Chapter 334: Chronic Hepatitis

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. 78), 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 have 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, seven 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, and tenofovir disoproxil fumarate (TDF).

Antiviral therapy for hepatitis B has evolved rapidly since the mid-1990s, as has the sensitivity of tests for HBV DNA. When IFN and lamivudine were evaluated in clinical trials, HBV DNA was measured by insensitive hybridization assays with detection thresholds of 10⁵−10⁶ virions/mL; when adefovir, entecavir, telbivudine, tenofovir, and PEG IFN 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 chronological order of publication of these efficacy trials).

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 IFN given subcutaneously at a daily dose of 5 million units, or three times a week at a dose of 10 million units, 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%). The likelihood of responding to IFN was higher in patients with lower levels of HBV DNA and substantial elevations of ALT. Although children can respond as well as adults, IFN therapy was not effective in very young children infected at birth. Similarly, IFN therapy was not effective in immunosuppressed persons, Asian patients 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). Among patients with HBeAg loss during therapy, long-term follow-up demonstrated that 80% experienced eventual loss of HBsAg (i.e., all serologic markers of infection, and normalization of ALT over a 9-year posttreatment period). 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.

Initial trials of brief-duration IFN therapy in patients with HBeAg-negative chronic hepatitis B were disappointing, suppressing HBV replication transiently during therapy but almost never resulting in sustained antiviral responses. In subsequent IFN trials among patients with HBeAg-negative chronic hepatitis B, however, more protracted courses, lasting up to 1.5 years, were reported to result in sustained remissions documented to last for several years, with suppressed HBV DNA and aminotransferase activity, 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.

Although no longer competitive with the newer generation of antivirals, IFN did represent the first successful antiviral approach and set a standard against which to measure subsequent drugs in the achievement of durable virologic, serologic, biochemical, and histologic responses; consolidation of virologic and biochemical benefit in the ensuing years after therapy; and improvement in 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.

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 patients with chronic hepatitis B. Although generally superseded by newer, more potent, less resistance-prone agents, lamivudine is still used in regions of the world where newer agents are not yet available or affordable. In clinical trials among patients with HBeAg-reactive chronic hepatitis B, lamivudine therapy at daily doses of 100 mg for 48−52 weeks suppressed HBV DNA by a median of ~5.5 log₁₀ copies/mL and to undetectable levels, as measured by PCR amplification assays, in ~40% of patients. Therapy was associated with HBeAg loss in 32−33%, HBeAg seroconversion (i.e., conversion from HBeAg-reactive to anti-HBe-reactive) in 16−21%, normalization of ALT in 40−75%, improvement in histology in 50−60%, retardation in hepatic fibrosis in 20−30%, and prevention of progression to cirrhosis. HBeAg responses occur even in patients resistant to IFN (e.g., those with high-level HBV DNA) or who failed in the past to respond to it. As is true for IFN therapy of chronic hepatitis B, patients with near-normal ALT activity tend not to experience HBeAg responses (despite suppression of HBV DNA), whereas those with ALT levels exceeding 5 × the upper limit of normal can expect 1-year HBeAg seroconversion rates of 50−60%. Generally, HBeAg seroconversions are confined to patients who achieve suppression of HBV DNA to <10⁴ copies/mL (equivalent to ~10³ IU/mL). Lamivudine-associated HBeAg responses are accompanied by a delayed posttreatment HBsAg seroconversion rate comparable to that seen after IFN-induced HBeAg responses. Among Western patients who undergo HBeAg responses during a year-long course of therapy and in whom the response is sustained for 4−6 months after cessation of therapy, the response is durable thereafter in the vast majority (>80%); therefore, the achievement of an HBeAg response represents a viable stopping point in therapy. Reduced durability has been reported in Asian patients; therefore, to support the durability of HBeAg responses, patients should receive a period of consolidation therapy of ≥6 months in Western patients and ≥1 year in Asian patients after HBeAg seroconversion (see treatment guidelines below). Close posttreatment monitoring is necessary to identify HBV reactivation promptly and to resume therapy. If HBeAg is unaffected by lamivudine therapy, the current approach is to continue therapy until an HBeAg response occurs, but long-term therapy may be required to suppress HBV replication and, in turn, limit liver injury; HBeAg seroconversions can increase to a level of 50% after 5 years of therapy. Histologic improvement continues to accrue with therapy beyond the first year; after a cumulative course of 3 years of lamivudine therapy, necroinflammatory activity is reduced in the majority of patients, and even cirrhosis has been shown to regress to precirrhotic stages in as many as three-quarters of patients.

Losses of HBsAg have been few during the first year of lamivudine therapy, and this observation had been cited as an advantage of IFN-based over lamivudine therapy; however, in head-to-head 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.

In patients with HBeAg-negative chronic hepatitis B (i.e., in those with precore and core-promoter HBV mutations), 1 year of lamivudine therapy results in HBV DNA suppression and normalization of ALT in three-quarters of patients and in histologic improvement in approximately two-thirds. Therapy has been shown to suppress HBV DNA by ~4.5 log₁₀ copies/mL (baseline HBV DNA levels are lower than in patients with HBeAg-reactive hepatitis B) and to undetectable levels in ~70%, as measured by sensitive PCR amplification assays. Lacking HBeAg at the outset, patients with HBeAg-negative chronic hepatitis B cannot achieve an HBeAg response—a stopping point in HBeAg-reactive patients; almost invariably, when therapy is discontinued, reactivation is the rule. Therefore, these patients require long-term therapy; with successive years, the proportion with suppressed HBV DNA and normal ALT increases.

Clinical and laboratory side effects of lamivudine are negligible and indistinguishable from those observed in placebo recipients. Still, lamivudine doses should be 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, occur 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 with HBeAg seroconversion in clinical trials were confined to lamivudine-treated patients. When therapy is stopped after a year of therapy, two- to threefold ALT elevations occur in 20−30% of lamivudine-treated patients, representing renewed liver-cell injury as HBV replication returns. Although these posttreatment flares are almost always transient and mild, rare severe exacerbations, especially in cirrhotic patients, have been observed, mandating close and careful clinical and virologic monitoring after discontinuation of treatment. Many authorities caution against discontinuing therapy in patients with cirrhosis, in whom posttreatment flares could precipitate decompensation.

Long-term monotherapy with lamivudine is 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 occur in 15−30% of patients; the frequency increases with each year of therapy, reaching 70% at year 5. Ultimately, patients with YMDD mutants experience degradation of clinical, biochemical, and histologic responses; therefore, if treatment is begun with lamivudine monotherapy, the emergence of lamivudine resistance, reflected clinically by a breakthrough from suppressed levels of HBV DNA and ALT, is managed by adding another antiviral to which YMDD variants are sensitive (e.g., adefovir, tenofovir; see below).

Currently, although lamivudine is very safe and still used widely in other parts of the world, in the United States and Europe, 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. In addition, lamivudine has been 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 has been shown to be effective in reducing the risk of progression to hepatic decompensation and, marginally, 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 was reduced by ~30%, supporting further the beneficial impact of oral antiviral therapy on the natural history of chronic hepatitis B.

Because lamivudine monotherapy can result universally in the rapid emergence of YMDD variants in persons with HIV infection, patients with chronic hepatitis B should be tested for anti-HIV prior to therapy; if HIV infection is identified, lamivudine monotherapy at the HBV daily dose of 100 mg is contraindicated. These patients should be treated 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 is part of the regimen, the daily dose should be 300 mg (Chap. 197). 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. Administration of lamivudine during the last months of pregnancy to mothers with high-level hepatitis B viremia (≥10⁸ IU/mL) can reduce the likelihood of perinatal transmission of hepatitis B.

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 and is equally effective in treatment-naïve patients and prior IFN nonresponders. In HBeAg-reactive chronic hepatitis B, a 48-week course of adefovir dipivoxil was shown to achieve histologic improvement (and reduce the progression of fibrosis) and normalization of ALT in just over one-half of patients, HBeAg seroconversion in 12%, HBeAg loss in 23%, and suppression to an undetectable level of HBV DNA in 13−21%, as measured by PCR. Similar to IFN and lamivudine, adefovir dipivoxil is more likely to achieve an HBeAg response in patients with high baseline ALT; among adefovir-treated patients with ALT level >5 × the upper limit of normal, HBeAg seroconversions occurred in 25%. The durability of adefovir-induced HBeAg responses is high (91% in one study); therefore, HBeAg response can be relied upon as a stopping point for adefovir therapy, after a period of consolidation therapy, as outlined above. Although data on the impact of additional therapy beyond 1 year are limited, biochemical, serologic, and virologic outcomes improve progressively as therapy is continued.

In patients with HBeAg-negative chronic hepatitis B, a 48-week course of 10 mg/d of adefovir dipivoxil resulted in histologic improvement in two-thirds, normalization of ALT in three-fourths, and suppression of HBV DNA to PCR-undetectable levels in one-half to two-thirds. As was true for lamivudine, because HBeAg responses—a potential stopping point—cannot be achieved in this group, reactivation is the rule when adefovir therapy is discontinued, and indefinite, long-term therapy is required. Treatment beyond the first year consolidates the gain of the first year; after 5 years of therapy, improvement in hepatic inflammation and regression of fibrosis were observed in three-fourths of patients, ALT was normal in 70%, and HBV DNA was undetectable in almost 70%. In one study, stopping adefovir after 5 years was followed by sustained suppression of HBV DNA and ALT, but most HBeAg-negative patients are treated indefinitely unless HBsAg loss, albeit very rare, is 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. Hypothetically, these are among the reasons that resistance to adefovir dipivoxil is much less likely than resistance to lamivudine; no resistance was encountered in 1 year of clinical trial therapy. In subsequent years, however, adefovir resistance begins 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). Among patients co-infected with HBV and HIV and who have normal CD4+ T cell counts, adefovir dipivoxil is effective in suppressing HBV dramatically (by 5 logs₁₀ in one study). Moreover, adefovir dipivoxil is effective in lamivudine-resistant, YMDD-mutant HBV and can be used when such lamivudine-induced variants emerge. When lamivudine resistance occurs, adding adefovir (i.e., maintaining lamivudine to preempt the emergence of adefovir resistance) is 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 are rarely encountered. If any nephrotoxicity does occur, it rarely appears before 6−8 months of therapy. Although renal tubular injury is a rare potential side effect, and although creatinine monitoring is recommended during treatment, the therapeutic index of adefovir dipivoxil is high, and the nephrotoxicity observed in clinical trials at higher doses was reversible. For patients with underlying renal disease, frequency of administration of adefovir dipivoxil should be reduced to every 48 h for creatinine clearances of 30−49 mL/min; to every 72 h for creatinine clearances of 10−29 mL/min; and to once a week, following dialysis, for patients undergoing hemodialysis. Adefovir dipivoxil is very well tolerated, and ALT elevations during and after withdrawal of therapy are similar to those observed and described above in clinical trials of lamivudine. An advantage of adefovir is its relatively favorable resistance profile; however, it is not as potent as the other approved oral agents, it does not suppress HBV DNA as rapidly or as uniformly as the others, it is the least likely of all agents to result in HBeAg seroconversion, and 20−50% of patients fail 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 nucleotide analogue tenofovir (see below), is no longer recommended as first-line therapy.

After long-acting PEG IFN was shown to be effective in the treatment of hepatitis C (see below), this more convenient drug 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 nucleoside analogues were conducted among patients with HBeAg-reactive and HBeAg-negative chronic hepatitis B.

In HBeAg-reactive chronic hepatitis B, two large-scale studies were done. In one study, PEG IFN-α 2b (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-α 2a (180 μg weekly for 48 weeks) in 814 primarily Asian patients, three-fourths 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%, normal ALT in 34−39%, and a mean reduction in HBV DNA of 2 log₁₀ copies/mL (PEG IFN-α 2b) to 4.5 log₁₀ copies/mL (PEG IFN-α 2a). 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%, normal ALT in 32−41%, and a mean reduction in HBV DNA of 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-α 2a 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 is associated with HBV genotype A > B > C > D (shown for PEG IFN-α2b but not for α-2a). PEG IFN-α 2a was approved in the US for hepatitis B in 2005; PEG IFN-α 2b, not approved for hepatitis B in the US, 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 and 0% of 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 which can be achieved with PEG IFN, in some cases by several orders of magnitude.

