InternalMed_Harrison

InternalMed_Harrison. hepatitis B (in whom such therapy can actually be detrimental, sometimes precipitating decompensation, often associated with severe adverse effects). Among patients with HBeAg loss during therapy, long-term follow-up has demonstrated that 80% experience 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 have been documented among IFN responders, supporting the conclusion that successful antiviral therapy improves the natural history of chronic hepatitis B.


InternalMed_Harrison

InternalMed_Harrison. Initial trials of brief-duration IFN therapy in patients with HBeAgnegative 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, have been 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.


InternalMed_Harrison

InternalMed_Harrison. 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 2034 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.


InternalMed_Harrison

InternalMed_Harrison. The first of the nucleoside analogues to be approved, the dideoxynucleoside lamivudine inhibits reverse transcriptase activity of both HIV and HBV and is a potent and effective agent for patients with chronic hepatitis B. Although generally superseded by newer, more potent agents, lamivudine is still used in regions of the world where newer agents are not yet approved are or not 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 approximately 5.5 log10 copies/ mL and to undetectable levels, as measured by PCR amplification assays, in approximately 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 fibrosis in 20−30%; and prevention of progression to cirrhosis. HBeAg


InternalMed_Harrison

InternalMed_Harrison. to anti-HBe-reactive) in 16−21%; normalization of ALT in 40−75%; improvement in histology in 50−60%; retardation in fibrosis in 20−30%; and prevention of progression to cirrhosis. HBeAg responses can occur even in subgroups who are 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), and 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 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


InternalMed_Harrison

InternalMed_Harrison. are accompanied by a 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. 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


InternalMed_Harrison

InternalMed_Harrison. 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.


InternalMed_Harrison

InternalMed_Harrison. 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.


InternalMed_Harrison

InternalMed_Harrison. 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 approximately 4.5 log10 copies/mL (baseline HBV DNA levels are lower than in patients with HBeAg-reactive hepatitis B) and to undetectable levels in approximately 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.


InternalMed_Harrison

InternalMed_Harrison. 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, occur at an identical frequency in placebo recipients, but ALT elevations associated with HBeAg seroconversion are confined to lamivudine-treated patients. When therapy is stopped after a year of therapy, twoto 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


InternalMed_Harrison

InternalMed_Harrison. 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.


InternalMed_Harrison

InternalMed_Harrison. 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-methionineaspartate-aspartate (YMDD) motif 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).


InternalMed_Harrison

InternalMed_Harrison. 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 has provided proof of the concept 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


InternalMed_Harrison

InternalMed_Harrison. 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.


InternalMed_Harrison

InternalMed_Harrison. 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. 226). 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. Limited data even suggest that administration of lamivudine during the last months of pregnancy to mothers with


InternalMed_Harrison

InternalMed_Harrison. and has been used safely in pregnant women with HIV infection and with HBV infection. Limited data even suggest that 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.


InternalMed_Harrison

InternalMed_Harrison. At an oral daily dose of 10 mg, the acyclic nucleotide analogue adefovir dipivoxil, the prodrug of adefovir, reduces HBV DNA by approximately 3.5−4 log10 copies/mL and is equally effective in treatmentnaïve patients and 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 (e.g., among adefovir-treated patients with ALT level >5 × the upper limit of normal), and 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


InternalMed_Harrison

InternalMed_Harrison. normal), and 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.


InternalMed_Harrison

InternalMed_Harrison. 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.


InternalMed_Harrison

InternalMed_Harrison. 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


InternalMed_Harrison

InternalMed_Harrison. 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-mutant HBV 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 nephro-2035 toxic. 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 elevations


InternalMed_Harrison

InternalMed_Harrison. these doses, the drug was nephro-2035 toxic. 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 elevations of creatinine 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 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


InternalMed_Harrison

InternalMed_Harrison. of 10−29 mL/min; and 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.


InternalMed_Harrison

InternalMed_Harrison. 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 have been conducted among patients with HBeAg-reactive and HBeAg-negative chronic hepatitis B.


InternalMed_Harrison

InternalMed_Harrison. In HBeAg-reactive chronic hepatitis B, two large-scale studies were done. One study evaluated PEG IFN-α 2b (100 μg weekly for 32 weeks, then 50 μg weekly for another 20 weeks for a total of 52 weeks, with 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 approximately 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 approximately 35%, HBeAg seroconversion in


InternalMed_Harrison

InternalMed_Harrison. (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 approximately 35%, HBeAg seroconversion in approximately 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


InternalMed_Harrison

InternalMed_Harrison. 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).


InternalMed_Harrison

InternalMed_Harrison. Based on these results, some authorities concluded that PEG IFN monotherapy should be the first-line therapy of choice in HBeAgreactive chronic hepatitis B; however, this conclusion has been challenged. Although a finite, 1-year course of PEG IFN results in a higher 2036 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


InternalMed_Harrison

InternalMed_Harrison. 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 3−6 years in previously


InternalMed_Harrison

InternalMed_Harrison. 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 3−6 years in previously treatment-naïve, entecavirtreated and 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


InternalMed_Harrison

InternalMed_Harrison. 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


InternalMed_Harrison

InternalMed_Harrison. 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


InternalMed_Harrison

InternalMed_Harrison. 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.


InternalMed_Harrison

InternalMed_Harrison. Entecavir, an oral cyclopentyl guanosine analogue polymerase inhibitor, 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 versus 5.5 log10 copies/mL), percentage with undetectable HBV DNA (<300 copies/mL by PCR; 67% versus 36%), histologic improvement (≥2-point improvement in necroinflammatory HAI score; 72% versus 62%), and normal ALT (68% versus 60%). The two treatments were indistinguishable in percentage with HBeAg loss (22% versus 20%) and seroconversion (21% versus 18%). Among patients treated with entecavir for 96 weeks, HBV DNA was undetectable cumulatively in 80% (versus 39% for lamivudine), and HBeAg seroconversions had occurred in 31% (versus 26% for lamivudine). After 3–6 years of entecavir, HBeAg


InternalMed_Harrison

InternalMed_Harrison. for 96 weeks, HBV DNA was undetectable cumulatively in 80% (versus 39% for lamivudine), and HBeAg seroconversions had occurred in 31% (versus 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 versus 4.5 log10 copies/mL) and in percentage with undetectable HBV DNA (90% versus 72%), histologic improvement (70% versus 61%), and normal ALT (78% versus 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


InternalMed_Harrison

InternalMed_Harrison. 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.


