 yr Rx NA up to 50% at 43% at 3 yrsd 31% at 2 yrs 30% at 2 yrs 40% at 5 yrs 18% at yr 2 (HBeAg 5 yrs 44% at 6 yrs loss 22%) Log10 HBV DNA reduction Not reported in clinical (mean copies/mL) trials, likely same as HBeAg-reactive TDF 4.5 5.5 Median 3.5–5 6.9 6.4 6.2 HBeAg-negative 4.1 4.4–4.7 Median 3.5–3.9 5.0 5.2 4.6 HBV DNA PCR negative (at then current PCR sensitivitya) at end of yr 1 HBeAg-reactive 10–25% 36–44% 13–21% 67% (91% at 4 yrs) 60% 76% 64% HBeAg-negative 63% 60–73% 48–77% 90% 88% 93% 94% ALT normalization at end of yr 1 HBeAg-reactive 39% 41–75% 48–61% 68% 77% 68% 72% HBeAg-negative 34–38% 62–79% 48–77% 78% 74% 76% 83% HBsAg loss, yr 1 3–4% ≤1% 0% 2% yr 1 12% 5 yr after No data 5% at yr 5 6% at yr 6 No data 8% at yr 5 1% 1 yr of Rx Histologic improvement Not included in clinical (≥2 point reduction in HAI) trials at yr 1 HBeAg-reactive 38% 6 months 49–62% 53–68% 72% 65% 74% after 61–66% 64% 70% 67% 72% HBeAg-negative 48% 6 months after Viral resistance None 15–30% at 1 yr None at 1 yr ≤1% at 1 yre Up to 5% at yr 1 0% at yr 1 0% at yr 1 70% at 5 yrs 29% at 5 yrs 1.2% at 6 yrse Up to 22% at 0% through yr 8 0% through yr 2 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. bAlthough 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. cDuration of therapy in clinical efficacy trials; use in clinical practice may vary. dBecause 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. e7% during a year of therapy (43% at year 4) in lamivudine-resistant patients. fDespite 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 are lower in HBeAg-negative than in HBeAg-positive chronic monitoring after discontinuation of treatment. Many authorities hepatitis B) and to undetectable levels in ~40% and ~70%, respec- cautioned against discontinuing therapy in patients with cirrhosis, tively. Lamivudine, which was shown to improve histology, retard in whom posttreatment flares could precipitate decompensation. hepatic fibrosis, and prevent progression to cirrhosis, was effective Long-term monotherapy with lamivudine was associated in patients resistant to IFN (e.g., those with high-level HBV DNA) with methionine-to-valine (M204V) or methionine-to-isoleucine or who had failed prior IFN therapy. As was true for IFN therapy of (M204I) mutations, primarily at amino acid 204 in the tyrosine-me- chronic hepatitis B, lamivudine-associated HBeAg seroconversion thionine-aspartate-aspartate (YMDD) motif of the C domain of occurred in ~20%; patients with near-normal ALT activity tended HBV DNA polymerase, analogous to mutations that occur in not to experience HBeAg responses (despite suppression of HBV HIV-infected patients treated with this drug. During a year of DNA), while patients with ALT levels ≥5× the upper limit of nor- therapy, YMDD mutations occurred in 15−30% of patients; the fre- mal could expect 1-year HBeAg seroconversion rates of 50−60%. quency increased with each year of therapy, reaching 70% at year 5. Generally, HBeAg seroconversions were confined to patients who Ultimately, patients with YMDD mutants experienced degradation achieved suppression of HBV DNA to 80%); therefore, the achievement of an HBeAg virals that have superior resistance profiles (see below); it is response represented a viable stopping point in therapy. Reduced no longer recommended as first-line therapy. Still, as the first durability, however, was reported in Asian patients; therefore, to successful oral antiviral agent for use in hepatitis B, lamivudine support the durability of HBeAg responses, a period of consoli- provided proof of principle that polymerase inhibitors can achieve dation therapy of ≥6 months in Western patients and ≥1 year in virologic, serologic, biochemical, and histologic benefits, includ- Asian patients was recommended after HBeAg seroconversion (see ing retardation and reversal of fibrosis and even of cirrhosis. In treatment guidelines below; a full 12-month consolidation period addition, lamivudine was shown to be effective in the treatment is recommended currently for treatment extension after oral-agent- of patients with decompensated hepatitis B (for whom IFN is con- induced HBeAg seroconversion). Close posttreatment monitoring traindicated), in some of whom decompensation can be reversed. was recommended to identify HBV reactivation promptly and to Moreover, among patients with cirrhosis or advanced fibrosis, PART 10 resume therapy. If HBeAg was unaffected by lamivudine therapy, lamivudine was shown to be effective in reducing the risk of lamivudine