In HBeAg-negative chronic hepatitis B, a trial of PEG IFN-α 2a (180 μg weekly for 48 weeks versus 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%, and normal ALT in 59%. In subjects 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 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 oral-agent-treated patients are of interest, but of limited clinical relevance, given the very high likelihood of virologic responses during such therapy.)

Entecavir, an oral cyclopentyl guanosine analogue polymerase inhibitor (approved 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 have been 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 first-line 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% versus 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 has been recorded 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 or tenofovir 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, a cytosine analogue (approved 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 HBeAg-reactive 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 has been associated with a low frequency of asymptomatic creatine kinase elevations and with a very low frequency of peripheral neuropathy; frequency of administration should be reduced for patients with impaired creatinine clearance. Its excellent potency notwithstanding, the inferior resistance and safety profile of telbivudine has limited its appeal; telbivudine is neither recommended as first-line therapy nor widely used.

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 and 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 add-on 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 toxicity; however, among patients treated with tenofovir, instances of acute renal failure and of low blood phosphate levels have been reported. Thus, in patients receiving tenofovir, monitoring bone density is not recommended, but periodic (at least annual) monitoring for renal injury is (serum creatinine and phosphate, urine glucose and protein). Frequency of tenofovir administration should be reduced for patients with impaired creatinine clearance.

A comparison of the six antiviral therapies in current use appears in Table 334-3; their relative potencies in suppressing HBV DNA are shown in Fig. 334-1.

Although the combination of lamivudine and PEG IFN suppresses HBV DNA more profoundly during therapy than does monotherapy with either drug alone (and is much less likely to be associated with lamivudine resistance), this combination used for a year is no better than a year of PEG IFN in achieving sustained responses. To date, combinations of oral nucleoside/nucleotide agents have not achieved an enhancement in virologic, serologic, or biochemical efficacy over that achieved by the more potent of the combined drugs given individually. In a 2-year trial of combination entecavir and tenofovir versus entecavir monotherapy, for a small subgroup of patients with very high HBV DNA levels (≥10⁸ IU/mL), a reduction in HBV DNA to <50 IU/mL was higher in the combination group (79% vs 62%); however, no differences in HBeAg responses or any other endpoint were observed between the combination-therapy and monotherapy groups, even in the high-HBV DNA subgroup. On the other hand, combining agents that are not cross-resistant (e.g., lamivudine or entecavir with adefovir or tenofovir) has the potential to reduce the risk or perhaps even to preempt entirely the emergence of drug resistance. In the future, the treatment paradigm may shift from the current approach of sequential monotherapy to preemptive combination therapy, perhaps not for all patients but for subsets (e.g., patients with very high levels of HBV DNA, immunosuppressed patients); however, designing and executing clinical trials that demonstrate superior efficacy and resistance profile of combination therapy over monotherapy with entecavir or tenofovir will remain challenging. Whereas, initially, in clinical studies of adefovir as rescue therapy for lamividune resistance, adding adefovir to lamivudine (combination therapy) was considered a better strategy than replacing lamivudine with adefovir monotherapy, according to the 2016 treatment recommendations of the American Association for the Study of Liver Diseases (AASLD), data to support adding or switching agents are insufficient. Therefore, while sound virologic principles would favor adding as opposed to switching, according to current recommendations involving the more potent first-line agents, entecavir for tenofovir resistance and tenofovir for entecavir resistance, either strategy is acceptable. For patients who already have acquired multidrug resistance (to both nucleoside analogues [lamivudine, entecavir, telbivudine] and nucleotide analogues [adefovir, tenofovir]), treatment with a combination of entecavir and tenofovir has been shown to be highly effective in suppressive HBV DNA and overcoming drug resistance.

In addition to the seven approved antiviral drugs for hepatitis B, emtricitabine, a fluorinated cytosine analogue very similar to lamivudine in structure, efficacy, and resistance profile, offers no advantage over lamivudine. A combination of emtricitabine and tenofovir is approved for the treatment of HIV infection and is an appealing combination therapy for hepatitis B, especially for lamivudine-resistant disease; however, neither emtricitabine nor the combination is approved for hepatitis B. Several initially promising antiviral agents have been abandoned because of toxicity (e.g., clevudine, which was linked to myopathy during its clinical development). As noted above, the current formulation of tenofovir, TDF, has been associated with renal toxicity and loss of bone density, especially in patients with HIV infection, less so in patients with HBV infection. A new formulation, tenofovir alafenamide (TAF), is a prodrug of tenofovir that is metabolized to the active agent in its target organ (the liver for HBV infection); such targeting permits higher dose delivery to the liver with markedly reduced systemic exposure. Studies in patients with chronic hepatitis B treated with 25 mg of TAF or 300 mg of TDF demonstrate comparable virologic efficacy as well as less reduction in bone mineral density and estimated glomerular filtration rate for TAF. Based on its better renal and bone safety profile than TDF, TAF has been approved for HBV infection and provides an alternative to TDF in patients with TDF-associated elevations in serum creatinine and/or reductions in serum phosphorus. Direct-acting antivirals (DAAs) have been very successful in the management of chronic hepatitis B; however, most patients require long-duration, usually indefinite, therapy. Ideally, an approach to achieving “cure” (eradication of HBV infection) with finite-duration therapy would be welcome. Currently, innovative approaches being investigated include viral entry inhibitors, nucleocapsid assembly inhibitors, HBV secretion (HBsAg release) inhibitors, immunomodulators (e.g., toll receptor agonists, T-cell vaccines, programmed cell death [PD-1] blockade, reconstitution of innate immune responses [e.g., retinoic acid-inducible gene-1, RIG-1, HBV mRNA recognition, and activation of innate immune signaling) and of adaptive immune responses, covalently closed circular (ccc) DNA silencing/inhibition/cleavage, RNA interference, and HBx inhibitors. While data supporting several of these unconventional approaches have begun to appear, none has been shown to “cure” hepatitis B, and none is likely to be competitive, unless it can be shown to go beyond current antivirals in achieving recovery (HBsAg seroconversion) from HBV infection. Finally, initial emphasis in the development of antiviral therapy for hepatitis B was placed on monotherapy; whether combination regimens will yield additive or synergistic efficacy remains to be determined.

Several learned societies and groups of expert physicians have issued treatment recommendations for patients with chronic hepatitis B; the most authoritative and updated (and free of financial support by pharmaceutical companies) are those of the AASLD and of the European Association for the Study of the Liver (EASL). Although the recommendations differ slightly, a consensus has emerged on most of the important points (Table 334-4). No treatment is recommended or available for inactive “nonreplicative” hepatitis B carriers (undetectable HBeAg with normal ALT and HBV DNA ≤10³ IU/mL documented serially over time). In patients with detectable HBeAg and HBV DNA levels >2 × 10⁴ IU/mL, treatment is recommended by the AASLD for those with ALT levels above 2 × the upper limit of normal. (The EASL recommends treatment in HBeAg-positive patients for HBV DNA levels >2 × 10³ IU/mL and ALT above the upper limit of normal.) For HBeAg-positive patients with ALT ≤2 × the upper limit of normal, in whom sustained responses are not likely and who would require multiyear therapy, antiviral therapy is not recommended currently. This pattern is common during the early decades of life among Asian patients infected at birth; even in this group, therapy would be considered for those >40 years of age, ALT persistently at the high end of the twofold range, and/or with a family history of HCC, especially if the liver biopsy shows moderate to severe necroinflammatory activity or fibrosis. In this group, when, eventually, ALT becomes elevated later in life, antiviral therapy should be instituted. For patients with HBeAg-negative chronic hepatitis B, ALT >2 × the upper limit of normal (above the upper limit of normal according to EASL), and HBV DNA >2 × 10³ IU/mL, antiviral therapy is recommended. If HBV DNA is >2 × 10³ IU/mL and ALT is 1 to >2 × the upper limit of normal, liver biopsy should be considered to help in arriving at a decision to treat if substantial liver injury is present (treatment in this subset would be recommended according to EASL guidelines, because ALT is elevated). Per current AASLD recommendations, antiviral treatment with oral agents can be stopped after HBeAg seroconversion in noncirrhotics, and the suggested period of consolidation therapy is 12 months with close monitoring for recurrent viremia (monthly × 6, then every 3 months for the rest of a year) after cessation of therapy. For patients with HBeAg-negative chronic hepatitis, the current recommendation with oral agents is for indefinite therapy; although sufficient data are lacking, stopping therapy in this group can be considered after HBsAg loss.

For patients with compensated cirrhosis, because antiviral therapy has been shown to retard clinical progression, treatment is recommended regardless of HBeAg status and ALT as long as HBV DNA is detectable at >2 × 10³ IU/mL (detectable at any level according to the EASL); monitoring without therapy is recommended for those with HBV DNA <2 × 10³ IU/mL, unless ALT is elevated. For patients with decompensated cirrhosis, treatment is recommended regardless of serologic and biochemical status, as long as HBV DNA is detectable. Patients with decompensated cirrhosis should be evaluated as candidates for liver transplantation.

Among the seven available drugs for hepatitis B, PEG IFN has supplanted standard IFN, entecavir has supplanted lamivudine, and tenofovir has supplanted adefovir. PEG IFN, entecavir, or tenofovir is recommended as first-line therapy (Table 334-3). PEG IFN requires finite-duration therapy, achieves the highest rate of HBeAg responses after a year of therapy, and does not support viral mutations, but it requires subcutaneous injections and is associated with inconvenience, more intensive clinical and laboratory monitoring, and intolerability. Oral nucleoside analogues require long-term therapy in most patients, and when used alone, lamivudine and telbivudine foster the emergence of viral mutations, adefovir somewhat less so, and entecavir (except in lamivudine-experienced patients) and tenofovir rarely at all. Oral agents do not require injections or cumbersome laboratory monitoring, are very well tolerated, lead to improved histology in 50−90% of patients, suppress HBV DNA more profoundly than PEG IFN, and are effective even in patients who fail to respond to IFN-based therapy. Although oral agents are less likely to result in HBeAg responses during the first year of therapy, as compared to PEG IFN, treatment with oral agents tends to be extended beyond the first year and, by the end of the second year, yields HBeAg responses (and even HBsAg responses) comparable in frequency to those achieved after 1 year of PEG IFN (and without the associated side effects) (Table 334-5). In a 2016 systematic review of 1716 patients involved in 25 clinical trials, responses after oral-agent therapy were found to be durable. Among patients with HBeAg-reactive chronic hepatitis B, the pooled rates of durable HBeAg seroconversions maintained after cessation of nucleoside/nucleotide analogue therapy (including all the oral agents) were 92% and 88% at posttreatment months 12 and 24, respectively, unaffected by the duration of post-HBeAg-response consolidation therapy (>6 months in all studies evaluated); the pooled rate of durable biochemical remission after therapy in this population was 76%. Even for HBeAg-negative chronic hepatitis B, for which most authorities recommend indefinite therapy, pooled rates of virologic remissions maintained after cessation of oral-agent therapy were 44%, 31%, and 30% at posttreatment months 12, 24, and 36, and the pooled rate of durable biochemical remission in this population was 57%.

Although adefovir and tenofovir are safe, renal monitoring (e.g., serum creatinine and phosphate, urine glucose and protein) is recommended. Substantial experience with lamivudine during pregnancy (see above) has identified no teratogenicity; although widely used during pregnancy, lamivudine remains classified as pregnancy category C. Although IFNs do not appear to cause congenital anomalies, these have antiproliferative properties and should be avoided during pregnancy. Adefovir during pregnancy has not been associated with birth defects; however, the risk of spontaneous abortion may be increased, and adefovir is categorized as pregnancy category C. Data on the safety of entecavir during pregnancy have not been published (pregnancy category C). Sufficient data in animals and limited data in humans suggest that telbivudine and tenofovir (both pregnancy category B) can be used safely during pregnancy; however, telbivudine is not an acceptable first-line drug. In general, then, except for lamivudine and tenofovir, and until additional data become available, the other antivirals for hepatitis B should be avoided or used with extreme caution during pregnancy.