InternalMed_Harrison

InternalMed_Harrison. 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 versus 0.48 log10 copies/mL), undetectable HBV DNA (72% versus 19%), normal ALT (61% versus 15%), HBeAg loss (10% versus 3%), and HBeAg seroconversion (8% versus 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; therefore, entecavir is not as attractive a choice as adefovir or tenofovir for patients with lamivudine-resistant hepatitis B.


InternalMed_Harrison

InternalMed_Harrison. In clinical trials, entecavir has 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.


InternalMed_Harrison

InternalMed_Harrison. Telbivudine, a cytosine analogue, 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 HBeAgnegative 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


InternalMed_Harrison

InternalMed_Harrison. 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 profile of telbivudine has limited its appeal; telbivudine is neither recommended as first-line therapy nor widely used.


InternalMed_Harrison

InternalMed_Harrison. Tenofovir disoproxil fumarate, an acyclic nucleotide analogue and potent antiretroviral agent used to treat HIV infection, is similar to adefovir but more potent in suppressing HBV DNA and inducing HBeAg responses; it is highly active against both wild-type and lamivudineresistant 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,


InternalMed_Harrison

InternalMed_Harrison. 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 2037 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 5 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 lamivudineresistant chronic hepatitis B. Frequency of tenofovir administration should be reduced for patients with impaired creatinine clearance.


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InternalMed_Harrison. A comparison of the six antiviral therapies in current use appears in Table 362-3; their relative potencies in suppressing HBV DNA are shown in Fig. 362-1. Although the combination of lamivudine and PEG IFN suppresses HBV DNA more profoundly during therapy than does monotherapy ComPARiSon of PEGylATED inTERfERon (PEG ifn), lAmiVuDinE, ADEfoViR, EnTECAViR, TElBiVuDinE, AnD TEnofoViR THERAPy foR CHRoniC HEPATiTiS Ba Route of administration Subcutaneous Oral Oral Oral Oral Oral injection Duration of therapyc 48–52 weeks ≥52 weeks ≥48 weeks ≥48 weeks ≥52 weeks ≥48 weeks HBeAg seroconversion 1 yr Rx 18–20% 16–21% 12% 21% 22% 21% >1 yr Rx NA up to 50% @ 5 yrs 43% @ 3 yrsd 31% @ 2 yrs 30% @ 2 yrs 40% @ 5 yrs (mean copies/mL) HBeAg-reactive 4.5 5.5 median 3.5–5 6.9 6.4 6.2 HBeAg-negative 4.1 4.4–4.7 median 3.5–3.9 5.0 5.2 4.6 HBV DNA PCR negative (<300–400 copies/mL; <1000 copies/mL for adefovir) at end of yr 1


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InternalMed_Harrison. HBsAg loss yr 1 3–4% ≤1% 0% 2% <1% 3% >yr 1 12% 5 yr after No data 5% at yr 5 6% at yr 6 No data 8% at yr 5 1 yr of Rx Histologic improvement (≥2 point reduction in HAI) at yr 1 HBeAg-reactive 38% 6 months 49–62% 53–68% 72% 65% 74% after HBeAg-negative 48% 6 months 61–66% 64% 70% 67% 72% after Viral resistance None 15–30% @ 1 yr None @ 1 yr ≤1% @ 1 yre Up to 5% @ yr 1 0% @ yr 1 70% @ 5 yrs 29% @ 5 yrs 1.2% @ 6 yrse Up to 22% @ yr 2 0% through yr 5 Pregnancy category C Cf C CBB Cost (US$) for 1 yr ~$18,000 ~$2,500 ~$6,500 ~$8,700g ~$6,000 ~$6,000 aGenerally, these comparisons are based on data on each drug tested individually versus placebo in registration clinical trials; because, with rare exception, these comparisons are not based on head-to-head testing of these drugs, relative advantages and disadvantages should be interpreted cautiously. bAlthough standard interferon α administered daily or three times a week is approved as therapy for chronic hepatitis B, it has been supplanted


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InternalMed_Harrison. and disadvantages should be interpreted cautiously. bAlthough standard interferon α administered daily or three times a week is approved as therapy for chronic hepatitis B, it has been supplanted by PEG IFN, which is administered once a week and is more effective. Standard interferon has no advantages over PEG IFN. cDuration of therapy in clinical efficacy trials; use in clinical practice may vary. dBecause of a computer-generated randomization error that resulted in misallocation of drug versus placebo during the second year of clinical trial treatment, the frequency of HBeAg seroconversion beyond the first year is an estimate (Kaplan-Meier analysis) based on the small subset in whom adefovir was administered correctly. e7% during a year of therapy (43% at year 4) in lamivudine-resistant patients. fDespite its Class C designation, lamivudine has an extensive pregnancy safety record in women with HIV/AIDS. gApproximately $17,400 for lamivudine-refractory patients.


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InternalMed_Harrison. Abbreviations: ALT, alanine aminotransferase; HAI, histologic activity index; HBeAg, hepatitis B e antigen; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; NA, not applicable; PEG IFN, pegylated interferon; PCR, polymerase chain reaction; Rx, therapy; yr, year. FIGURE 362-1 Relative potency of antiviral drugs for hepatitis B, as reflected by median log10 HBV DNA reduction in HBeAgpositive chronic hepatitis B. These data are from individual reports of large, randomized controlled registration trials that were the basis for approval of the drugs. In most instances, these data do not represent direct comparisons among the drugs, because study populations were different, baseline patient variables were not always uniform, and the sensitivity and dynamic range of the HBV DNA assays used in the trials varied. ADV, adefovir dipivoxil; ETV, entecavir; LAM, lamivudine; PEG IFN, pegylated interferon α2a; TBV, telbivudine; TDF, tenofovir disoproxil fumarate.