was continued until an HBeAg response occurred, but progression to hepatic decompensation and, based on subsequent long-term therapy was required to suppress HBV replication and, in population studies, the risk of HCC. In the half decade following turn, limit liver injury; HBeAg seroconversions increased to a level the introduction in the United States of lamivudine therapy for of 50% after 5 years of therapy. After a cumulative course of 3 years hepatitis B, referral of patients with HBV-associated end-stage liver Disorders of the Gastrointestinal System of lamivudine therapy, necroinflammatory activity was reduced in disease for liver transplantation fell by ~30%, supporting further the majority of patients, and even cirrhosis was shown to regress to the beneficial impact of oral antiviral therapy on the natural his- precirrhotic stages in as many as three-quarters of patients. tory of chronic hepatitis B. Losses of HBsAg were few during the first year of lamivudine Because lamivudine monotherapy in persons with HIV infec- therapy, and this observation had been cited as an advantage of tion can result universally in the rapid emergence of YMDD vari- IFN-based therapy over lamivudine therapy; however, in head-to- ants, testing for HIV infection was recommended for all patients head comparisons between standard IFN and lamivudine mono- with chronic hepatitis B prior to lamivudine therapy; if HIV infec- therapy, HBsAg losses were rare in both groups. Trials in which tion was identified, lamivudine monotherapy at the HBV daily dose lamivudine and IFN were administered in combination failed to of 100 mg was contraindicated. These patients require treatment for show a benefit of combination therapy over lamivudine monother- both HIV and HBV with an HIV drug regimen that includes or is apy for either treatment-naïve patients or prior IFN nonresponders. supplemented by at least two drugs active against HBV; antiretro- Patients with HBeAg-negative chronic hepatitis B (i.e., in those viral therapy (ART) often contains two drugs with antiviral activity with precore and core-promoter HBV mutations and who lack against HBV (e.g., tenofovir and emtricitabine), but if lamivudine HBeAg) cannot achieve an HBeAg response to nucleoside analogue was part of the regimen, the 300-mg daily dose was required therapy—a stopping point in HBeAg-reactive patients; almost (Chap. 202). The safety of lamivudine during pregnancy has not invariably, when therapy was discontinued, reactivation was the rule. been established; however, the drug is not teratogenic in rodents Therefore, these patients required long-term lamivudine therapy. and has been used safely in pregnant women with HIV infection Clinical and laboratory side effects of lamivudine were negligible and with HBV infection. As shown for subsequent nucleoside and indistinguishable from those observed in placebo recipients; analogues, administration of lamivudine during the last months of however, lamivudine doses were reduced in patients with reduced pregnancy to mothers with high-level hepatitis B viremia reduced creatinine clearance. During lamivudine therapy, transient ALT the likelihood of perinatal transmission of hepatitis B. elevations, resembling those seen during IFN therapy and dur- ing spontaneous HBeAg-to-anti-HBe seroconversions, occurred ADEFOVIR DIPIVOXIL in one-fourth of patients. These ALT elevations may result from At an oral daily dose of 10 mg, the acyclic nucleotide analogue ade- restored cytolytic T-cell activation permitted by suppression of fovir dipivoxil, the prodrug of adefovir (approved for hepatitis B in HBV replication. Similar ALT elevations, however, occurred at 2002), reduces HBV DNA by ~3.5−4 log10 copies/mL, i.e., it is less an identical frequency in placebo recipients; however, ALT ele- potent than lamivudine or any of the newer antiviral agents. For vations associated temporally with HBeAg seroconversion in a summary of its virologic, serologic, biochemical, and histologic clinical trials were confined to lamivudine-treated patients. When efficacy, as well as its resistance profile, please refer to Table 341-3. therapy was stopped after a year of therapy, two- to threefold ALT Like IFN and lamivudine, adefovir dipivoxil is more likely to elevations occurred in 20−30% of lamivudine-treated patients, achieve an HBeAg response in patients with high baseline ALT; representing renewed liver-cell injury as HBV replication returned. HBeAg responses to it are highly durable and can be relied upon as Although these posttreatment flares were almost always transient a treatment stopping point, after a period of consolidation therapy; and mild, rare severe exacerbations, especially in cirrhotic patients, and biochemical, serologic, and virologic outcomes improve over were observed, mandating close and careful clinical and virologic time with continued therapy.  