For children aged 2 to <18 with HBeAg-reactive hepatitis B (most children will be HBeAg-reactive; no studies have been done in children with HBeAg-negative chronic hepatitis B), treatment is recommended if HBV DNA is detectable and ALT levels are elevated, but not if ALT levels are normal. Each of the available drugs, except telbivudine, is approved for different childhood age groups (standard IFN α-2b age ≥1 year; PEG IFN α-2a age ≥5 years [approved for hepatitis C, not B, but can be used in hepatitis B]; lamivudine and entecavir age ≥2 years; adefovir and tenofovir age ≥12 years). Package inserts should be consulted for childhood doses.

As noted above, some physicians prefer to begin with PEG IFN, while other physicians and patients prefer oral agents as first-line therapy. For patients with decompensated cirrhosis, the emergence of resistance can result in further deterioration and loss of antiviral effectiveness. Therefore, in this patient subset, the threshold for relying on therapy with a very favorable resistance profile (e.g., entecavir or tenofovir) or on combination therapy is low. PEG IFN should not be used in patients with compensated or decompensated cirrhosis.

For patients with end-stage chronic hepatitis B who undergo liver transplantation, reinfection of the new liver is almost universal in the absence of antiviral therapy. The majority of patients become high-level viremic carriers with minimal liver injury. Before the availability of antiviral therapy, an unpredictable proportion experienced severe hepatitis B−related liver injury, sometimes a fulminant-like hepatitis and sometimes a rapid recapitulation of the original severe chronic hepatitis B (Chap. 332). Currently, however, prevention of recurrent hepatitis B after liver transplantation has been achieved definitively by combining hepatitis B immune globulin with one of the low-resistance oral nucleoside (entecavir) or nucleotide analogues (tenofovir) (Chap. 338); preliminary data suggest that the newer, more potent, and less resistance-prone oral agents may be used instead of hepatitis B immune globulin for posttransplantation therapy. In patients documented at the time of liver transplantation to have undetectable HBV DNA in serum and cccDNA in the liver (i.e., with low risk for recurrence of HBV infection), a preliminary clinical trial suggested that, after patients received 5 years of combined therapy, both hepatitis B immune globulin and oral-agent therapy can be withdrawn sequentially (over two 6-month periods) with a success rate, as monitored over a median of 6 years postwithdrawal, of 90% and an anti-HBs seroconversion rate of 60% (some with transient reappearance of HBV DNA and/or HBsAg).

Patients with HBV-HIV co-infection can have progressive HBV-associated liver disease and, occasionally, a severe exacerbation of hepatitis B resulting from immunologic reconstitution following ART. Lamivudine should never be used as monotherapy in patients with HBV-HIV infection because HIV resistance emerges rapidly to both viruses. Adefovir has been used successfully to treat chronic hepatitis B in HBV-HIV co-infected patients but is no longer considered a first-line agent for HBV. Entecavir has low-level activity against HIV and can result in selection of HIV resistance; therefore, it should be avoided in HBV-HIV co-infection. Tenofovir and the combination of tenofovir and emtricitabine in one pill are approved therapies for HIV and represent excellent choices for treating HBV infection in HBV-HIV co-infected patients. Generally, even for HBV-HIV co-infected patients who do not yet meet treatment criteria for HIV infection, treating for both HBV and HIV is recommended.

Patients with chronic hepatitis B who undergo cytotoxic chemotherapy for treatment of malignancies as well as patients treated with immunosuppressive, anticytokine, or antitumor necrosis factor therapies (the risk varies, from highest [e.g., B-cell-depleting agents, anthracycline derivatives, moderate/high-dose corticosteroids for ≥4 weeks] to moderate [e.g., tumor necrosis factor alpha inhibitors, cytokine or integrin inhibitors, tyrosine kinase inhibitors, low-dose corticosteroids for ≥4 weeks], to lowest [e.g., immunosuppressive agents like methotrexate and azathioprine, intraarticular corticosteroids, any dose of corticosteroids for ≤1 week]) experience enhanced HBV replication and viral expression on hepatocyte membranes during chemotherapy coupled with suppression of cellular immunity. When chemotherapy is withdrawn, such patients are at risk for reactivation of hepatitis B, often severe and occasionally fatal. Such rebound reactivation represents restoration of cytolytic T cell function against a target organ enriched in HBV expression. Preemptive treatment with the first of the oral HBV antivirals, lamivudine, prior to the initiation of chemotherapy was shown to reduce the risk of such reactivation substantially; treating after reactivation has occurred is less effective. The newer, more potent oral antiviral agents, entecavir and tenofovir, which are even more effective in preventing hepatitis B reactivation and with a lower risk of antiviral drug resistance, are preferred. The optimal duration of antiviral therapy after completion of chemotherapy is not known, but a suggested approach is 6 months (12 months for B-cell-depleting agents) for inactive hepatitis B carriers and longer-duration therapy in patients with baseline HBV DNA levels >2 × 10³ IU/mL, until standard clinical endpoints are met (Table 334-4). Such chemotherapy-associated reactivation of hepatitis B is common (4–68%, median 25%, in a meta-analysis) in persons with ongoing HBV infection (HBsAg-reactive); however, such reactivation can occur albeit less commonly in persons who have cleared HBsAg, but express anti-HBc (moderate risk, <10%) and rarely (<5%) even in persons with serologic evidence of recovery from HBV infection (anti-HBs-reactive, anti-HBc-reactive). Therefore, most authorities (e.g., Centers for Disease Control and Prevention; AASLD; American Gastroenterological Association; EASL) recommend HBsAg and anti-HBc (± anti-HBs) screening of all patients undergoing such chemotherapy and preemptive antiviral prophylaxis for HBsAg-reactive persons and close on-therapy monitoring of anti-HBc-reactive/anti-HBs-reactive persons with treatment if and when reactivation occurs.

TREATMENT: Chronic Hepatitis D

Management is not well defined, and the host cellular RNA polymerase upon which HDV replication depends cannot be targeted by conventional antiviral agents. Glucocorticoids are ineffective and are not used. Preliminary experimental trials of IFN-α suggested that conventional doses and durations of therapy lower levels of HDV RNA and aminotransferase activity only transiently during treatment but have no impact on the natural history of the disease. In contrast, high-dose IFN-α (9 million units three times a week) for 12 months was reported to be associated with a sustained loss of HDV replication and clinical improvement in up to 50% of patients. Moreover, in anecdotal reports, the beneficial impact of treatment has been observed to persist for 15 years and to be associated with a reduction in grade of hepatic necrosis and inflammation, reversion of advanced fibrosis (improved stage), and clearance of HDV RNA in some patients. A suggested approach to therapy has been high-dose, long-term IFN for at least a year and, in responders, extension of therapy until HDV RNA and HBsAg clearance; however, extension of therapy to a second year provided no advantage, and sustained responses after completion of therapy have been rare. PEG IFN has also been shown to be more effective in the treatment of chronic hepatitis D (e.g., after 48 weeks of therapy, associated with undetectable HDV RNA, durable for at least 24 posttreatment weeks, in a quarter to a half of patients) and is a more convenient replacement for standard IFN; however, loss of virologic responses (reappearance of HDV RNA) was observed during long-term (median 4.5-year) monitoring in over half of initial, 24-week-posttreatment responders. Even extending PEG IFN therapy for 5 years and driving treatment doses up to 270 μg weekly (of PEG IFN- α2a), as reported in a small trial among 13 patients, while achieving serologic, virologic, histologic, biochemical, and clinical improvement, yielded sustained virologic responses (SVRs) in only 3 patients (58–246 weeks of posttreatment observation). None of the nucleoside analogue antiviral agents for hepatitis B is effective in hepatitis D, and adding oral nucleoside agents to PEG IFN is no more effective than PEG IFN monotherapy. While recommended, PEG IFN therapy is far from satisfactory. Preliminary trials have been performed with an oral prenylation inhibitor, lonafarnib, and with an inhibitor of HBV/HDV viral entry into hepatocytes, myrcludex B. Prenylation, the posttranslational covalent addition of the prenyl lipid farnesyl to large HDV antigen, is required for this HDV protein to interact and form secreted viral particles with HBsAg. In 14 patients treated twice daily for 28 days with 100 or 200 mg of lonafarnib, HDV RNA fell by 0.73 log₁₀ IU/mL and 1.54 log₁₀ IU/mL, respectively, before rebounding after completion of therapy. Hepatitis B virus entry into hepatocytes requires the binding of the myristolated N-terminal pre-S1 peptide of large HBsAg to sodium taurocholate co-transporting peptide, the functional receptor for HBV into hepatocytes. The application of myrcludex B, a synthetic homologous myristolated lipopeptide that competes for binding with HBsAg, was reported in a study of 24 patients (with a baseline mean of 4.1–4.2 log₁₀ copies/mL of HDV RNA) randomized to 24 weeks of treatment with myrcludex B (2 mg daily subcutaneously) as monotherapy or combined with PEG IFN compared to PEG IFN alone. A reduction in HDV RNA occurred in all three groups, by 1.67 log₁₀ copies/mL (in two of eight patients RNA became undetectable), 2.59 log₁₀ copies/mL (in five of eight patients RNA became undetectable), and 2.17 log₁₀ copies/mL (in two of eight patients RNA became undetectable), respectively. No change occurred, however, in the level of HBsAg, which would have been expected. In these two exploratory brief-duration trials, sustained responses were not achieved, and toxicities were encountered (e.g., intermittent vomiting and weight loss [lonafarnib] and transient amylase and lipase elevations [myrcludex B]); however, from these proof-of-principle trials, potentially, more definitive and larger-scale studies will follow.

In patients with end-stage liver disease secondary to chronic hepatitis D, liver transplantation has been effective. If hepatitis D recurs in the new liver without the expression of hepatitis B (an unusual serologic profile in immunocompetent persons but common in transplant patients), liver injury is limited. In fact, the outcome of transplantation for chronic hepatitis D is superior to that for chronic hepatitis B; in such patients, combination hepatitis B immune globulin and nucleoside analogue therapy for hepatitis B is indicated (Chap. 338).

TREATMENT: Chronic Hepatitis C

Therapy for chronic hepatitis C has evolved substantially in the 25 years since IFN-α was introduced for this indication in 1991. The therapeutic armamentarium grew to include PEG IFN with ribavirin and, then, in 2011, the introduction of the first protease inhibitors, telaprevir and boceprevir, used in combination with PEG IFN and ribavirin in patients with HCV genotype 1. The field of antiviral therapy for hepatitis C was transformed beginning in 2013, with the approval of the first nucleoside analogue, sofosbuvir. As of 2016, no fewer than six, all-oral, highly effective (>95%), low-resistance, well tolerated, short-duration (usually 12 weeks) combination regimens of DAA drugs are available. The remarkable historical evolution of antiviral therapy for hepatitis C is instructive.

IFN-based therapy has been supplanted by DAA agents introduced in the second decade of the twenty-first century; however, many important lessons about antiviral therapy for chronic hepatitis C were learned from the experience with IFN-based treatment, and many of the limitations of—and disparities in responsiveness to—IFN-based therapy have been overcome by current-generation DAA treatments. When first approved, IFN-α was administered via subcutaneous injection three times a week for 6 months but achieved an SVR (Fig. 334-2) (defined then as a reduction of HCV RNA to undetectable levels by PCR when measured ≥24 weeks after completion of therapy) <10%. Doubling the duration of therapy—but not increasing the dose or changing IFN preparations—increased the SVR rate to ~20%, and addition to the regimen of daily ribavirin, an oral guanosine nucleoside, increased the SVR rate to 40%. When used alone, ribavirin is ineffective and does not reduce HCV RNA levels appreciably, but ribavirin enhances the efficacy of IFN by reducing the likelihood of virologic relapse after the achievement of an end-treatment response (Fig. 334-2) (response measured during, and maintained to the end of, treatment). Proposed mechanisms to explain the role of ribavirin include subtle direct reduction of HCV replication, inhibition of host inosine monophosphate dehydrogenase activity (and associated depletion of guanosine pools), immune modulation, induction of virologic mutational catastrophe, and enhancement of IFN-stimulated gene expression. Ribavirin, despite its poorly understood mechanism of action, retains a modest role in supporting DAA agents as well (see below). IFN therapy results in activation of the JAK-STAT signal transduction pathway, which culminates in the intracellular elaboration of genes and their protein products that have antiviral properties. Hepatitis C proteins inhibit JAK-STAT signaling at several steps along the pathway, and exogenous IFN restores expression of IFN-stimulated genes and their antiviral effects.