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InternalMed_Harrison. 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% versus 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 and adefovir or tenofovir) has the potential to reduce the risk or perhaps


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InternalMed_Harrison. even in the high-HBV DNA subgroup. On the other hand, combining agents that are not cross-resistant (e.g., lamivudine and 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.


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InternalMed_Harrison. 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 yet 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). Because direct-acting antivirals have been so successful in the management of chronic hepatitis B, more unconventional approaches— e.g., immunologic (e.g., toll receptor agonists) or genetic manipulation (e.g., RNA interference—gene silencing—to reduce HBV DNA transcription)—are not likely to be competitive, unless they can be


InternalMed_Harrison

InternalMed_Harrison. e.g., immunologic (e.g., toll receptor agonists) or genetic manipulation (e.g., RNA interference—gene silencing—to reduce HBV DNA transcription)—are not likely to be competitive, unless they 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.


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InternalMed_Harrison. 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 American Association for the Study of Liver Diseases (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 362-4). 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


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InternalMed_Harrison. 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


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InternalMed_Harrison. 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).


InternalMed_Harrison

InternalMed_Harrison. 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.


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InternalMed_Harrison. 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 362-3). 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


InternalMed_Harrison

InternalMed_Harrison. 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,


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InternalMed_Harrison. Chronic hepatitis >103 1 to >2 × ULNd Consider liver biopsy; treath if biopsy shows moderate to severe inflammation or fibrosis Chronic hepatitis >104 >2 × ULNd Treath,i Cirrhosis compensated >2 × 103 < or > ULN Treate with oral agents, not PEG IFN <2 × 103 < or > ULN Treath with oral agentsg, not PEG IFN; refer for liver transplantation Undetectable aBased on practice guidelines of the American Association for the Study of Liver Diseases (AASLD). Except as indicated in footnotes, these guidelines are similar to those issued by the European Association for the Study of the Liver (EASL). bLiver disease tends to be mild or inactive clinically; most such patients do not undergo liver biopsy. cThis pattern is common during early decades of life in Asian patients infected at birth. dAccording to the EASL guidelines, treat if HBV DNA is >2 × 103 IU/mL and ALT >ULN. eOne of the potent oral drugs with a high barrier to resistance (entecavir or tenofovir) or PEG IFN can be used as first-line


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InternalMed_Harrison. to the EASL guidelines, treat if HBV DNA is >2 × 103 IU/mL and ALT >ULN. eOne of the potent oral drugs with a high barrier to resistance (entecavir or tenofovir) or PEG IFN can be used as first-line therapy (see text). These oral agents, but not PEG IFN, should be used for interferon-refractory/ intolerant and immunocompromised patients. PEG IFN is administered weekly by subcutaneous injection for a year; the oral agents are administered daily for at least a year and continued indefinitely or until at least 6 months after HBeAg seroconversion. fAccording to EASL guidelines, patients with compensated cirrhosis and detectable HBV DNA at any level, even with normal ALT, are candidates for therapy. Most authorities would treat indefinitely, even in HBeAg-positive disease after HBeAg seroconversion. gBecause the emergence of resistance can lead to loss of antiviral benefit and further deterioration in decompensated cirrhosis, a low-resistance regimen is recommended—entecavir or tenofovir


InternalMed_Harrison

InternalMed_Harrison. gBecause the emergence of resistance can lead to loss of antiviral benefit and further deterioration in decompensated cirrhosis, a low-resistance regimen is recommended—entecavir or tenofovir monotherapy or combination therapy with the more resistance-prone lamivudine (or telbivudine) plus adefovir. Therapy should be instituted urgently. hBecause HBeAg seroconversion is not an option, the goal of therapy is to suppress HBV DNA and maintain a normal ALT. PEG IFN is administered by subcutaneous injection weekly for a year; caution is warranted in relying on a 6-month posttreatment interval to define a sustained response, because the majority of such responses are lost thereafter. Oral agents, entecavir or tenofovir, are administered daily, usually indefinitely or until, as very rarely occurs, virologic and biochemical responses are accompanied by HBsAg seroconversion. iFor older patients and those with advanced fibrosis, consider lowering the HBV DNA threshold to >2 × 103 IU/mL.


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InternalMed_Harrison. Abbreviations: AASLD, American Association for the Study of Liver Diseases; ALT, alanine aminotransferase; EASL, European Association for the Study of the Liver; HBeAg, hepatitis B e antigen; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; PEG IFN, pegylated interferon; ULN, upper limit of normal.


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InternalMed_Harrison. 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 362-5). Although adefovir and tenofovir are safe, creatinine monitoring is recommended. Substantial experience with lamivudine during pregnancy (see above) has identified no teratogenicity. Although interferons do not appear to cause congenital anomalies, interferons have antiproliferative properties and should be avoided during pregnancy. Adefovir during pregnancy has not been associated with birth defects; however, there may be an increased risk of spontaneous abortion. Data on the safety of entecavir during pregnancy have not been published. Sufficient data in animals and limited data in humans suggest that telbivudine and tenofovir can be used safely during pregnancy. In general, except perhaps for lamivudine, and until additional data become available, the other antivirals for hepatitis B should be avoided or used


InternalMed_Harrison

InternalMed_Harrison. tenofovir can be used safely during pregnancy. In general, except perhaps for lamivudine, and until additional data become available, the other antivirals for hepatitis B should be avoided or used with extreme caution during pregnancy.


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InternalMed_Harrison. 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.


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InternalMed_Harrison. 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. 360). Currently, however, prevention of recurrent hepatitis B after liver transplantation has been achieved definitively by combining hepatitis B immune globulin with one of the oral nucleoside or nucleotide analogues (Chap. 368); 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.


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InternalMed_Harrison. 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 HBVHIV co-infected patients who do not yet meet treatment criteria for HIV infection, treating for both HBV and HIV is recommended.