In HBeAg-negative chronic hepatitis B, as was true for lami- comparison arms of lamivudine monotherapy and combination PEG 2597 vudine, because HBeAg responses—a potential stopping point— IFN plus lamivudine. At the end of therapy (48−52 weeks) in the cannot be achieved, reactivation is the rule when adefovir therapy PEG IFN monotherapy arms, HBeAg loss occurred in ~30%, HBeAg is discontinued, and indefinite, long-term therapy is required. seroconversion in 22−27%, undetectable HBV DNA ( B > C > D (shown for PEG IFN-α2b but not for effectiveness in lamivudine-resistant, YMDD-mutant HBV, led to PEG IFN-α2a). PEG IFN-α2a was approved in the United States for its adoption for lamivudine-resistant hepatitis B. When lamivudine hepatitis B in 2005; PEG IFN-α2b, which is not approved for hepa- resistance occurred, adding adefovir (i.e., maintaining lamivudine titis B in the United States, is used in other countries. to preempt the emergence of adefovir resistance) was superior to Based on these results, some authorities concluded that PEG switching to adefovir. Almost invariably, patients with adefovir-in- IFN monotherapy should be the first-line therapy of choice in duced HBV mutations respond to lamivudine (or newer agents, HBeAg-reactive chronic hepatitis B; however, this conclusion has CHAPTER 341 Chronic Hepatitis such as entecavir, see below). When, in the past, adefovir had been been challenged. Although a finite, 1-year course of PEG IFN evaluated as therapy for HIV infection, doses of 60−120 mg were results in a higher rate of sustained response (6 months after required to suppress HIV, and, at these doses, the drug was nephro- treatment) than is achieved with oral nucleoside/nucleotide ana- toxic. Even at 30 mg/d, creatinine elevations of 44 μmol/L (0.5 mg/ logue therapy, the comparison is confounded by the fact that oral dL) occurred in 10% of patients; however, at the HBV-effective dose agents are not discontinued at the end of 1 year. Instead, taken of 10 mg, such creatinine elevations were encountered rarely and orally and free of side effects, therapy with oral agents is extended hardly ever before 6−8 months of therapy. Although renal tubular indefinitely or until after the occurrence of an HBeAg response. injury was a rare potential side effect, and although creatinine moni- The rate of HBeAg responses after 2 years of oral-agent nucleo- toring was recommended during treatment, the therapeutic index of side analogue therapy is at least as high as, if not higher than, that adefovir dipivoxil was high, and the nephrotoxicity observed in clin- achieved with PEG IFN after 1 year; favoring oral agents is the ical trials at higher doses was reversible. For patients with underly- absence of injections, difficult-to-tolerate side effects, and labora- ing renal disease, frequency of administration of adefovir had to be tory monitoring as well as lower direct and indirect medical care reduced, and it could be given only once a week for patients under- costs and inconvenience. The association of HBsAg responses with going hemodialysis. Adefovir was very well tolerated, and ALT ele- PEG IFN therapy occurs in such a small proportion of patients that vations during and after withdrawal of therapy were similar to those subjecting everyone to PEG IFN for the marginal gain of HBsAg observed and described above in clinical trials of lamivudine. An responses during or immediately after therapy in such a very small advantage of adefovir was its relatively favorable resistance profile; minority is questionable. Moreover, HBsAg responses occur in a however, it was not as potent as the other approved oral agents, it did comparable proportion of patients treated with early-generation not suppress HBV DNA as rapidly or as uniformly as the others, it nucleoside/nucleotide analogues in the years after therapy, and, was the least likely of all agents to result in HBeAg seroconversion, with the newer, more potent nucleoside analogues, the frequency and 20−50% of patients failed to suppress HBV DNA by 2 log10 of HBsAg loss during the first year of therapy equals that of (“primary nonresponders”). For these reasons, adefovir, which has PEG IFN and is exceeded during year 2 and beyond (see below). been supplanted in both treatment-naïve and lamivudine-resistant Of course, resistance is not an issue during PEG IFN therapy, but patients by the more potent, less resistance-prone tenofovir (see the risk of resistance is much lower with new agents (≤1% up to below), is no longer recommended as first-line therapy. 