Treatment with the combination of PEG IFN and ribavirin increased responsiveness (frequency of SVR) to as high as 55% overall—to >40% in genotypes 1 and 4, and to >80% in genotypes 2 and 3. Even in the absence of biochemical and virologic responses, histologic improvement occurred in approximately three-fourths of all treated patients. In chronic hepatitis C, ALT levels fall precipitously during therapy, and up to 90% of virologic responses are achieved within the first 12 weeks of therapy; responses thereafter are rare. Most relapses occur within the first 12 weeks after treatment; therefore, an SVR at week 12 posttreatment (SVR₁₂) is roughly equivalent to a 24-week SVR, and SVR₁₂ has become the new standard. SVRs are very durable; normal ALT, improved histology, and absence of HCV RNA in serum and liver have been documented a decade after successful therapy, and “relapses” 2 years after sustained responses are almost unheard of. Thus, an SVR to antiviral therapy of chronic hepatitis C is tantamount to a cure, which is followed by marked improvements in liver-disease outcomes (see below).

Patient variables that correlate with sustained virologic responsiveness to IFN-based therapy include favorable genotype (genotypes 2 and 3 as opposed to genotypes 1 and 4; genotype 1b as opposed to genotype 1a); low baseline HCV RNA level (<800,000 IU/mL), low HCV quasispecies diversity, and histologically mild hepatitis and minimal fibrosis, especially absence of cirrhosis; immunocompetence, low liver iron levels, age <40; female gender; and absence of obesity, insulin resistance, type 2 diabetes mellitus, and hepatic steatosis. High levels of HCV RNA, more histologically advanced liver disease, and high HCV quasispecies diversity all go hand in hand with advanced duration of infection and reduced IFN responsiveness. Also associated with poor responses to IFN-based therapy are African-American ethnicity (contributed to, but not explained entirely by, a higher proportion with genotype 1, slower early treatment viral kinetics, impaired HCV-specific immunity, and host genetic differences in IL28B alleles, described below), Latino ethnicity, and poor treatment adherence (<80% of IFN and ribavirin doses and <80% of prescribed duration of therapy). Ironically, patients whose disease was least likely to progress were the ones most likely to respond to IFN and vice versa. For patients treated with combination IFN-ribavirin, therapy for those with genotype 1 usually required a full 48 weeks with SVRs in the range of 40–45%, whereas in those with genotypes 2 and 3, a 24-week course of therapy sufficed with SVRs in the range of 80% (although refined tailoring of treatment duration could be indicated based on rapidity of response or associated cofactors, see below).

Genetic changes in the virus may explain differences in treatment responsiveness in some patients (e.g., among patients with genotype 1b, responsiveness to IFN is enhanced in those with amino-acid-substitution mutations in the nonstructural protein 5A gene). As described above in the discussion of spontaneous recovery from acute hepatitis C, IFN gene variants discovered in genome-wide association studies were shown to have a substantial impact on responsiveness of patients with genotype 1 to antiviral therapy. In studies of patients treated with PEG IFN and ribavirin, variants of the IL28B SNP that code for IFN-λ3 (a type III IFN, the receptors for which are more discretely distributed than IFN-α receptors and more concentrated in hepatocytes) correlate significantly with responsiveness. Patients homozygous for the C allele at this locus have the highest frequency of achieving an SVR (~80%), those homozygous for the T allele at this locus are least likely to achieve an SVR (~25%), and those heterozygous at this locus (C/T) have an intermediate level of responsiveness (SVRs in ~35%).

Side effects of IFN therapy are described in the section on treatment of chronic hepatitis B. The most pronounced side effect of ribavirin therapy is hemolysis—an expected reduction in hemoglobin of up to 2−3 g or in hematocrit of 5−10% but also a small, unpredictable proportion with profound, brisk hemolysis, resulting in symptomatic anemia; therefore, close monitoring of blood counts is crucial, and ribavirin should be avoided in patients with anemia or hemoglobinopathies; in patients with coronary artery disease or cerebrovascular disease, in whom anemia can precipitate an ischemic event; in patients with renal insufficiency (the drug is excreted renally); and in pregnancy (the drug is teratogenic, mandating scrupulous use of efficient contraception during, and for several months after, therapy in women of child-bearing age [because of their antiproliferative properties, IFNs also are contraindicated during pregnancy]). When symptomatic anemia occurs, ribavirin dose reductions or addition of erythropoietin to boost red blood cell levels may be required; erythropoietin was shown to improve patients’ quality of life but not the likelihood of achieving an SVR. If ribavirin was stopped during therapy, SVR rates fell, but responsiveness could be maintained as long as ribavirin was not stopped and the total ribavirin dose exceeded 60% of the planned dose.

Ribavirin can also cause nasal and chest congestion, pruritus, and precipitation of gout. Combination IFN-ribavirin therapy is more difficult to tolerate than IFN monotherapy and more likely to lead to dose reductions and discontinuation of therapy.

Studies of viral kinetics have shown that despite a virion half-life in serum of only 2−3 h, the level of HCV is maintained by a high replication rate of 10¹² hepatitis C virions per day. IFN-α blocks virion production or release with an efficacy that increases with increasing drug doses; moreover, the calculated death rate for infected cells during IFN therapy is inversely related to the level of HCV RNA. Patients with the most rapid death rate of infected hepatocytes are more likely to achieve undetectable HCV RNA at 3 months; in practice, failure to achieve an early virologic response (EVR), a ≥2-log₁₀ reduction in HCV RNA by week 12, predicts failure to experience a subsequent SVR. Similarly, patients in whom HCV RNA becomes undetectable within 4 weeks (i.e., who achieve a rapid virologic response [RVR]) have a very high likelihood of achieving an SVR (Fig. 334-2). Surprisingly, however, high-dose induction with IFN-based therapy did not yield higher SVR rates.

For the treatment of chronic hepatitis C, standard IFNs were supplanted beginning in 2001 by PEG IFNs. These have elimination times up to sevenfold longer than standard IFNs (i.e., a substantially longer half-life) and achieve prolonged concentrations, permitting administration once (rather than three times) a week. Instead of the frequent drug peaks (linked to side effects) and troughs (when drug is absent) associated with frequent administration of short-acting IFNs, administration of PEG IFNs results in drug concentrations that are more stable and sustained over time. Once-a-week PEG IFN monotherapy is twice as effective as monotherapy with its standard IFN counterpart, approaches the efficacy of combination standard IFN plus ribavirin, and is as well tolerated as standard IFNs, without more difficult-to-manage thrombocytopenia and leukopenia than standard IFNs. For most of the decade prior to 2011, when protease inhibitors were introduced for HCV genotype 1 (see below), the standard of care was a combination of PEG IFN plus ribavirin for all HCV genotypes.

Two PEG IFNs are available: PEG IFN-α2b, a 12-kD, linear PEG molecule bound to IFN-α2b, and PEG IFN-α2a, a larger, 40-kD, branched PEG molecule bound to IFN-α2a; because of its larger size and smaller volume of extravascular distribution, PEG IFN-α2a can be given at a uniform dose independent of weight, whereas the dose of the smaller PEG IFN-α2b, which has a much wider volume distribution, must be weight-based. The standard dose of PEG IFN α2a was 180 μg and of PEG IFN-α2b 1.5 μg/kg. The ribavirin dose adopted for both PEG IFNs was, for genotype 1, 1000 mg (for patients <75 kg) to 1200 mg (for patients ≥75 kg) and, for genotypes 2 and 3, 800 mg; a broader ribavirin dose/weight range was approved subsequently for PEG IFN-α2b in patients with genotype 1: <65 kg, 800 mg; 65−85 kg, 1000 mg; >85−105 kg, 1200 mg; and >105 kg, 1400 mg. For both drugs, recommended treatment durations were 48 weeks for genotype 1 and 24 weeks for genotypes 2 and 3 (somewhat more refractory, justifying a full 48 weeks especially for advanced hepatic fibrosis or cirrhosis and/or high-level HCV RNA). Between the two PEG IFNs, PEG IFN-α2a appeared to be slightly better tolerated and slightly more effective than PEG IFN-α2b in registration trials (SVRs for genotype 1: 41–51% vs 40–42%, respectively) as well as in subsequent head-to-head trials and a systematic review of randomized trials (SVR in genotypes 1–4: 48–55% vs 32–40%, respectively).

Until the 2011 introduction of protease inhibitors, unless ribavirin was contraindicated (see above), combination PEG IFN plus ribavirin was the recommended course of therapy. Even after the introduction of protease inhibitors for genotypes 1 and 4, however, PEG IFN–ribavirin remained the standard of care for patients with genotypes 2 and 3 until late 2013. For patients treated with combination PEG IFN–ribavirin, measurement of quantitative HCV RNA levels at 12 weeks was helpful in guiding therapy; if a 2-log₁₀ drop in HCV RNA had not been achieved by this time, chances for an SVR were negligible, and additional therapy was futile. If the 12-week HCV RNA had fallen by 2 log₁₀ (EVR), the chances for an SVR at the end of therapy were approximately two-thirds; if the 12-week HCV RNA was undetectable (“complete” EVR), the chances for an SVR exceeded 80% (Fig. 334-2).

The frequency of an SVR to PEG IFN–ribavirin therapy could be increased by tailoring therapy according to baseline variables and on-treatment virologic responsiveness. In patients with baseline variables weighing against a response (e.g., HCV RNA >800,000 IU/mL, weight >85 kg), by raising the dose of PEG IFN (e.g., to as high as 270 μg of PEG IFN-α2a) and/or the dose of ribavirin to as high as 1600 mg daily (if tolerated or supplemented by erythropoietin); or by extending therapy from 48 to 72 weeks for patients with genotype 1 and a slow virologic response (i.e., failure of HCV RNA to fall rapidly to undetectable levels within 4 weeks [absence of a RVR]), SVR rates could be improved somewhat. In contradistinction, in patients with genotype 1 (and 4) who had a 4-week RVR (which occurred in ≤20%), especially in the subset with low baseline HCV RNA, abbreviating the duration of therapy to 24 weeks, resulted in SVR rates of ~90%. Responsiveness to IFN-ribavirin-based therapy was diminished in immunocompromised patients and in patients with HIV-HCV co-infection and contraindicated in patients with decompensated liver disease or end-stage renal disease. The cumbersome nature of IFN-ribavirin-based therapy (injections, complicated laboratory monitoring, side effects and poor tolerability, modest efficacy, variables and patient subsets associated with poor responsiveness, tailored therapy, futility rules, etc.) was supplanted eventually (in 2016) by DAAs for all genotypes (see below). Most of the variables associated with poor responsiveness to IFN-based therapy became irrelevant, and difficult-to-treat patient subpopulations began to experience responses to DAAs that were indistinguishable from responses in standard patients (see below).