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InternalMed_Harrison. 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 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 lamivudine prior to the initiation of chemotherapy has been shown to reduce the risk of such reactivation. The newer, more potent oral antiviral agents are with chronic hepatitis C (see below). The clinical and laboratory features of chronic HDV infection are summarized in Chap. 360. Administration Weekly injection Daily, orally


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InternalMed_Harrison. Administration Weekly injection Daily, orally Tolerability Poorly toler-Well tolerated, limited moniated, intensive toring monitoring Duration of therapy Finite 48 weeks ≥1 year, indefinite in most patients Maximum mean HBV DNA 4.5 log 6.9 log During 1 year of therapy ~30% ~20% During >1 year of Not applicable 30% (year 2) to up to 50% therapy During 1 year of therapy 3–4% 0–3% During >1 year of therapy Not applicable 3–8% @ 5 years of therapy After 1 year of therapy– 12% @ 5 years 3.5% @ 5 years HBeAg-negative Antiviral resistance None Lamivudine: ~30% year 1, ~70% year 5 Adefovir: 0% year 1, ~30% Telbivudine: up to 4% year 1, 22% year 2 Entecavir: ≤1.2% through year 6 Tenofovir: 0% through year 5 Use in cirrhosis, transplanta-No Yes tion, immunosuppressed Cost, 1 year of therapy ++++ + to ++ Abbreviations: HBV, hepatitis B virus; HBeAg, hepatitis B e antigen; HBsAg, hepatitis B surface antigen; PEG IFN, pegylated interferon.


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InternalMed_Harrison. Abbreviations: HBV, hepatitis B virus; HBeAg, hepatitis B e antigen; HBsAg, hepatitis B surface antigen; PEG IFN, pegylated interferon. even more effective in preventing hepatitis B reactivation and with a lower risk of antiviral drug resistance. The optimal duration of antiviral therapy after completion of chemotherapy is not known, but a suggested approach is 6 months 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 362-4).


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InternalMed_Harrison. Chronic hepatitis D virus (HDV) may follow acute co-infection with HBV but at a rate no higher than the rate of chronicity of acute hepatitis B. That is, although HDV co-infection can increase the severity of acute hepatitis B, HDV does not increase the likelihood of progression to chronic hepatitis B. When, however, HDV superinfection occurs in a person who is already chronically infected with HBV, long-term HDV infection is the rule, and a worsening of the liver disease is the expected consequence. Except for severity, chronic hepatitis B plus D has similar clinical and laboratory features to those seen in chronic hepatitis B alone. Relatively severe and progressive chronic hepatitis, with or without cirrhosis, is the rule, and mild chronic hepatitis is the exception. Occasionally, however, mild hepatitis or even, rarely, inactive carriage occurs in patients with chronic hepatitis B plus D, and the disease may become indolent after several years of infection. A distinguishing


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InternalMed_Harrison. however, mild hepatitis or even, rarely, inactive carriage occurs in patients with chronic hepatitis B plus D, and the disease may become indolent after several years of infection. A distinguishing serologic feature of chronic hepatitis D is the presence in the circulation of antibodies to liver-kidney microsomes (anti-LKM); however, the anti-LKM seen in hepatitis D, anti-LKM3, are directed against uridine diphosphate glucuronosyltransferase and are distinct from anti-LKM1 seen in patients with autoimmune hepatitis and in a subset of patients


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InternalMed_Harrison. Management is not well defined. 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 may be associated with a sustained loss of HDV replication and clinical improvement in up to 50% of patients. Moreover, 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. PEG IFN has also been shown to be effective in the


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InternalMed_Harrison. 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. PEG IFN has also been shown to be 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 of patients) and is a more convenient replacement for standard IFN. None of the nucleoside analogue antiviral agents for hepatitis B are effective in hepatitis D. 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


InternalMed_Harrison

InternalMed_Harrison. 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. 368).


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InternalMed_Harrison. Regardless of the epidemiologic mode of acquisition of hepatitis C virus (HCV) infection, chronic hepatitis follows acute hepatitis C in 50−70% of cases; chronic infection is common even in those with a return to normal in aminotransferase levels after acute hepatitis C, adding up to an 85% likelihood of chronic HCV infection after acute hepatitis C. Few clues had emerged to explain host differences associated with chronic infection until recently, when variation in a single nucleotide polymorphism (SNP) on chromosome 19, IL28B (which codes for IFN-λ3), was identified that distinguished between responders and nonresponders to antiviral therapy (see below). The same variants correlated with spontaneous resolution after acute infection: 53% in genotype C/C, 30% in genotype C/T, but only 23% in genotype T/T. The association with HCV clearance after acute infection is even stronger when IL28B haplotype is combined with haplotype G/G of an SNP near HLA class II DBQ1*03:01.


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InternalMed_Harrison. In patients with chronic hepatitis C followed for 20 years, progression to cirrhosis occurs in about 20−25%. Such is the case even for patients with relatively clinically mild chronic hepatitis, including those without symptoms, with only modest elevations of aminotransferase activity, and with mild chronic hepatitis on liver biopsy. Even in cohorts of well-compensated patients with chronic hepatitis C referred for clinical research trials (no complications of chronic liver disease and with normal hepatic synthetic function), the prevalence of cirrhosis may be as high as 50%. Most cases of hepatitis C are identified initially in asymptomatic patients who have no history of acute hepatitis C (e.g., those discovered while attempting to donate blood, while undergoing lab testing as part of an application for life insurance, or as a result of routine laboratory tests). The source of HCV infection in many of these cases is not defined, although a long-forgotten percutaneous exposure (e.g.,


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InternalMed_Harrison. application for life insurance, or as a result of routine laboratory tests). The source of HCV infection in many of these cases is not defined, although a long-forgotten percutaneous exposure (e.g., injection drug use) in the remote past can be elicited in a substantial proportion and probably accounts for most infections; most of these infections were acquired in the 1960s and 1970s, coming to clinical attention decades later.


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InternalMed_Harrison. Approximately one-third of patients with chronic hepatitis C have normal or near-normal aminotransferase activity; although one-third to one-half of these patients have chronic hepatitis on liver biopsy, the grade of liver injury and stage of fibrosis tend to be mild in the vast majority. In some cases, more severe liver injury has been reported— even, rarely, cirrhosis, most likely the result of previous histologic activity. Among patients with persistent normal aminotransferase activity sustained over ≥5−10 years, histologic progression has been shown to be rare; however, approximately one-fourth of patients with normal aminotransferase activity experience subsequent aminotransferase elevations, and histologic injury can be progressive once abnormal biochemical activity resumes. Therefore, continued clinical monitoring is indicated, even for patients with normal aminotransferase activity.