3−8 years in previously treatment-naïve, entecavir-treated patients and 0% in tenofovir-treated patients; see below). Finally, the level of PEGYLATED IFN HBV DNA inhibition that can be achieved with the newer agents, After long-acting PEG IFN was shown to be effective in the and even with lamivudine, exceeds that achieved with PEG IFN, in treatment of hepatitis C (see below), this more convenient IFN some cases by several orders of magnitude. preparation was evaluated in the treatment of chronic hepatitis B. In HBeAg-negative chronic hepatitis B, a trial of PEG IFN-α2a Once-a-week PEG IFN is more effective than the more frequently (180 μg weekly for 48 weeks vs comparison arms of lamivudine administered, standard IFN, and several large-scale trials of PEG monotherapy and of combination therapy) in 564 patients showed IFN versus oral lamivudine were conducted in patients with chronic that PEG IFN monotherapy resulted at the end of therapy in sup- hepatitis B. pression of HBV DNA by a mean of 4.1 log10 copies/mL, undetect- In HBeAg-reactive chronic hepatitis B, two large-scale studies were able HBV DNA (2 × ULNd Treate Cirrhosis compensated >2 × 103 < or > ULN Treate with oral agents, not PEG IFN ULN Treatment suggestedf Cirrhosis decompensated Detectable < or > ULN Treate with oral agentsg, not PEG IFN; refer for liver transplantation Undetectable < or > ULN Observe; refer for liver transplantation HBeAg-negative b ≤2 × 103 ≤ULN Inactive carrier; treatment not necessary Chronic hepatitis >2 × 103 1 to >2 × ULNd 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 Chronic hepatitis >2 × 103 >2 × ULNd Treath,i Cirrhosis compensated >2 × 103 < or > ULN Treate with oral agents, not PEG IFN ULN Treatment suggestedf Cirrhosis decompensated Detectable < or > ULN Treath with oral agentsg, not PEG IFN; refer for liver transplantation Undetectable < or > ULN 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). bLiver 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. dAccording 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. fAccording 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 HBeAg- positive disease after HBeAg seroconversion. gBecause 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. hBecause 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. iFor 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. recommended according to EASL guidelines, because ALT is ele- TABLE 341-5 Pegylated Interferon Versus Oral Nucleoside Analogues 2601 vated). Per current AASLD recommendations, antiviral treatment for the Treatment of Chronic Hepatitis B with oral agents can be stopped after HBeAg seroconversion in NUCLEOSIDE noncirrhotics, and the suggested period of consolidation therapy is PEG IFN ANALOGUES 12 months with close monitoring for recurrent viremia (monthly × 6, Administration Weekly injection Daily, orally then every 3 months for the rest of a year) after cessation of therapy. For patients with HBeAg-negative chronic hepatitis, the current Tolerability Poorly tolerated, Well tolerated, limited intensive monitoring monitoring recommendation with oral agents is for indefinite therapy; stopping therapy in this group can be considered after HBsAg loss. Duration of therapy Finite 48 weeks ≥1 year, indefinite in most patients The potential for stopping antiviral therapy in noncirrhotic HBeAg-negative patients after protracted (≥2–5 years) antiviral Maximum mean HBV DNA 4.5 log10 6.9 log10 suppression therapy has been the subject of several studies. After such pro- longed courses of entecavir or tenofovir, in one study (DARING-B), Effective in high-level HBV No Yes DNA (≥109 IU/mL) 18-month virologic relapse rates (HBV DNA >2000 IU/mL) in 57 patients were high (in 72%), but only 26% met study criteria for HBeAg seroconversion ~30% ~20% resumption of therapy (ALT >10× upper limit of normal, ALT >5× During 1 year of therapy Not applicable 30% (year 2) to up to 50% upper limit of normal with bilirubin >2 mg/mL, ALT >3× upper During >1 year of therapy (year 5) limit of normal with HBV DNA >105 IU/mL, or ALT >2× upper HBeAg-negative 17% at 5 years 7% at 4 years limit