Persons with chronic HCV infection have been shown to suffer increased liver-related mortality. On the other hand, successful antiviral therapy of chronic hepatitis C resulting in an SVR has been shown to improve survival (and to reduce the need for liver transplantation); to lower the risk of liver failure, liver-related death, and all-cause mortality; to slow the progression of chronic hepatitis C; and to reverse fibrosis and even cirrhosis. Whereas the 10-year and 20-year survival in the absence of an SVR is reduced in cirrhotic patients with chronic hepatitis C, survival at these intervals after an SVR has been found to be indistinguishable from that of the general population. Although successful treatment reduces mortality and liver failure (3-4-fold 10-year reduction) in cirrhotic patients (and in those with advanced fibrosis) and reduces the need for liver transplantation and the likelihood of HCC (14-fold 10-year reduction), the risk of liver-related death and HCC persists, albeit at a much reduced level, necessitating continued clinical monitoring and cancer surveillance after SVR in cirrhotics. On the other hand, in the absence of an SVR, IFN-based therapy does not reduce the risk of HCC. Similarly, for nonresponders to PEG IFN–ribavirin therapy, three trials of long-term maintenance therapy with PEG IFN showed no benefit in reducing the risk of histologic progression or clinical decompensation, including the development of HCC. Fortunately, PEG IFN-ribavirin nonresponders can now be retreated with DAAs and experience SVR rates comparable to those in treatment-naïve persons (see below).

The HCV RNA genome encodes a single polyprotein, which is cleaved during and after translation by host and viral-encoded proteases. One protease involved in the cleavage of the viral polyprotein is an NS3/4A viral protein that has serine protease activity. Telaprevir and boceprevir are serine protease inhibitors that target NS3/4A. In 2011, telaprevir and boceprevir used in combination with PEG IFN and ribavirin were approved by the U.S. Food and Drug Administration (FDA) as the first oral DAA agents for the treatment of hepatitis C genotype 1 (not other genotypes) in adults with stable liver disease, both in patients who had not been treated before or who had failed previous treatment. Although now replaced by more effective, all-oral regimens, these first-in-class agents represented a breakthrough in the treatment of chronic hepatitis C and established milestones against which subsequent therapies could be measured.

Because resistance developed rapidly during monotherapy with telaprevir and boceprevir, these drugs had to be used in combination with PEG IFN and ribavirin. Ribavirin in particular appeared to reduce relapse rates significantly in protease inhibitor-based regimens, such that those who could not take or were intolerant to ribavirin were unlikely to benefit from the addition of these agents. Telaprevir and boceprevir regimens consisted of periods of triple therapy (protease inhibitor plus PEG IFN plus ribavirin) and periods of dual therapy (PEG IFN plus ribavirin). Telaprevir regimens began with 12 weeks of triple therapy followed by dual therapy of a duration based on HCV RNA status at weeks 4 and 12 (“response-guided therapy”) and prior treatment status. Boceprevir-based regimens consisted of a 4-week lead-in period of dual (PEG IFN–ribavirin) therapy followed by triple therapy and, in some instances, a further extension of dual therapy, with duration of response-guided therapy based on HCV RNA status at weeks 4, 8, and 24 and prior treatment status.

For patients with HCV genotype 1, protease inhibitors improved the frequency of RVRs and SVRs significantly as compared to PEG IFN plus ribavirin alone. In treatment-naïve patients, telaprevir-based SVRs were achieved in up to 79% of patients who received 12 weeks of triple therapy followed by 12–36 weeks of dual therapy, and among those with EVRs (undetectable HCV RNA at weeks 4 and 12) and response-guided therapy stopped at week 24 (12 weeks of triple therapy, then 12 weeks of dual therapy), SVRs occurred in 83–92%. In studies with boceprevir in treatment-naïve patients, SVRs occurred in 59–66% of patients, and among those with undetectable HCV RNA at 8 weeks, the SVR rate increased to 86–88%. Adding to the complexity of treatment with these protease inhibitors were absolute stopping rules for futility, that is, absence of HCV RNA reductions at critical treatment milestones, which were shown to be invariably predictive of nonresponse (telaprevir: HCV RNA >1000 IU/mL at weeks 4 or 12, or detectable at week 24; boceprevir: HCV RNA ≥100 IU/mL at week 12, or detectable at week 24).

In patients previously treated unsuccessfully with PEG IFN plus ribavirin, telaprevir-based treatment achieved SVRs in 83–88% of prior relapsers, 54–59% of partial responders (HCV RNA reduced by ≥2 log₁₀ IU/mL but not to undetectable levels), and 29–33% of null responders (HCV RNA reduced by <2 log₁₀ IU/mL). With boceprevir, a similar degradation in SVR rate occurred as a function of prior responsiveness—in 75% of prior relapsers, in 40–52% of previous partial responders; in ~30–40% of null responders. In a substantial proportion of protease inhibitor nonresponders, resistance-associated substitutions (RASs, previously referred to as resistance-associated variants, RAVs) could be identified, but these variants were not archived, and wild-type HCV reemerged in almost all cases within 1.5 to 2 years. SVRs to these protease inhibitors were highest in prior relapsers and treatment-naïve patients (white > black ethnicity), lower in prior partial responders, lower still in prior null responders, and lowest in cirrhotic prior null responders, for whom no benefit accrued over PEG IFN/ribavirin treatment. Responses to protease inhibitor triple-drug regimens were higher in patients with IL28B C than non-C genotypes, HCV genotype 1b than genotype 1a, less advanced than more advanced fibrosis stage, whites than blacks, lower body mass index (BMI) than elevated BMI, and, for boceprevir, achievement of a >1 log₁₀ HCV RNA reduction during 4 weeks of PEG IFN–ribavirin lead-in therapy. Age and HCV RNA level were less influential and insulin resistance was noninfluential on response to these antiviral agents.

Both of these protease inhibitors had substantial toxicities. Telaprevir was associated with a severe, generalized (trunk and extremities), often confluent, maculopapular, pruritic rash in ~6% of treated patients (that required careful dermatologic monitoring in all patients and systemic corticosteroid therapy in the most severely affected). Other common side effects included pruritus, rectal burning, nausea, diarrhea, fatigue, dysgeusia (altered or unpleasant taste), and anemia, which required close monitoring, could be relatively refractory, occasionally requiring transfusion and even hospitalization (especially in cirrhotic prior nonresponders). Anemia occurred in half of boceprevir-treated patients, neutropenia in up to 30% and thrombocytopenia in 3–4%. Other side effects of boceprevir include fatigue, nausea, headache, dysgeusia, dry mouth, vomiting, and diarrhea.

Both drugs came with an inconveniently high pill burden and had to be administered every 8 hours with food (TVR with a 20-g fat meal). Use of protease inhibitors was further complicated by numerous drug-drug interactions. As telaprevir and boceprevir are both eliminated by and inhibit CYP3A4, these agents could not be administered with other medications that induce CYP3A4 or are dependent on CYP3A4 for elimination. Care had to be taken to examine for any potential interactions between these protease inhibitors and other medications the patient was taking, and a convenient website became available to check for such drug-drug interactions (www.hep-druginteractions.org).

Despite the improvement in SVRs with protease-inhibitor-based regimens for genotype 1 compared to PEG IFN-ribavirin (e.g., in treatment-naïve patients 66–79% vs 38–44%), triple-drug protease-inhibitor therapy was hampered by amplified intolerability, the complexity of response-guided regimens and futility stopping rules, the inconvenience of thrice-daily dosing with meals and a high pill burden, the need for PEG IFN injections and ribavirin with all their intolerability, and multiple drug-drug interactions. Moreover, side effects appeared to be more severe and burdensome once these drugs entered practice, especially in cirrhotic nonresponders, in whom studies reported from Europe showed serious adverse events in up to 45% and deaths in up to 3%. All these issues, as well as rapidly accelerating progress on next-generation and all-oral DAA therapy (see below), conspired to temper enthusiasm for these new antivirals; after a brief stint as recommended therapy (2011–2013), these drugs became obsolete and are no longer recommended.

Since late 2013, the number of new antiviral agents for hepatitis C has expanded substantially, and, currently, PEG IFN-based treatments have been supplanted by six therapeutic regimens: all oral, IFN-free, highly efficacious (>95% SVR), well tolerated, with high barriers to resistance, simple dosing and low pill burdens, treatment durations as brief as 8 to 12 weeks, and, in many cases, pangenotypic efficacy (Table 334-6). These drugs are distributed among three classes of DAAs: NS3/4 protease inhibitors (which cleave the single HCV polyprotein into constituent structural and nonstructural proteins), NS5B nucleoside and nonnucleoside polymerase inhibitors (which interfere with the RNA-dependent RNA polymerase [a replicase] involved in synthesis of viral RNA), and NS5A inhibitors (which interfere with a membrane-associated phosphoprotein essential to the HVC RNA replication complex).

The first of the new DAA agents (approved in November 2013) was simeprevir, a second-generation protease inhibitor for genotype 1, followed shortly thereafter (December 2013) by sofosbuvir, a pangenotypic nucleoside polymerase inhibitor. For genotype 1, both of these agents had to be combined with PEG IFN and ribavirin; for genotypes 2 and 3, sofosbuvir was administered with ribavirin, without PEG IFN; however, these treatment regimens have been supplanted by combinations of all-oral, IFN-free, DAAs, and ribavirin is rarely needed, retained only for very limited indications.

Simeprevir: When simeprevir was used with PEG IFN, its efficacy (genotype 1b > 1a) was similar to that of first-generation protease inhibitors, but required only once-a-day dosing without the complexity of response-guided therapy. Similar to first-generation protease inhibitors, simeprevir was hampered by many drug-drug interactions and side effects (including photosensitivity, rash, and mild hyperbilirubinemia); moreover, patients, with HCV NS3 polymorphism Q80K had markedly reduced drug efficacy, necessitating pretreatment genetic testing and disqualifying a substantial proportion (approximately a third) of potential treatment candidates. Little about simeprevir supported its adoption in combination with PEG IFN and ribavirin. On the other hand, the combination of simeprevir (150 mg) along with sofosbuvir (400 mg) for 12 weeks was found to be effective in treatment-naïve (97% SVR₁₂) or treatment-experienced (95% SVR₁₂) patients without cirrhosis and in treatment-naïve (88% SVR₁₂) or treatment-refractory (79% SVR₁₂) patients with cirrhosis (it remains one of the recommended regimens for genotype 1).

Sofosbuvir: Sofosbuvir, the first nonprotease inhibitor DAA to be approved, has an excellent profile—high potency, high barrier to resistance, pangenotypic activity, very well tolerated with limited adverse effects (most commonly mild fatigue, insomnia, headache, and nausea), once-daily oral administration, and relative freedom from major drug-drug interactions. Sofosbuvir has efficacy in all genotypes (1 to 6); in treatment-naïve subjects and prior nonresponders to PEG IFN-based and protease-inhibitor-based therapy; with PEG IFN-RBV or in IFN-free regimens; in combination with RBV or with NS5A inhibitors; and for treatment periods as brief as 8 to 12 weeks to as long as 24 weeks. Currently, sofosbuvir is used in combination with either the protease inhibitor simeprevir (as described above) or, more commonly, with one of three NS5A inhibitors. Thus, sofosbuvir is a component of four of the six recommended DAA regimens for genotype 1, two of the four regimens for genotype 4, and both of the regimens for genotypes 2, 3, 5, and 6 (Table 334-6).