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InternalMed_Harrison. Despite this substantial rate of progression of chronic hepatitis C, and despite the fact that liver failure can result from end-stage chronic hepatitis C, the long-term prognosis for chronic hepatitis C in a majority of patients is relatively benign. Mortality over 10−20 years among patients with transfusion-associated chronic hepatitis C has been shown not to differ from mortality in a matched population of transfused patients in whom hepatitis C did not develop. Although death in the hepatitis group is more likely to result from liver failure, and although hepatic decompensation may occur in ~15% of such patients over the course of a decade, the majority (almost 60%) of patients remain asymptomatic and well compensated, with no clinical sequelae of chronic liver disease. Overall, chronic hepatitis C tends to be very slowly and insidiously progressive, if at all, in the vast majority of patients, whereas in approximately one-fourth of cases, chronic hepatitis C will progress


InternalMed_Harrison

InternalMed_Harrison. chronic hepatitis C tends to be very slowly and insidiously progressive, if at all, in the vast majority of patients, whereas in approximately one-fourth of cases, chronic hepatitis C will progress eventually to end-stage cirrhosis. In fact, because HCV infection is so prevalent, and because a proportion of patients progress inexorably to end-stage liver disease, hepatitis C is the most frequent indication for liver transplantation (Chap. 368). In the United States, hepatitis C accounts for up to 40% of all chronic liver disease, and, as of 2007, mortality caused by hepatitis C surpassed that associated with HIV/AIDS. Moreover, because the prevalence of HCV infection is so much higher in the “baby boomer” cohort borne between 1945 and 1965, three-quarters of the mortality associated with hepatitis C occurs in this age cohort. Referral bias may account for the more severe outcomes described in cohorts of patients reported from tertiary care centers (20-year progression of ≥20%) versus


InternalMed_Harrison

InternalMed_Harrison. hepatitis C occurs in this age cohort. Referral bias may account for the more severe outcomes described in cohorts of patients reported from tertiary care centers (20-year progression of ≥20%) versus the more benign outcomes in cohorts of patients monitored from initial bloodproduct-associated acute hepatitis or identified in community settings (20-year progression of only 4−7%). Still unexplained, however, are the wide ranges in reported progression to cirrhosis, from 2% over 17 years in a population of women with hepatitis C infection acquired from contaminated anti-D immune globulin to 30% over ≤11 years in recipients of contaminated intravenous immune globulin.


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InternalMed_Harrison. Progression of liver disease in patients with chronic hepatitis C has been reported to be more likely in patients with older age, longer duration of infection, advanced histologic stage and grade, more complex quasispecies diversity, increased hepatic iron, concomitant other liver disorders (alcoholic liver disease, chronic hepatitis B, hemochromatosis, α1 antitrypsin deficiency, and steatohepatitis), HIV infection, and obesity. Among these variables, however, duration of infection appears to be one of the most important, and some of the others probably reflect disease duration to some extent (e.g., quasispecies diversity, hepatic iron accumulation). No other epidemiologic or clinical features of chronic hepatitis C (e.g., severity of acute hepatitis, level of aminotransferase activity, level of HCV RNA, presence or absence of jaundice during acute hepatitis) are predictive of eventual outcome. Despite the relatively benign nature of chronic hepatitis C over time in many patients,


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InternalMed_Harrison. level of HCV RNA, presence or absence of jaundice during acute hepatitis) are predictive of eventual outcome. Despite the relatively benign nature of chronic hepatitis C over time in many patients, cirrhosis following chronic hepatitis C has been associated with the late development, after several decades, of HCC (Chap. 111); the annual rate of HCC in cirrhotic patients with hepatitis C is 1−4%, occurring primarily in patients who have had HCV infection for 30 years or more.


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InternalMed_Harrison. Perhaps the best prognostic indicator in chronic hepatitis C is liver histology; the rate of hepatic fibrosis may be slow, moderate, or rapid. Patients with mild necrosis and inflammation as well as those with limited fibrosis have an excellent prognosis and limited progression to cirrhosis. In contrast, among patients with moderate to severe necroinflammatory activity or fibrosis, including septal or bridging 2041 fibrosis, progression to cirrhosis is highly likely over the course of 10−20 years. The pace of fibrosis progression may be accelerated by such factors as concomitant HIV infection, other causes of liver disease, excessive alcohol use, and hepatic steatosis. Among patients with compensated cirrhosis associated with hepatitis C, the 10-year survival rate is close to 80%; mortality occurs at a rate of 2−6% per year; decompensation at a rate of 4−5% per year; and, as noted above, HCC at a rate of 1−4% per year. A discussion of the pathogenesis of liver injury in patients with


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InternalMed_Harrison. occurs at a rate of 2−6% per year; decompensation at a rate of 4−5% per year; and, as noted above, HCC at a rate of 1−4% per year. A discussion of the pathogenesis of liver injury in patients with chronic hepatitis C appears in Chap. 360. Clinical features of chronic hepatitis C are similar to those described above for chronic hepatitis B. Generally, fatigue is the most common symptom; jaundice is rare. Immune complex−mediated extrahepatic complications of chronic hepatitis C are less common than in chronic hepatitis B (despite the fact that assays for immune complexes are often positive in patients with chronic hepatitis C), with the exception of essential mixed cryoglobulinemia (Chap. 360), which is linked to cutaneous vasculitis and membranoproliferative glomerulonephritis as well as lymphoproliferative disorders such as B-cell lymphoma and unexplained monoclonal gammopathy. In addition, chronic hepatitis C has been associated with extrahepatic complications unrelated to


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InternalMed_Harrison. well as lymphoproliferative disorders such as B-cell lymphoma and unexplained monoclonal gammopathy. In addition, chronic hepatitis C has been associated with extrahepatic complications unrelated to immune-complex injury. These include Sjögren’s syndrome, lichen planus, porphyria cutanea tarda, type 2 diabetes mellitus, and the metabolic syndrome (including insulin resistance and steatohepatitis).