of normal and HBV DNA >2 × 103 IU/mL on three sequential posttreatment HBV DNA (lamivudine) visits). Moreover, 25% underwent HBsAg loss. In a similar study suppression (FINITE), virologic relapse rates were high, but 62% did not meet HBsAg loss 3–4% 0–3% criteria for retreatment, and 19% lost HBsAg. In contrast, in a During 1 year of therapy Not applicable 3–8% at 5 years of study among Asian patients, only ~30% had sustained responses During >1 year of therapy 12% at 5 years therapy for which resumption of therapy was not introduced, and HBsAg After 1 year of 3.5% at 5 years responses were negligible. In other reports, including on patients therapy–HBeAg-negative with 8 years of TDF treatment prior to stopping, only 35–60% had Antiviral resistance None Lamivudine: ~30% year 1, sustained treatment-free outcomes, and only 5–13% lost HBsAg. ~70% year 5 In the only randomized, controlled trial of stopping therapy versus Adefovir: 0% year 1, CHAPTER 341 Chronic Hepatitis continuing therapy in HBeAg-negative patients after prolonged ~30% year 5 antiviral therapy (Toronto STOP study), only 33% had sustained Telbivudine: up to 4% responses after cessation of therapy, and HBsAg loss occurred with year 1, 22% year 2 equal, small frequencies in both the stop-treatment group (4%) Entecavir: ≤1.2% through and the continue-treatment group (5%). Generally, then, although year 6 HBsAg loss can be achieved in a small fraction and although a sub- Tenofovir: 0% through group may not require reintroduction of therapy in the short run, year 8 enthusiasm for this approach is limited, and for most HBeAg-nega- Use in cirrhosis, No Yes tive patients, recommendations support indefinite treatment, unless transplantation, they experience HBsAg loss. immunosuppressed For patients with compensated cirrhosis, because antiviral ther- Cost, 1 year of therapy ++++ + to ++ apy has been shown to retard clinical progression, treatment is Abbreviations: HBV, hepatitis B virus; HBeAg, hepatitis B e antigen; HBsAg, recommended regardless of HBeAg status and ALT as long as hepatitis B surface antigen; PEG IFN, pegylated interferon. 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 6 months in all studies evaluated); the viral mutations, but it requires subcutaneous injections and is asso- pooled rate of durable biochemical remission after therapy in this ciated with inconvenience, more intensive clinical and laboratory population was 76%. Even for HBeAg-negative chronic hepatitis B, monitoring, and intolerability. Oral nucleoside analogues require for which most authorities recommend indefinite therapy, pooled long-term therapy in most patients, and when used alone, lami- rates of virologic remissions maintained after cessation of oral- vudine and telbivudine foster the emergence of viral mutations, agent therapy were 44%, 31%, and 30% at posttreatment months 12, adefovir somewhat less so, and entecavir (except in lamivudine- 24, and 36, and the pooled rate of durable biochemical remission in experienced patients) and tenofovir rarely at all. Oral agents do not this population was 57%. require injections or cumbersome laboratory monitoring, are very Although adefovir and tenofovir (TDF) are safe, renal moni- well tolerated, lead to improved histology in 50−90% of patients, toring (e.g., serum creatinine and phosphate, urine glucose and suppress HBV DNA more profoundly than PEG IFN, and are protein) is recommended (not for TAF). Substantial experience effective even in patients who fail to respond to IFN-based therapy. with lamivudine during pregnancy (see above) has identified no Although oral agents are less likely to result in HBeAg responses teratogenicity; although widely used during pregnancy, lamivudine during the first year of therapy, as compared to PEG IFN, treatment remains classified as pregnancy category C. Although IFNs do not  2602 appear to cause congenital anomalies, these have antiproliferative activity against HIV and can result in selection of HIV resistance; properties and should be avoided during pregnancy. Adefovir dur- therefore, it is not preferable in HBV-HIV co-infection. Tenofovir ing pregnancy has not been associated with birth defects; however, and the combination of tenofovir and emtricitabine in one pill are the risk of spontaneous abortion may be increased, and adefovir is approved therapies for HIV and represent excellent choices for categorized as pregnancy category C. Data on the safety of entecavir treating HBV infection in HBV-HIV co-infected patients. Gener- during