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Chapter: Basic & Clinical Pharmacology : Antiviral Agents

Treatment of Hepatitis B Virus Infection

The goals of chronic HBV therapy are to sustain suppression of HBV replication, resulting in slowing of progression of hepatic disease (with retardation of hepatic fibrosis and even reversal of cirrhosis), prevention of complications (ie, cirrhosis, hepatic failure, and hepa-tocellular carcinoma), and reduction of the need for liver transplanta-tion.


The goals of chronic HBV therapy are to sustain suppression of HBV replication, resulting in slowing of progression of hepatic disease (with retardation of hepatic fibrosis and even reversal of cirrhosis), prevention of complications (ie, cirrhosis, hepatic failure, and hepa-tocellular carcinoma), and reduction of the need for liver transplanta-tion. This translates into suppression of HBV DNA to undetectable levels, seroconversion of HBeAg (or more rarely, HBsAg) from posi-tive to negative, and reduction in elevated hepatic transaminase lev-els. These end points are correlated with improvement in necroinflammatory disease, a decreased risk of hepatocellular carci-noma and cirrhosis, and a decreased need for liver transplantation. All the currently licensed therapies achieve these goals. However, because current therapies suppress HBV replication without eradi-cating the virus, initial responses may not be durable. The covalently closed circular (ccc) viral DNA exists in stable form indefinitely within the cell, serving as a reservoir for HBV throughout the life of the cell and resulting in the capacity to reactivate. Relapse is more common in patients co-infected with HBV and hepatitis D virus.

As of 2010 seven drugs were approved for treatment of chronic HBV infection in the United States: five oral nucleoside/nucleotide analogs (lamivudine, adefovir dipivoxil, tenofovir, entecavir, telbivudine) and two injectable interferon drugs (interferon alfa-2b, pegylated interferon alfa-2a) (Table 49–6). The use of interferon has been supplanted by long-acting pegylated interferon, allowing once-weekly rather than daily or thrice-weekly dosing. In general, nucleoside/nucleotide analog therapies have better tolerability and ultimately produce a higher response rate than the interferons (though less rapid); however, response may be less sustained after discontinuation of the nucleoside/nucleotide therapies, and emer-gence of resistance may be problematic. The nucleotides are effec-tive in nucleoside resistance and vice versa. In addition, oral agents may be used in patients with decompensated liver disease, and the therapy is chronic rather than finite as with interferon therapy.

Several anti-HBV agents have anti-HIV activity as well, includ-ing lamivudine, adefovir dipivoxil, and tenofovir. Emtricitabine, an antiretroviral NRTI, is under clinical evaluation for HBV treat-ment in combination with tenofovir, which may be particularly suited to individuals co-infected with HIV and HBV. Because NRTI agents may be used in patients co-infected with HBV and HIV, it is important to note that acute exacerbation of hepatitis may occur upon discontinuation or interruption of these agents.


Although initially and abortively developed for treatment of HIV infection, adefovir dipivoxil gained approval, at lower and less toxic doses, for treatment of HBV infection. Adefovir dipivoxil is the diester prodrug of adefovir, an acyclic phosphonated adenine nucleotide analog (Figure 49–2). It is phosphorylated by cellular kinases to the active diphosphate metabolite and then competi-tively inhibits HBV DNA polymerase and causes chain termina-tion after incorporation into viral DNA. Adefovir is active in vitro against a wide range of DNA and RNA viruses, including HBV, HIV, and herpesviruses.

Oral bioavailability of adefovir dipivoxil is about 59% and is unaffected by meals; it is rapidly and completely hydrolyzed to the parent compound by intestinal and blood esterases. Protein bind-ing is low (< 5%). The intracellular half-life of the diphosphate is prolonged, ranging from 5 to 18 hours in various cells; this makes once-daily dosing feasible. Adefovir is excreted by a combination of glomerular filtration and active tubular secretion and requires dose adjustment for renal dysfunction; however, it may be admin-istered to patients with decompensated liver disease.

Of the oral agents, adefovir may be slower to suppress HBV DNA levels and the least likely to induce HBeAg seroconversion. Although emergence of resistance is rare during the first year of therapy, it approaches 30% at the end of 4 years. Naturally occur-ring (ie, primary) adefovir-resistant rt233 HBV mutants have recently been described. There is no cross-resistance between adefovir and lamivudine.

Adefovir dipivoxil is well tolerated. A dose-dependent nephro-toxicity has been observed in clinical trials, manifested by increased serum creatinine with decreased serum phosphorous and more common in patients with baseline renal insufficiency and those receiving high doses (60 mg/d). Other potential adverse effects are headache, diarrhea, asthenia, and abdominal pain. As with other NRTI agents, lactic acidosis and hepatic steatosis are considered a risk owing to mitochondrial dysfunction. No clini-cally important drug-drug interactions have been recognized todate; however, co-administration with drugs that reduce renal function or compete for active tubular secretion may increase serum concentrations of adefovir or the co-administered drug. Pivalic acid, a by-product of adefovir dipivoxil metabolism, can esterify free carnitine and result in decreased carnitine levels. However, it is not felt necessary to administer carnitine supple-mentation with the low doses used to treat patients with HBV (10 mg/d). Adefovir is embryotoxic in rats at high doses and is genotoxic in preclinical studies.