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InternalMed_Harrison. Laboratory features of chronic hepatitis C are similar to those in patients with chronic hepatitis B, but aminotransferase levels tend to fluctuate more (the characteristic episodic pattern of aminotransferase activity) and to be lower, especially in patients with long-standing disease. An interesting and occasionally confusing finding in patients with chronic hepatitis C is the presence of autoantibodies. Rarely, patients with autoimmune hepatitis (see below) and hyperglobulinemia have false-positive immunoassays for anti-HCV. On the other hand, some patients with serologically confirmable chronic hepatitis C have circulating anti-LKM. These antibodies are anti-LKM1, as seen in patients with autoimmune hepatitis type 2 (see below), and are directed against a 33-amino-acid sequence of cytochrome P450 IID6. The occurrence of anti-LKM1 in some patients with chronic hepatitis C may result from the partial sequence homology between the epitope recognized by anti-LKM1 and two segments of


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InternalMed_Harrison. P450 IID6. The occurrence of anti-LKM1 in some patients with chronic hepatitis C may result from the partial sequence homology between the epitope recognized by anti-LKM1 and two segments of the HCV polyprotein. In addition, the presence of this autoantibody in some patients with chronic hepatitis C suggests that autoimmunity may be playing a role in the pathogenesis of chronic hepatitis C.


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InternalMed_Harrison. Histopathologic features of chronic hepatitis C, especially those that distinguish hepatitis C from hepatitis B, are described in Chap. 360.


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InternalMed_Harrison. Therapy for chronic hepatitis C has evolved substantially in the two decades since IFN-α was introduced for this indication. The therapeutic armamentarium has grown to include PEG IFN with ribavirin and, in 2011, the introduction of protease inhibitors telaprevir and boceprevir used in combination with PEG IFN and ribavirin in patients with HCV genotype 1. When first approved, IFN-α was administered via subcutaneous injection three times a week for 6 months but achieved a sustained virologic response (SVR) (Fig. 362-2) (a reduction of HCV RNA to undetectable levels by PCR when measured ≥6 months after completion of therapy) below 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


InternalMed_Harrison

InternalMed_Harrison. 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. 362-2) (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 –8–4–2 0 4 8 12162024324048526072 Weeks after start of therapy


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InternalMed_Harrison. FIGURE 362-2 Classification of virologic responses based on outcomes during and after a 48-week course of pegylated interferon (PEG IFN) plus ribavirin antiviral therapy in patients with hepatitis C, genotype 1 or 4 (for genotype 2 or 3, the course would be 24 weeks). Nonresponders can be classified as null responders (hepatitis C virus [HCV] RNA reduction of <2 log10 IU/mL) or partial responders (HCV RNA reduction ≥2 log10 IU/mL but not suppressed to undetectable) by week 24 of therapy. In responders, HCV RNA can become undetectable, as shown with sensitive amplification assays, within 4 weeks (RVR, rapid virologic response); can be reduced by ≥2 log10 IU/mL within 12 weeks (early virologic response, EVR; if HCV RNA is undetectable at 12 weeks, the designation is “complete” EVR); or at the end of therapy, 48 weeks (ETR, end-treatment response). In responders, if HCV RNA remains undetectable for 24 weeks after ETR, week 72, the patient has a sustained virologic response (SVR), but if


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InternalMed_Harrison. end of therapy, 48 weeks (ETR, end-treatment response). In responders, if HCV RNA remains undetectable for 24 weeks after ETR, week 72, the patient has a sustained virologic response (SVR), but if HCV RNA becomes detectable again, the patient is considered to have relapsed. In patients treated with protease inhibitor–based therapy, several additional milestones are monitored: (1) among boceprevirtreated patients, the level of HCV RNA reduction (>1 log10 or ≥1 log10 IU/mL) during the 4-week PEG IFN–ribavirin lead-in phase; (2) during boceprevir therapy, undetectable HCV RNA at week 8 (week 4 of triple-drug therapy; RVR); and (3) among telaprevir-treated patients, undetectable HCV RNA at week 4 and 12 (extended RVR). (Reproduced with permission, courtesy of Marc G. Ghany, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health and the American Association for the Study of Liver Diseases. Hepatology 49:1335, 2009.) of guanosine pools), immune


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InternalMed_Harrison. of Diabetes and Digestive and Kidney Diseases, National Institutes of Health and the American Association for the Study of Liver Diseases. Hepatology 49:1335, 2009.) of guanosine pools), immune modulation, induction of virologic mutational catastrophe, and enhancement of IFN-stimulated gene expression. 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.


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InternalMed_Harrison. 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. Still, many important lessons about antiviral therapy for chronic hepatitis C were learned from the experience with IFN monotherapy and combination IFN-ribavirin therapy. Even in the absence of biochemical and virologic responses, histologic improvement occurs in approximately three-fourths of all treated patients. In chronic hepatitis C, unlike the case in hepatitis B, responses to therapy are not accompanied by transient, acute hepatitis-like aminotransferase elevations. Instead, ALT levels fall precipitously during therapy. 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 is roughly equivalent to a 24-week SVR. SVRs are very


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InternalMed_Harrison. therapy; responses thereafter are rare. Most relapses occur within the first 12 weeks after treatment; therefore, an SVR at week 12 posttreatment is roughly equivalent to a 24-week SVR. 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.


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InternalMed_Harrison. Patient variables that tend to correlate with sustained virologic responsiveness to IFN-based therapy include favorable genotype (genotypes 2 and 3 as opposed to genotypes 1 and 4); low baseline HCV RNA level (<2 million copies/mL, which is equivalent to <800,000 IU/mL, the current convention of quantitation); histologically mild hepatitis and minimal fibrosis; age <40; female gender; and absence of obesity, insulin resistance, and type 2 diabetes mellitus. Patients with cirrhosis can respond, but they are less likely to do so. For patients treated with combination IFNribavirin, therapy for those with genotype 1 should last a full 48 weeks, whereas in those with genotypes 2 and 3, a 24-week course of therapy suffices (although refined tailoring of treatment duration may be indicated based on rapidity of response or associated cofactors, see below). The response rate in African Americans is disappointingly low for reasons that are not fully understood. Potentially contributing to, but