pregnancy have not been published (pregnancy category C). ally, even for HBV-HIV co-infected patients who do not yet meet Sufficient data in animals and limited data in humans suggest that treatment criteria for HIV infection, treating for both HBV and telbivudine and tenofovir (both pregnancy category B) can be used HIV is recommended. In HIV-HBV co-infection, TAF is preferable safely during pregnancy; however, telbivudine is not an acceptable to TDF because of its better safety profile. first-line drug. In general, then, except for lamivudine and tenofo- Patients with chronic hepatitis B who undergo cytotoxic che- vir, and until additional data become available, the other antivirals motherapy for treatment of malignancies as well as patients treated for hepatitis B should be avoided or used with extreme caution dur- with immunosuppressive, anticytokine, or anti–tumor necrosis ing pregnancy. Tenofovir is the current drug of choice in pregnancy. factor (TNF) therapies (the risk varies, from highest [e.g., B cell– For children aged 2 to 2 × several studies confirm a differential effect of TDF on long-term 103 IU/mL, until standard clinical endpoints are met (Table 341-4). HCC risk, many others do not. Therefore, currently, the prepon- Such chemotherapy-associated reactivation of hepatitis B is com- derance of data is insufficient to support this benefit of TDF over mon (4–68%, median 25%, in a meta-analysis) in persons with entecavir. ongoing HBV infection (HBsAg-reactive); however, such reactiva- For patients with end-stage chronic hepatitis B who undergo tion can occur, albeit less commonly, in persons who have cleared liver transplantation, reinfection of the new liver is almost universal HBsAg but express anti-HBc (moderate risk, 80% in genotypes 2 and 3, 2013, with the approval of the first nucleoside analogue polymerase requiring only 24 weeks of therapy—and histologic improvement inhibitor, sofosbuvir. Although several of these combination regi- in approximately three-fourths of patients. After initiation of IFN mens have been supplanted by better, later-generation drugs, as of treatment, ALT levels fell precipitously, and up to 90% of virologic 2020, five all-oral, highly effective (>95%), low-resistance, pangeno- responses were achieved within the first 12 weeks of therapy. Failure typic, well-tolerated, short-duration (primarily 8–12 weeks) combi- to achieve an early virologic response (EVR), a ≥2-log10 reduction in nation regimens of DAA drugs are recommended. The remarkable HCV RNA by week 12, predicted failure to experience a subsequent historical evolution of antiviral therapy for hepatitis C is instructive. SVR. Similarly, patients in whom HCV RNA became undetectable THE INTERFERON ERA (1991–2011) within 4 weeks (i.e., who achieve a rapid virologic response [RVR]) had a very high likelihood of achieving an SVR (Fig. 341-2). Sur- IFN-based therapy has been supplanted by DAA agents introduced prisingly, however, high-dose induction with IFN-based therapy in the second decade of the twenty-first century; however, many did not yield higher SVR rates. important lessons about antiviral therapy for chronic hepatitis C Most relapses occurred within the first 12 weeks after treatment, were learned from the experience with IFN-based treatment, and and absence of HCV RNA 12 weeks after completion of therapy has many of the limitations of—and disparities in responsiveness to— become the current standard for SVR (SVR12); relapses are very rare IFN-based therapy have been overcome by current-generation 6 months to a year after SVR and almost unheard of after 2 years. DAA treatments. Mechanistically, HCV proteins inhibit several Of documented durability decades after successful therapy, an SVR steps of the JAK-STAT signal transduction pathway, and by acti- to antiviral therapy for chronic hepatitis C is tantamount to a cure vation of JAK-STAT signaling, exogenous IFN culminates in and and is followed by marked improvements in liver-disease outcomes restores intracellular expression of IFN-stimulated genes and their (see below). protein products that have antiviral properties. Patient variables that correlated with IFN-based SVRs included When first approved, subcutaneous IFN-α three times a week favorable genotype (genotypes 2 and 3 as opposed to genotypes 1 for 6 months achieved an SVR (Fig. 341-2) (defined then as a and 4; genotype 1b as opposed to genotype 1a); low baseline HCV reduction of HCV RNA to PCR-undetectable levels ≥24 weeks after RNA level (