Entecavir is an orally administered guanosine nucleoside analog (Figure 49–2) that competitively inhibits all three functions of HBV DNA polymerase, including base priming, reverse transcrip-tion of the negative strand, and synthesis of the positive strand of HBV DNA. Oral bioavailability approaches 100% but is decreased by food; therefore, entecavir should be taken on an empty stomach. The intracellular half-life of the active phosphorylated compound is 15 hours. It is excreted by the kidney, undergoing both glomerular filtration and net tubular secretion.

Comparison with lamivudine in patients with chronic HBV infection demonstrated similar rates of HBeAg seroconversion but significantly higher rates of HBV DNA viral suppression with entecavir, normalization of serum alanine aminotransferase levels, and histologic improvement in the liver. Entecavir appears to have a higher barrier to the emergence of resistance than lamivudine. Although selection of resistant isolates with the S202G mutation has been documented during therapy, clinical resistance is rare (< 1% at 4 years). Also, decreased susceptibility to entecavir may occur in association with lamivudine resistance.

Entecavir is well tolerated. The most frequent adverse events are headache, fatigue, dizziness, and nausea. Lung adenomas and carci-nomas in mice, hepatic adenomas and carcinomas in rats and mice, vascular tumors in mice, and brain gliomas and skin fibromas in rats have been observed at varying exposures. Co-administration of entecavir with drugs that reduce renal function or compete for active tubular secretion may increase serum concentrations of either entecavir or the co-administered drug.


The pharmacokinetics of lamivudine are described earlier (see section, Nucleoside and Nucleotide Reverse Transcriptase Inhibitors). The more prolonged intracellular half-life in HBV cell lines (17–19 hours) than in HIV-infected cell lines (10.5–15.5 hours) allows for lower doses and less frequent administration. Lamivudine can be safely administered to patients with decompensated liver disease.

Lamivudine inhibits HBV DNA polymerase and HIV reverse transcriptase by competing with deoxycytidine triphosphate for incorporation into the viral DNA, resulting in chain termination. Lamivudine achieves 3–4 log decreases in viral replication in most patients and suppression of HBV DNA to undetectable levels in about 44% of patients. Seroconversion of HBeAg from positive to negative occurs in about 17% of patients and is durable at 3 years in about 70% of responders. Continuation of treatment for 4–8 months after seroconversion may improve the durability of response. Response in HBeAg-negative patients is initially high but less durable.

Although lamivudine initially results in rapid and potent virus suppression, chronic therapy may ultimately be limited by the emer-gence of lamivudine-resistant HBV isolates (eg, L180M or M204I/V), estimated to occur in 15–30% of patients at 1 year and 70% at 5 years of therapy. Resistance has been associated with flares of hepati-tis and progressive liver disease. Cross-resistance between lamivudine and emtricitabine or entecavir may occur; however, adefovir main-tains activity against lamivudine-resistant strains of HBV.

In the doses used for HBV infection, lamivudine has an excel-lent safety profile. Headache, nausea, and dizziness are rare. Co-infection with HIV may increase the risk of pancreatitis. No evidence of mitochondrial toxicity has been reported.


Telbivudine is a thymidine nucleoside analog with activity against HBV DNA polymerase. It is phosphorylated by cellular kinases to the active triphosphate form, which has an intracellular half-life of 14 hours. The phosphorylated compound competitively inhibits HBV DNA polymerase, resulting in incorporation into viral DNA and chain termination. It is not active in vitro against HIV-1.

Oral bioavailability is unaffected by food. Plasma protein-binding is low (3%) and distribution wide. The serum half-life is approximately 15 hours and excretion is renal. There are no known metabolites and no known interactions with the CYP450 system or other drugs.

In a comparative trial against lamivudine in patients with chronic HBV infection, significantly more patients receiving telbivudine achieved the combined end point of suppression of HBV DNA to less than 5 log copies/mL plus loss of serum HBeAg. The mean reduction in HBV DNA from baseline, the proportion with ALT normalization, and HBeAg seroconversion all were greater in those receiving telbivudine. Liver biopsies per-formed 1 year later showed less scarring. However, emergence of resistance, typically due to the M204I mutation, may occur in up to 22% of patients with durations of therapy exceeding 1 year, and may result in virologic rebound.

Adverse effects are mild; they include fatigue, headache, abdominal pain, upper respiratory infection, increased creatine kinase levels, and nausea and vomiting. Both uncomplicated myalgia and myopathy have been reported, as has peripheral neuropathy. As with other nucleoside analogs, lactic acidosis and severe hepatomegaly with steatosis may occur during therapy as well as flares of hepatitis after discontinuation.


Tenofovir, a nucleotide analog of adenosine in use as an antiretro-viral agent, has recently gained licensure for the treatment ofpatients with chronic HBV infection. The characteristics of teno-fovir are described earlier. Tenofovir maintains activity against lamivudine- and entecavir-resistant hepatitis virus isolates but has reduced activity against adefovir-resistant strains. Although similar in structure to adefovir dipivoxil, comparative trials showed a significantly higher rate of complete response, defined as serum HBV DNA levels less than 400 copies/mL, as well as of histologic improvement, in patients with chronic HBV infection receiving tenofovir than in those receiving adefovir dipivoxil. The emergence of resistance appears to be substantially less frequent during therapy with tenofovir than with adefovir.


Compounds in clinical development for the treatment of patients with HBV infection include the nucleoside analogs emtricitabine and clevudine, as well as the immunologic modulator thymosinalpha-1, agents that facilitate uptake by the liver using conjuga-tion to ligands, and RNA interference compounds.

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