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InternalMed_Harrison. on rapidity of response or associated cofactors, see below). The response rate in African Americans is disappointingly low for reasons that are not fully understood. Potentially contributing to, but not explaining entirely, low responsiveness in African Americans are a higher proportion with genotype 1, slower early viral kinetics during therapy, impaired HCV-specific immunity, and recently recognized host genetic differences in IL28B alleles, described below. The response rate in Latino patients is also low, despite the fact that the frequency of the favorable IL28B C allele is as common in Hispanic patients as in whites. Moreover, the likelihood of a sustained response is best if adherence to the treatment regimen is high (i.e., if patients receive ≥80% of the IFN and ribavirin doses and if they continue treatment for ≥80% of the anticipated duration of therapy). Other variables reported to correlate with increased responsiveness include brief duration of infection, low HCV


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InternalMed_Harrison. doses and if they continue treatment for ≥80% of the anticipated duration of therapy). Other variables reported to correlate with increased responsiveness include brief duration of infection, low HCV quasispecies diversity, immunocompetence, absence of hepatic steatosis, and low liver iron levels. High levels of HCV RNA, more histologically advanced liver disease, and high quasispecies diversity all go hand in hand with advanced duration of infection, which is one of the most important clinical variables determining IFN responsiveness. The ironic fact, then, is that patients whose disease is least likely to progress are the ones most likely to respond to IFN and vice versa.


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InternalMed_Harrison. 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 recently in genome-wide association studies have been 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


InternalMed_Harrison

InternalMed_Harrison. 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%). The fact that C/C is common in whites of European ancestry and even more so in Japanese persons but rare in African Americans helps explain the differences in observed responsiveness among these population groups.


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InternalMed_Harrison. Side effects of IFN therapy are described above in the section on treatment of chronic hepatitis B. The most pronounced side effect of ribavirin therapy is hemolysis; a reduction in hemoglobin of up to 2−3 g or in hematocrit of 5−10% can be anticipated. A small, unpredictable proportion of patients experience 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 and in patients with coronary artery disease or cerebrovascular disease, in whom anemia can precipitate an ischemic event. When symptomatic anemia occurs, ribavirin dose reductions or addition of erythropoietin to boost red blood cell levels may be required; erythropoietin has been shown to improve patients’ quality of life but not the likelihood of achieving an SVR. If ribavirin is stopped during therapy, SVR rates fall, but responsiveness can be maintained as long as ribavirin is not


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InternalMed_Harrison. improve patients’ quality of life but not the likelihood of achieving an SVR. If ribavirin is stopped during therapy, SVR rates fall, but responsiveness can be maintained as long as ribavirin is not stopped and the total ribavirin dose exceeds 60% of the planned dose. In addition, ribavirin, which is excreted renally, should not be used in patients with renal insufficiency; the drug is teratogenic, precluding its use during pregnancy and mandating the scrupulous use of efficient contraception during therapy (IFNs, too, because of their antiproliferative properties, are contraindicated during pregnancy).


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InternalMed_Harrison. 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. In one large clinical trial of combination therapy versus monotherapy, among those in the 1-year treatment group, 21% of the combination group (but only 14% of the monotherapy group) had to discontinue treatment, whereas 26% of the combination group (but only 9% of the mono-therapy group) required dose reductions.


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InternalMed_Harrison. 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 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. 362-2). Therefore, to achieve rapid viral clearance from serum and the liver, high-dose induction therapy has been advocated. In


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InternalMed_Harrison. response [RVR]) have a very high likelihood of achieving an SVR (Fig. 362-2). Therefore, to achieve rapid viral clearance from serum and the liver, high-dose induction therapy has been advocated. In practice, however, high-dose induction with IFN-based therapy has not yielded higher sustained response rates.


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InternalMed_Harrison. For the treatment of chronic hepatitis C, standard IFNs were supplanted 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


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InternalMed_Harrison. 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.


InternalMed_Harrison

InternalMed_Harrison. Two PEG IFNs are available: PEG IFN-α2b and -α2a. PEG IFN-α2b consists of a 12-kD, linear PEG molecule bound to IFN-α2b, whereas PEG IFN-α2a consists of 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 (Table 362-6). In the registration trial for PEG IFN-α2b plus ribavirin, the best regimen was 48 weeks of 1.5 μg/kg of PEG IFN once a week plus 800 mg of ribavirin daily. A post hoc analysis suggested that weight-based dosing of ribavirin would have been more effective than the fixed 800-mg dose used in the study (a broader dose/weight range was approved subsequently; see below). In the first registration trial for PEG IFN-α2a plus ribavirin, the best regimen was 48 weeks of 180 μg of PEG IFN plus 1000 mg (for patients <75 kg) to


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InternalMed_Harrison. range was approved subsequently; see below). In the first registration trial for PEG IFN-α2a plus ribavirin, the best regimen was 48 weeks of 180 μg of PEG IFN plus 1000 mg (for patients <75 kg) to 1200 mg (for patients ≥75 kg) of ribavirin. SVRs of 54 and 56% were reported in these two studies, respectively. A subsequent aIn the registration trial for PEG IFN-α2b plus ribavirin, the optimal regimen was 1.5 μg of PEG IFN plus 800 mg of ribavirin; however, a post hoc analysis of this study suggested that higher ribavirin doses are better. In subsequent trials of PEG IFN-α2b with ribavirin in patients with genotype 1, the following daily ribavirin doses have been validated: 800 mg for patients weighing <65 kg, 1000 mg for patients weighing >65–85 kg, 1200 for patients weighing >85–105 kg, and 1400 mg for patients weighing >105 kg. b1000 mg for patients weighing <75 kg; 1200 mg for patients weighing ≥75 kg. cIn the registration trial for PEG IFN-α2b plus ribavirin, all patients were


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InternalMed_Harrison. and 1400 mg for patients weighing >105 kg. b1000 mg for patients weighing <75 kg; 1200 mg for patients weighing ≥75 kg. cIn the registration trial for PEG IFN-α2b plus ribavirin, all patients were treated for 48 weeks; however, data from other trials of standard interferons and the other PEG IFN demonstrated that 24 weeks suffices for patients with genotypes 2 and 3. For patients with genotype 3 who have advanced fibrosis/cirrhosis and/or high-level HCV RNA, a full 48 weeks is preferable. dAttempts to compare the two PEG IFN preparations based on the results of registration clinical trials are confounded by differences between trials of the two agents in methodologic details (different ribavirin doses, different methods for recording depression, and other side effects) and study-population composition (different proportion with bridging fibrosis/ cirrhosis, proportion from the United States versus international, mean weight, proportion with genotype 1, and proportion with high-level