Sofosbuvir/ledipasvir: The DAA combination that has had a dominant role in the treatment of hepatitis C is sofosbuvir (400 mg) plus the NS5A inhibitor ledipasvir (90 mg) in a once-a-day, fixed-dose, single pill, approved in October 2014 for genotype 1 and in November 2015 for genotypes 4, 5, and 6. Phase-III trials were conducted in treatment-naïve noncirrhotic patients, in treatment-naïve cirrhotic and noncirrhotic patients, and in treatment-experienced cirrhotic and noncirrhotic patients treated for 8, 12, or 24 weeks, both with and without ribavirin. In treatment-naïve noncirrhotics, an SVR₁₂ was achieved in 97–99% of subjects, and no benefit was observed by extending therapy from 12 to 24 weeks or by adding ribavirin. Moreover, for treatment-naïve, noncirrhotic patients with baseline HCV RNA <6 × 10⁶ IU/mL, a treatment duration of 8 weeks was as effective as one of 12 weeks (94–95% SVR₁₂), which may be a consideration for a proportion of patients. In cirrhotic patients, SVR₁₂ was achieved in 97–100% of treatment-naïve subjects (no advantage of extending therapy from 12 to 24 weeks or of adding ribavirin); however, for cirrhotic prior nonresponders to IFN-based therapy, 12 weeks of therapy was inferior (86% SVR₁₂) to 24 weeks of therapy (100% SVR₁₂). This combination, which is equally effective in patients with HIV-HCV co-infection and in African-American patients, has been shown to be highly effective in patients with decompensated cirrhosis and in patients with hepatitis C after liver transplantation and after kidney transplantation. On the other hand, the safety and efficacy of sofosbuvir/ledipasvir in patients with advanced renal failure have not been established, and all sofosbuvir-containing regimens can be associated with severe bradycardia in patients taking the antiarrhythmic agent amiodarone, especially along with beta blockers; sofosbuvir-containing combinations are contraindicated with amiodarone. Drug-drug interactions are few, but P-gp inducers, like St. John’s wort and rifampin, and proton-pump gastric acid inhibitors, like omeprazole, may reduce sofosbuvir/ledipasvir concentrations. Generally, responsiveness to sofosbuvir/ledipasvir is not reduced in patients with baseline RASs to these agents, with the exception of treatment-experienced patients who have baseline NS5A RASs (for whom EASL recommends adding ribavirin or, if ribavirin in contraindicated, extending treatment to 24 weeks).

Paritaprevir/ritonavir, ombitasvir, and dasabuvir: The combination of ritonavir (100 mg)-boosted paritaprevir (150 mg), a protease inhibitor; ombitasvir (25 mg), an NS5A inhibitor; dasabuvir (250 mg), a nonnucleoside polymerase inhibitor; ± weight-based ribavirin (total of five drugs) was approved in December 2014 for genotypes 1 and 4. Paritaprevir/ritonavir and ombitasvir, formulated in a single tablet, are taken once daily, and both dasabuvir (a separate pill) and weight-based ribavirin (when included in the regimen) are taken twice daily. In clinical trials, this combination achieved SVR₁₂ rates of 87–100% in treatment-naïve and treatment-experienced patients with genotype 1; without ribavirin, this combination in genotype 1a is ~7% less responsive than genotype 1b. Therefore, in treatment-naïve patients with genotype 1a, this combination is administered with ribavirin for 12 weeks in the absence of cirrhosis (95–97% SVR₁₂) or for 24 weeks in the presence of compensated cirrhosis (94% SVR₁₂), while in patients with genotype 1b, the combination does not require ribavirin, and the duration of therapy is 12 weeks for both noncirrhotics and cirrhotics (99–100% SVR₁₂). In prior nonresponders without cirrhosis, the combination is administered for 12 weeks, with ribavirin in genotype 1a (96% SVR₁₂), without ribavirin in genotype 1b (100% SVR₁₂). In prior nonresponders with cirrhosis, the combination is administered for 24 weeks with ribavirin in genotype 1a (SVR₁₂ 100% in prior relapsers and partial responders, 95% in prior null responders [in whom treatment without ribavirin was associated with an 80% SVR₁₂]), but only for 12 weeks and without ribavirin in genotype 1b (100% SVR₁₂). For genotype 4, the regimen is given for 12 weeks with ribavirin, but without dasabuvir in treatment-naïve and treatment-experienced patients (100% SVR₁₂), including those with compensated cirrhosis. In July 2016, the FDA approved a long-acting formulation of dasabuvir, allowing once-a-day instead of twice-a-day treatment; for genotype 1a, twice-daily ribavirin dosing remains.

This combination is well tolerated with generally mild side effects, for example, fatigue, asthenia, insomnia, headache, and pruritus. Hyperbilirubinemia (primarily unconjugated) and elevations in alanine aminotransferase activity may occur but resolve during or shortly after treatment. Because of occasional hyperbilirubinemia and potential hepatotoxicity (FDA warning letter issued October 2015 regarding hepatic failure/decompensation reported in treated cirrhotic patients), this combination is not recommended in patients with decompensated cirrhosis, and treated cirrhotic patients should be monitored closely for decompensation; however, the safety and efficacy of this combination have been demonstrated for patients with advanced renal insufficiency. Similar to other regimens containing protease inhibitors, drug-drug interactions are common with other drugs that induce CYP3A4 or are dependent on CYP3A4 for elimination. Checking for potential drug-drug interactions is important prior to initiating therapy with this drug combination (www.hep-druginteractions.org). Responsiveness to this multidrug regimen is not reduced in patients with baseline RASs to these agents.

Compared to sofosbuvir/ledipasvir, this regimen has the disadvantage of requiring twice-a-day ribavirin therapy for genotype 1a and of being contraindicated in decompensated cirrhosis; however, it has the advantage of offering a 12-week, ribavirin-free regimen for prior null responders with cirrhosis and providing an option for patients with renal failure.

Sofosbuvir and Daclatasvir: Daclatasvir, an NS5A inhibitor, along with the polymerase inhibitor sofosbuvir, was approved by the FDA in July 2015 for genotype 3 and in February 2016 for genotype 1 (AASLD-Infectious Diseases Society of America [IDSA] guidelines [see below] include its recommendation as well for genotype 2; in August 2014, this combination was approved in Europe for genotypes 1, 2, 3, and 4, and EASL recommends it for all these genotypes as well as for genotypes 5 and 6). At the time of its approval for genotype 3, daclatasvir filled a need inadequately met by other available combination DAAs. Although data on genotype 3 are the most robust, clinical trials of this combination in genotypes 1 and 2 support its efficacy and recommendations for first-line (genotype 1) and alternative (genotype 2) treatment, in some cases with ribavirin (Table 334-6). Daclatasvir, a 60-mg tablet, and sofosbuvir, a separate 400 mg tablet are taken once-a-day for 12 to 24 weeks.

In clinical trials among treatment-naïve or treatment-experienced patients, SVR₁₂ rates for 12 weeks of daclatasvir plus sofosbuvir were 98% with genotype 1 (comparable results in genotypes 1a and 1b), 92% for genotype 2, and 89% for genotype 3. For noncirrhotic patients, the addition of ribavirin or the extension of therapy to 24 weeks did not improve efficacy. In patients with compensated cirrhosis, limited prospective data and data from observational cohorts suggested that extending therapy to 24 weeks, with or without ribavirin, improved efficacy. In cirrhotics, SVR₁₂ was achieved in 93% with Child Class-Pugh A and B but in only 56% with Class-C decompensated cirrhosis. For patients with genotype 3 and cirrhosis, the combination was effective in treatment-naïve patients (94% SVR₁₂), but less so in prior nonresponders (69% SVR₁₂). Outcomes in patients with HIV-HCV co-infection were comparable.

Like other sofosbuvir-NS5A inhibitor combinations, daclatasvir plus sofosbuvir is well tolerated (mild fatigue, headache, nausea, diarrhea in 5–14%), but can cause severe bradycardia when administered with amiodarone (contraindicated), especially along with beta blockers. Because daclatasvir is a substrate for CYP3A, CYP3A inducers can reduce daclatasvir levels, and CYP3A inhibitors reduce daclatasvir levels. Similarly, daclatasvir, an inhibitor of P-gp, OATP1B1 and 1B3, and BCP, can increase the levels of drugs that are substrates of these transporters. As noted above for other DAAs, checking for potential drug-drug interactions is advisable prior to initiating therapy (www.hep-druginteractions.org). Responsiveness to daclatasvir-containing drug-combination therapy is reduced in cirrhotic patients with genotype 1a and in both cirrhotic and noncirrhotic patients with genotype 3 who have baseline daclatasvir-associated NS5A RASs.

Although daclatasvir-sofosbuvir is approved for genotypes 1 and 3 and recommended as an alternative for genotype 2, better documented efficacy and simplicity of other regimens have limited the popularity of this drug combination.

Elbasvir/Grazoprevir: Elbasvir (50 mg), an NS5A inhibitor, combined in a single, fixed-dose pill with grazoprevir (100 mg), an NS3/4 protease inhibitor, was approved in January 2016 as a once-a-day (with or without food) treatment for genotypes 1 and 4. In clinical trials, a 12-week course was effective in treatment-naïve and treatment-experienced patients without cirrhosis or with compensated cirrhosis. In treatment-naïve patients, this combination yielded an SVR₁₂ in 92% of patients with genotype 1a, 99% with genotype 1b, and 100% with genotype 4 (very small numbers, however); 10 patients with genotype 6 were included, but only 80% achieved SVR₁₂. Cirrhotic and noncirrhotic patients had comparable rates of SVR₁₂, 97% and 94%, respectively. For this drug combination, however, ~11% of patients with genotype 1a harbor NS5A polymorphisms, that is, RASs, at baseline. If present, these NS5A RASs reduce efficacy of elbasvir/grazoprevir (unlike baseline RASs to the most of the other combination DAA regimens described above and below) from 99% to 58% in treatment-naïve patients. Therefore, all patients with genotype 1a require baseline RAS testing; if these RASs are present, treatment extension to 16 weeks and the addition of weight-based ribavirin bring the SVR₁₂ up to expected levels of close to 100%. In treatment-experienced patients, both extending treatment to 16 weeks and adding ribavirin were studied; however, generally, in the absence of baseline NS5A RASs, SVR₁₂ rates were not increased over those without ribavirin for 12 weeks (94–97%). For genotype 1a, among prior nonresponders to PEG IFN/ribavirin, 12 weeks of elbasvir/grazoprevir suffices without ribavirin except for patients with baseline NS5A RASs, who require 16 weeks of therapy and ribavirin. Among nonresponders to prior protease-inhibitor therapy, even in the absence of baseline NS5A RASs, ribavirin should be added to a 12-week regimen; in the presence of baseline NS5A RASs, treatment should be extended to 16 weeks and ribavirin added. For genotype 1b, NS5A RASs are not an issue, and the only subgroup requiring modification of a 12-week course of therapy are prior nonreponders to protease-inhibitor regimens, for whom ribavirin is added. For genotype 4, the recommended regimen for all prior nonresponders (whether to PEG IFN/ribavirin or protease inhibitor regimens) is 16 weeks of elbasvir/grazoprevir plus ribavirin (Table 334-6).

This combination is just as effective in patients with HIV-HCV co-infection and in patients with advanced renal failure (including those requiring hemodialysis); however, it is contraindicated in decompensated cirrhosis. Like other protease inhibitor regimens, elbasvir/grazoprevir can be associated with aminotransferase elevations and potential hepatotoxicity; because these drugs are excreted by the liver, in decompensated liver disease, plasma drug concentrations may become elevated substantially. Therefore, all treated patients should have alanine aminotransferase screening periodically during therapy, and the drug should be stopped for elevations exceeding 10-fold or for elevations of conjugated bilirubin, alkaline phosphatase, or prothrombin time.

Elbasvir/grazoprevir is well tolerated, with only low levels of mild adverse effects (fatigue, headache, nausea in 5–11%) seen just as frequently in placebo recipients. Both elbasvir and grazoprevir are substrates for CYP3A and are subject to multiple potential drug-drug interactions. Therefore, this combination should not be used with potent CYP3A inducers; conversely, CYP3A and OATP1B1 inhibitors can lead to untoward elevations of plasma elbasvir/grazoprevir concentrations. Checking for potential drug-drug interactions is advisable prior to initiating therapy (www.hep-druginteractions.org).

Compared to other available regimens for genotypes 1 and 4, elbasvir/grazoprevir has the disadvantage/inconvenience of requiring baseline NS5A RAS testing but the advantages of a comparable regimen for cirrhotics and noncirrhotics, for treatment-naïve and treatment-experienced patients, and for patients with normal renal function and with renal failure.

Sofosbuvir/velpatasvir: The combination in a single, fixed-dose pill of velpatasvir (100 mg), a highly potent, pangenotypic NS5A inhibitor, along with the polymerase inhibitor sofosbuvir (400 mg) was approved in June 2016 for genotypes 1–6, in treatment-naïve and treatment-experienced noncirrhotics and cirrhotics. Ribavirin is not required, including in patients with genotypes 2 and 3, except in patients with decompensated cirrhosis.

In a series of clinical trials, this combination for 12 weeks in the absence of ribavirin was shown to yield 99% SVR₁₂ (range 97–100%) in genotypes 1, 2, 4, 5, and 6 and 95% in genotype 3. Baseline NS5A RASs had no impact on responsiveness.

Prior to the availability of this drug combination, patients with genotype 3, especially those with cirrhosis and prior null response to other therapies, proved to be the most refractory subset of patients. In treatment-naïve patients with genotype 3, 12 weeks of sofosbuvir/velpatasvir (95% SVR₁₂) was superior to 24 weeks of sofosbuvir plus ribavirin (80% SVR₁₂). In patients with genotype 3, the combination of sofosbuvir/velpatasvir for 12 weeks was comparable in noncirrhotics (97% SVR₁₂) and cirrhotics (91% SVR₁₂) and in treatment-naïve (97% SVR₁₂) and treatment-experienced (90% SVR₁₂) patients, superior in all these categories to 24 weeks of sofosbuvir plus ribavirin (87%, 66%, 86%, and 63%, respectively). In cirrhotic null responders, most available IFN-free regimens for genotype 3 (including daclatasvir plus sofosbuvir, approved specifically for this genotype) achieved SVR₁₂ rates in the range of ~60–75%, while the combination of PEG IFN, ribavirin, and sofosbuvir could boost SVR₁₂ to the mid-80% range. For treatment-experienced patients with genotype 3, sofosbuvir/velpatasvir in noncirrhotics and cirrhotics had similarly high efficacy (91% and 89% SVR₁₂, respectively); this was the highest recorded SVR₁₂ for genotype-3 cirrhotic null responders treated with IFN-free DAA regimens. Finally, in patients with genotypes 1–4 and 6 and with decompensated, Class-B cirrhosis (55% treatment-experienced), sofosbuvir/velpatasvir plus ribavirin for 12 weeks yielded an SVR₁₂ in 94%; this result was better than sofosbuvir/velpatasvir without ribavirin for 12 weeks (83% SVR₁₂) or 24 weeks (86% SVR₁₂).

Like other all-oral DAAs, sofosbuvir/velpatasvir was very well tolerated; in noncirrhotic and compensated cirrhotic patients, mild headache and fatigue was seen in >10%—this occurred in a comparable proportion of placebo recipients; in decompensated cirrhosis, mild fatigue, headache, nausea, insomnia, diarrhea, and anemia (ribavirin was part of the regimen) was seen in >10%. Like other sofosbuvir-containing regimens, sofosbuvir/velpatasvir should not be administered along with amiodarone (potential serious bradycardia); in addition, P-gp inducers and moderate-to-potent CYP3A inducers can reduce plasma levels of sofosbuvir and/or velpatasvir. Checking for drug-drug interactions prior to therapy is advisable (www.hep-druginteractions.org). Baseline RASs do not influence responsiveness to this combination.

Most treatment needs have been met by contemporary DAA regimens described above; however, several additional, highly potent, pangenotypic drug combinations are in development. For example, an investigative protease inhibitor (voxilaprevir) added to the polymerase inhibitor/NS5A inhibitor combination of sofosbuvir/velpatasvir yields a very well tolerated triple-drug combination with 97% SVR₁₂ across all HCV genotypes and patient subgroups. These include noncirrhotic/cirrhotic, treatment-naïve/treatment-experienced groups, including those who had prior NS5A treatment and results were independent of the number of prior DAA drug classes received; no effects of baseline NS5A RASs were noted. Several experimental combinations may allow even briefer durations of therapy. In a small, exploratory trial, a 6-week combination of sofosbuvir plus an experimental pangenotypic, very high potency, very low resistance NS5A inhibitor (odalasvir) achieved SVR₁₂ in 100% of 12 patients with genotype 1. Similarly, in a 6-week triple combination of odalasvir with the protease inhibitor simeprevir and an experimental polymerase inhibitor (“AL-335”), SVR₁₂ was observed in 100% of 20 treatment-naïve noncirrhotic patients with genotype 1. In phase-II clinical trials, 8 weeks of an experimental combination of two high-potency, pangenotypic DAAs, a protease inhibitor (“ABT-493”) plus an NS5A inhibitor (“ABT-530”), yielded 100% SVR₁₂ in treatment-naïve noncirrhotic patients with genotypes 1, 2, and 3. In cirrhotics with genotype 3 and in patients with genotypes 4, 5, and 6, 12 weeks of therapy with this DAA combination yielded 100% SVR₁₂. In patients with prior DAA treatment failure, 12 weeks of this double-combination sufficed to achieve a ≥95% SVR₁₂; neither baseline NS5A nor protease inhibitor RASs influenced SVR₁₂ rates. No safety issues have been encountered, and the potential for drug-drug interactions is limited. These promising combinations are undergoing phase-II and phase-III trials.

Less advanced is the development of inhibitors of host proteins, such as oral, nonimmunosuppressive inhibitors of cyclophilin A (which interacts with NS5A during HCV replication) and subcutaneous antisense antagonists of host liver-expressed micro-RNA-122 (which promotes HCV replication). Given the accelerated progress of all-oral, short-treatment-duration, high-efficacy, DAAs, these alternative approaches may not be practical or competitive; moreover, development of both approaches has been retarded by emerging toxicities such as pancreatitis associated with cyclophilin inhibitors and jaundice associated with micro-RNA-122.

Although data on the impact of DAAs on the natural history of chronic hepatitis C are still limited, preliminary findings are that successful therapy is associated with a gradual reduction in fibrosis progression and a regression of advanced fibrosis (cirrhosis), improvement in survival among patients with decompensated cirrhosis, and a decline in the number of patients with hepatitis C being referred for liver transplantation. Based on the known prevalence, natural history, and rate of progression of chronic hepatitis C and on the efficacy of DAA therapies and their impact on the complications of hepatitis C, modeling estimates have suggested that the availability and application of these therapies have the potential to reduce the hepatitis C-associated disease burden including liver-related death, HCC, decompensated cirrhosis, and liver transplantation by 50–70% between 2015 and 2050.

Because the pace of new drug development and approval has been so rapid, the AASLD and the IDSA have been providing a consensus of updated treatment recommendations for patients with hepatitis C; these recommendations, which continue to be revised regularly based on new data, are available online at www.hcvguidelines.org and should be consulted before initiating therapy (Table 334-6). The EASL issues similar (but not identical) treatment recommendations annually for hepatitis C (www.easl.eu), most recently in September 2016. Divergences between AASLD-IDSA and EASL recommendations are noted in Table 334-6.

Prior to therapy, HCV genotype should be determined, because the genotype dictates which treatment regimens are indicated (Table 334-6). Monitoring of serum HCV RNA levels pretreatment, during treatment, and posttreatment is crucial in assessing response to therapy; moreover, the baseline level may contribute to determining the duration of therapy (e.g., in noncirrhotic patients with genotype 1 and HCV RNA <6 × 10⁶ IU/mL, 8 [instead of the usual 12] weeks of sofosbuvir/ledipasvir may be a consideration). The goal of treatment is to eradicate HCV RNA during therapy and to document that the virus remains undetectable for at least 12 weeks after completion of therapy (SVR₁₂). Several reports have appeared describing hepatitis B reactivation, often severe, during and after DAA therapy in patients coinfected with HCV and HBV who were not being treated for their HBV infections. Therefore, screening for HBV infection is recommended prior to initiating DAA therapy for hepatitis C (which should have been done to determine HBV-immunity status as a prelude to recommended hepatitis B vaccination in patients with chronic hepatitis C), and therapy for HBV infection (for those meeting HBV treatment criteria, see above) should be initiated prior to or simultaneously with HCV therapy.

Patients with chronic hepatitis C who have detectable HCV RNA in serum, whether or not aminotransferase levels are increased, and chronic hepatitis of any grade and stage are candidates for antiviral therapy with DAA agents. The only exception would be patients with short life expectancies, for whom treating hepatitis C would have no influence on longevity. Certainly, for patients with advanced liver disease, early treatment merits a high priority. Although patients with persistently normal aminotransferase activity tend to progress histologically very slowly or not at all, they respond to antiviral therapy just as well as do patients with elevated aminotransferase levels; therefore, such patients are potential candidates for antiviral therapy. As noted above, antiviral therapy has been shown to improve survival and complication-free survival and to slow progression of and to reverse fibrosis.

HCV genotype determines the regimen to be selected (Table 334-6). Similarly, the absence or presence of cirrhosis/advanced fibrosis determines the treatment options from which to select, including the antiviral agents to be used, the duration of therapy, and the need for ribavirin (Table 334-6). A pretreatment liver biopsy to assess histologic grade and stage provides substantial information about progression of hepatitis C in the past, has prognostic value for future progression, and can identify such histologic factors as steatosis and stage of fibrosis, which can influence responsiveness to therapy. As therapy has improved for patients with a broad range of histologic severity, and as noninvasive measures of the stage of fibrosis (e.g., assessment of liver elasticity by imaging) have gained in accuracy and popularity, noninvasive approaches have supplanted histology in most cases. If cirrhosis/advanced fibrosis is present prior to therapy, the risk of HCC, although reduced substantially by successful therapy, is not eliminated, and twice yearly posttreatment imaging for HCC surveillance (and endoscopic surveillance for esophageal varices at intervals of 1–3 years) is indicated even after an SVR. In patients with low-level fibrosis at baseline, achievement of an SVR allows the cessation of such surveillance.

Patients who have relapsed after, or failed to respond to, a course of IFN-based or DAA agent-based therapy are candidates for retreatment with a DAA therapy regimen (Table 334-6). For patients who have failed to respond to a DAA combination, options include increasing the duration of therapy with the failed regimen, adding ribavirin, or changing the drug class (e.g., after failed protease and polymerase inhibitors, switching to an NS5A-containing combination). In the presence of cirrhosis or a need for urgent retreatment, patients who have failed protease inhibitor plus polymerase inhibitor combination therapy or who have failed an NS5A combination are candidates for RAS testing and tailored therapy based on such resistance testing. If reliable RAS testing is not available, adding ribavirin or extending the duration of therapy are options. For prior nonresponders to IFN-based therapy, NS5A inhibitor-containing regimens are highly effective; however, reduced responsiveness can be encountered, especially in cirrhotic patients. For this relatively refractory group, ideally, the most potent/effective NS5A regimen should be selected to give such patients the best chance of responding and to avoid treatment-emergent NS5A RASs. Additional details for treatment of such patient subgroups can be found at www.hcvguidelines.org.

Persons with acute hepatitis C are also candidates for antiviral therapy (Chap. 332) with the same DAA agents approved for chronic hepatitis C; delaying the initiation of therapy for an observation period of 12–16 weeks (and even up to 6 months) has been recommended to allow for spontaneous recovery, especially in light of the fact that most cases of acute hepatitis C are not clinically severe or rapidly progressive. The duration of therapy for acute hepatitis C has not been determined definitively; however, in a small study of 20 patients, 6 weeks of sofosbuvir/ledipasvir sufficed for a 100% SVR₁₂. According to 2016 EASL recommendations, patients with acute hepatitis C should be treated for 8 weeks with a genotype-appropriate DAA regimen consisting of sofosbuvir plus one of the three approved NS5A inhibitors without ribavirin (extended to 12 weeks for patients with acute hepatitis C and HIV co-infection or for patients with acute hepatitis C and a baseline HCV RNA level >1 million IU/mL). In patients with biochemically and histologically mild chronic hepatitis C, the rate of progression is slow; however, such patients respond just as well to antiviral therapy as those with elevated aminotransferase levels and more histologically severe hepatitis. Because of the high cost of DAA treatments, initially a higher priority was assigned to patients with advanced fibrosis/cirrhosis; however, this controversial approach was relied upon by some medical insurers and pharmacy benefit management organizations to withhold therapy from patients with low-level fibrosis. Unfortunately, delaying therapy until fibrosis becomes advanced misses the opportunity to prevent all the dire consequences of chronic hepatitis C (liver failure, death/transplantation, HCC), which can be reduced, but not eliminated completely once advanced fibrosis is established. Therefore, therapy for patients with mild disease is justified as well as cost-effective.