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InternalMed_Harrison. composition (different proportion with bridging fibrosis/ cirrhosis, proportion from the United States versus international, mean weight, proportion with genotype 1, and proportion with high-level HCV RNA). In the head-to-head comparison of the two PEG IFN preparations in the IDEAL trial reported in 2009, the two drugs were comparable in tolerability and efficacy. PEG IFN-α2b was administered at a weekly weight-based dose of 1.0 μg/kg or 1.5 μg/kg, and PEG IFN-α2a at a weekly fixed dose of 180 μg. For PEG IFN-α2b, daily ribavirin weight-based doses ranged between 800 and 1400 mg based on weight criteria (see footnote a, above), whereas for PEG IFN-α2a, daily ribavirin weight-based doses ranged between 1000 and 1200 mg (see footnote b, above). For the two PEG IFN-α2b study arms, ribavirin dose reductions for ribavirin-associated adverse effects were done in 200to 400-mg decrements; for PEG IFN-α2a, the ribavirin dose was reduced to 600 mg for intolerability. Sustained virologic


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InternalMed_Harrison. dose reductions for ribavirin-associated adverse effects were done in 200to 400-mg decrements; for PEG IFN-α2a, the ribavirin dose was reduced to 600 mg for intolerability. Sustained virologic responses occurred in 38.0% of the low-dose PEG IFN-α2b group, 39.8% of the standard, full-dose PEG IFN-α2b group, and 40.9% of the PEG IFN-α2a group.


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InternalMed_Harrison. Abbreviations: HCV RNA, hepatitis C virus RNA; PEG, polyethylene glycol. study of PEG IFN-α2a plus ribavirin showed that, for patients with genotypes 2 and 3, a duration of 24 weeks and a ribavirin dose of 800 mg were sufficient. Among the three studies, for patients in the optimal treatment arm, SVR rates for patients with genotype 1 were 42−51%, and for patients with genotypes 2 and 3, rates were 76−82%. Between genotypes 2 and 3, genotype 3 is somewhat more refractory, and some authorities would extend therapy for a full 48 weeks in patients with genotype 3, especially if they have advanced hepatic fibrosis or cirrhosis and/or high-level HCV RNA.


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InternalMed_Harrison. In the initial registration trials for combination PEG IFN plus ribavirin, both combination PEG IFN regimens were compared to standard IFN-α2b plus ribavirin. Side effects of the combination PEG IFN-α2b regimen were comparable to those for the combination standard IFN regimen; however, when the combination PEG IFN-α2a regimen was compared with the combination standard IFN-α2b regimen, flu-like symptoms and depression were less common in the combination PEG IFN group. Although ascertainment of side effects differed between studies of the two drugs, when each was tested against standard IFN-α2b plus ribavirin, combination PEG IFN-α2a plus ribavirin appeared to be better tolerated. In a head-to-head trial of the two PEG IFNs (the IDEAL trial), the two PEG IFNs were found to be comparable in efficacy (achievement of SVR) and tolerability, although headache, nausea, fever, myalgia, depression, and drug 2044 discontinuation for any reason were less frequent in patients treated with PEG


InternalMed_Harrison

InternalMed_Harrison. in efficacy (achievement of SVR) and tolerability, although headache, nausea, fever, myalgia, depression, and drug 2044 discontinuation for any reason were less frequent in patients treated with PEG IFN-α2a than standard-dose PEG IFN-α2b. In contrast, neutropenia and rash were more frequent in patients treated with PEG IFN-α2a than standard-dose PEG IFN-α2b. In two subsequent head-to-head trials and a systematic review of randomized trials, PEG IFN-α2a was more effective than PEG IFN-α2b (SVR in genotypes 1–4: 48–55% versus 32–40%, respectively). In trials of PEG IFN-α2b among patients with HCV genotype 1, a broader range of weight-based daily ribavirin doses has been validated: 800 mg for weight <65 kg, 1000 mg for weight 65−85 kg, 1200 mg for weight >85−105 kg, and 1400 mg for weight >105 kg. Recommended doses for the two PEG IFNs plus ribavirin and other comparisons between the two therapies are shown in Table 362-6. Until the 2011 introduction of protease inhibitors, unless


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InternalMed_Harrison. >105 kg. Recommended doses for the two PEG IFNs plus ribavirin and other comparisons between the two therapies are shown in Table 362-6. Until the 2011 introduction of protease inhibitors, unless ribavirin was contraindicated (see above), combination PEG IFN plus ribavirin was the recommended course of therapy—24 weeks for genotypes 2 and 3 and 48 weeks for genotype 1. For patients with genotypes 1 and 4, the standard of care now includes protease inhibitors or other direct-acting antiviral agents (see below); 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 is helpful in guiding therapy; if a 2-log10 drop in HCV RNA has not been achieved by this time, chances for an SVR are negligible, and additional therapy is futile. If the 12-week HCV RNA has fallen by 2 log10 (EVR), the chances for an SVR at the end of


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InternalMed_Harrison. RNA has not been achieved by this time, chances for an SVR are negligible, and additional therapy is futile. If the 12-week HCV RNA has fallen by 2 log10 (EVR), the chances for an SVR at the end of therapy are approximately two-thirds; if the 12-week HCV RNA is undetectable (“complete” EVR), the chances for an SVR exceed 80% (Fig. 362-2). Because absence of an EVR is such a strong predictor of the absence of an ultimate SVR, therapy is discontinued for failure to achieve a 12-week 2-log10 drop in HCV RNA (EVR). Studies have suggested that the frequency of an SVR to PEG IFN– ribavirin therapy can be increased in patients with baseline variables weighing against a response (e.g., HCV RNA >8 × 105 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 tailoring treatment based on viral response to prolong the duration of viral clearance