Patients with compensated cirrhosis can respond to therapy, and their likelihood of a sustained response with DAAs is comparable to that in noncirrhotics. Patients with decompensated cirrhosis, who were not candidates for IFN-based antiviral therapy, respond well to DAA therapy regimens consisting of combinations of polymerase inhibitors and NS5A inhibitors (e.g., sofosbuvir/ledipasvir, sofosbuvir/velpatasvir); however, protease-inhibitor-containing combinations have been associated with potential hepatotoxicity and hepatic decompensation and are contraindicated in this patient subset. Patients with decompensated cirrhosis should be referred to a liver transplantation center. DAAs are highly effective not only for patients with end-stage liver disease awaiting liver transplantation but also for patients with recurrent hepatitis C after liver transplantation. Ideally, patients should be treated prior to liver transplantation; however, a concern is that eradication of HCV infection will disqualify such patients from accepting donor livers from persons with HCV infection, thus contracting the potential donor pool and limiting accessibility to donor organs and timely transplantation. In addition, responsiveness to DAA therapy appears to be reduced in patients with decompensated cirrhosis and with high model for end-stage liver disease (MELD) scores; in this subgroup, responsiveness after liver transplantation would be substantially better. Therefore, advocacy has been expressed (recommended by EASL) for postponing DAA therapy in patients with high-MELD HCV-associated end-stage liver disease until after liver transplantation; the decision whether to treat pretransplantation or posttransplantation should be individualized thoughtfully for each patient, based on such factors as MELD score, time anticipated prior to availability of a donor organ, relative clinical stability, and co-morbidities (Chap. 338). The cutaneous and renal vasculitis of HCV-associated essential mixed cryoglobulinemia (Chap. 332) may respond to antiviral therapy, but sustained responses were rare after discontinuation of therapy in the IFN era, and prolonged, potentially indefinite, therapy was recommended. Now that more effective DAAs are available, a 12-week course of sofosbuvir-based combination therapy has been shown to yield an SVR₁₂ rate exceeding 80% in cryoglobulinemic vasculitis. Anecdotal reports suggest that IFN-based antiviral therapy may be effective in porphyria cutanea tarda or lichen planus associated with hepatitis C; whether the more appealing DAAs are effective in these groups remains to be documented.

In patients with HCV/HIV co-infection, hepatitis C is more progressive and severe than in HCV-monoinfected patients. Although patients with HCV/HIV co-infection responded less well to IFN-based antiviral therapy for hepatitis C, they respond as well as patients with HCV infection alone to DAA combination regimens. In HCV/HIV-infected patients, ribavirin can potentiate the toxicity of didanosine (e.g., lactic acidosis) and the lipoatrophy of stavudine, and zidovudine can exacerbate ribavirin-associated hemolytic anemia; therefore, these drug combinations should be avoided.

Patients with a history of injection drug use and alcoholism can be treated successfully for chronic hepatitis C, preferably in conjunction with drug and alcohol treatment programs. Moreover, because injection-drug users, as a source of transmission to others, account disproportionately for perpetuating the spread of HCV infection in the population, the impact of treating active injection-drug users is amplified by reducing such transmission. The approved oral combinations of DAAs are effective in patients with mild-modest renal failure and require no dose adjustments; however, in patients with severe renal impairment (creatinine clearances <30 mL/minute), data are limited on the use of sofosbuvir-containing combinations. For such patients, including those undergoing hemodialysis, recommended combinations are 12 weeks of elbasvir/grazoprevir for genotypes 1a, 1b, and 4 or 12 weeks of paritaprevir/ritonavir, ombitasvir, and dasabuvir for genotype 1b. In genotype 1a, the addition of 200 mg/day of ribavirin to paritaprevir/ritonavir, ombitasvir, and dasabuvir, if the hemoglobin level exceeds 10 g/dL, is an alternative regimen but requires vigilance for the onset of ribavirin-induced hemolytic anemia. For patients with severe renal impairment and HCV genotypes 2, 3, 5, or 6, PEG IFN with low-dose ribavirin (200 mg daily, if the hemoglobin exceeds 10 g/dL) is recommended. After renal transplantation, levels of SVR₁₂ in patients treated with the approved oral DAA combinations have approached 100%.

No clinical studies of the use of DAAs during pregnancy are available. Ribavirin is contraindicated during pregnancy; therefore, any regimen including ribavirin should not be used. Sofosbuvir; sofosbuvir + ledipasvir; and paritaprevir/ritonavir, ombitasvir, and dasabuvir are classified as pregnancy category B; the other DAAs do not have a pregnancy classification. Therefore, these therapies are not indicated routinely in pregnancy and should be used, with caution, only if the benefit of treatment is compelling and justified compared to the potential for fetal risk.

Choosing among available treatment options: The large number of recommended all-oral DAA combinations can be daunting to treating clinicians. In some instances, the combination approved is determined by insurance payers; however, cost considerations aside, how is the clinician to choose among the options? The most popular of the regimens has been fixed-dose, single-pill sofosbuvir/ledipasvir, which is effective for all genotypes except 2 and 3, which requires no baseline RAS testing, and which can be used in noncirrhotic patients with genotype 1 and low-level viremia for as brief a period as 8 weeks. For genotypes 2 and 3, fixed-dose, single-pill sofosbuvir/velpatasvir appears to be the combination of choice; because this combination is so effective across all genotypes, in the future, for simplicity, clinicians may resort to a “one-size-fits-all” regimen such as this one in all patients (except for those with advanced renal failure). In addition, this regimen is the only one that can be used in almost all situations (independent of genotype, treatment experience, and cirrhosis) without ribavirin, and the duration of which is almost always 12 weeks; exceptions: a) ribavirin recommended for decompensated cirrhosis, b) EASL recommends adding ribavirin in treatment-experienced patients with genotype 3 or, if ribavirin is contraindicated, extending treatment to 24 weeks (Table 334-6, footnote c). As noted above, protease-inhibitor-containing DAA regimens (elbasvir/grazoprevir; paritaprevir/ritonavir, ombitasvir, and dasabuvir; simeprevir and sofosbuvir) are contraindicated in decompensated cirrhosis. For advanced renal failure, safety and efficacy have been documented for elbasvir/grazoprevir and paritaprevir/ritonavir, ombitasvir, and dasabuvir, but not for sofosbuvir-NS5A combinations.

TREATMENT: Autoimmune Hepatitis

The mainstay of management in autoimmune hepatitis is glucocorticoid therapy. Several controlled clinical trials have documented that such therapy leads to symptomatic, clinical, biochemical, and histologic improvement as well as increased survival. A therapeutic response can be expected in up to 80% of patients. Unfortunately, therapy has not been shown in clinical trials to prevent ultimate progression to cirrhosis; however, instances of reversal of fibrosis and cirrhosis have been reported in patients responding to treatment, and rapid treatment responses within 1 year do translate into a reduction in progression to cirrhosis. Although some advocate the use of prednisolone (the hepatic metabolite of prednisone), prednisone is just as effective and is favored by most authorities. Therapy may be initiated at 20 mg/d, but a popular regimen in the United States relies on an initiation dose of 60 mg/d. This high dose is tapered successively over the course of a month down to a maintenance level of 20 mg/d. An alternative, but equally effective, more appealing approach is to begin with half the prednisone dose (30 mg/d) along with azathioprine (50 mg/d). With azathioprine maintained at 50 mg/d, the prednisone dose is tapered over the course of a month down to a maintenance level of 10 mg/d. The advantage of the combination approach is a reduction, over the span of an 18-month course of therapy, in serious, life-threatening complications of steroid therapy (e.g., cushingoid features, hypertension, diabetes, osteoporosis) from 66% down to under 20%. Genetic analysis for thiopurine S-methyltransferase allelic variants does not correlate with azathioprine-associated cytopenias or efficacy and is not assessed routinely in patients with autoimmune hepatitis. In combination regimens, 6-mercaptopurine may be substituted for its prodrug azathioprine, but this is rarely required. Azathioprine alone, however, is not effective in achieving remission, nor is alternate-day glucocorticoid therapy. Limited experience with budesonide in noncirrhotic patients suggests that this steroid side effect−sparing drug may be effective; however, the few randomized controlled trials of budesonide have not consistently shown efficacy. Although therapy has been shown to be effective for severe autoimmune hepatitis (AST ≥10 × the upper limit of normal or ≥5 × the upper limit of normal in conjunction with serum globulin greater than or equal to twice normal; bridging necrosis or multilobular necrosis on liver biopsy; presence of symptoms), therapy is not indicated for mild forms of chronic hepatitis, and the efficacy of therapy in mild or asymptomatic autoimmune hepatitis has not been established.

Improvement of fatigue, anorexia, malaise, and jaundice tends to occur within days to several weeks; biochemical improvement occurs over the course of several weeks to months, with a fall in serum bilirubin and globulin levels and an increase in serum albumin. Serum aminotransferase levels usually drop promptly, but improvements in AST and ALT alone do not appear to be reliable markers of recovery in individual patients; histologic improvement, characterized by a decrease in mononuclear infiltration and in hepatocellular necrosis, may be delayed for 6−24 months. Still, if interpreted cautiously, aminotransferase levels are valuable indicators of relative disease activity, and, although recommended, many authorities do not advocate for serial liver biopsies to assess therapeutic success or to guide decisions to alter or stop therapy. Rapidity of response is more common in older patients (≥69 years) and those with HLA DBR1*04; although rapid responders may progress less slowly to cirrhosis and liver transplantation, they are no less likely than slower responders to relapse after therapy. Therapy should continue for at least 12−18 months. After tapering and cessation of therapy, the likelihood of relapse is at least 50%, even if posttreatment histology has improved to show mild chronic hepatitis, and the majority of patients require therapy at maintenance doses indefinitely. Continuing azathioprine alone (2 mg/kg body weight daily) after cessation of prednisone therapy has been shown to reduce the frequency of relapse. Long-term maintenance with low-dose prednisone (≤10 mg daily) has also been shown to keep autoimmune hepatitis in check without the theoretical risk of azathioprine marrow suppression and, in young women of child-bearing age, teratogenicity; however, maintenance azathioprine is more effective in preserving remission.

In medically refractory cases, an attempt should be made to intensify treatment with high-dose glucocorticoid monotherapy (60 mg daily) or combination glucocorticoid (30 mg daily) plus high-dose azathioprine (150 mg daily) therapy. After a month, doses of prednisone can be reduced by 10 mg a month, and doses of azathioprine can be reduced by 50 mg a month toward ultimate, conventional maintenance doses. Patients refractory to this regimen may be treated with cyclosporine, tacrolimus, or mycophenolate mofetil. Similarly, in exploratory studies, infusions of monoclonal antibodies directed at tumor necrosis factor (infliximab) and against the B-lymphocyte antigen CD20 (rituximab) have been reported to be of clinical benefit (improved aminotransferase levels, immunoglobulin G levels, histologic inflammatory activity) as rescue therapy for refractory autoimmune hepatitis. To date, however, only limited, often anecdotal, data in small numbers of patients support these alternative approaches. If medical therapy fails, or when chronic hepatitis progresses to cirrhosis and is associated with life-threatening complications of liver decompensation, liver transplantation is the only recourse (Chap. 338); in patients with severe autoimmune hepatitis, failure of the bilirubin to improve after 2 weeks of therapy should prompt early consideration of the patient for liver transplantation. Recurrence of autoimmune hepatitis in the new liver occurs rarely in most experiences but in as many as 35−40% of cases in others; nonetheless, 5-year patient and graft survival exceed 80%.

Like all patients with chronic liver disease, patients with autoimmune hepatitis should be vaccinated against hepatitis A and B, ideally before immunosuppressive therapy is begun, if practical. Patients with autoimmune hepatitis and cirrhosis should be screened for HCC with ultrasound at 6-month intervals and for gastroesophageal varices with upper gastrointestinal endoscopy at intervals of 1–3 years, based on severity of liver disease.