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Antiviral Therapy (Non-HIV)
Although some viral infections are self-limited, others can cause significant morbidity and mortality. Effective therapy is available for many of these infections. This chapter reviews currently available antiviral agents for the treatment of infections caused by viruses other than human immunodeficiency virus (HIV). Not all agents discussed are licensed in all countries.
Currently available agents can be classified into those that inhibit viral replication at the cellular level or bind the virus (antivirals), those that modify the host antiviral response to infection (immunomodulators), and those that directly inactivate viral particles (microbicides/virucides). Antiviral agents can be classified based on their mechanism of action. For example, nucleic acid analogues inhibit viral DNA or RNA synthesis by competing with endogenous nucleic acids and block the viral DNA polymerase or RNA transcriptases. By comparison, protease inhibitors prevent viral replication by binding to the enzymes that cleave viral protein precursors into active proteins.
Antiviral strategies that are not covered in this chapter include local destructive measures that destroy both host tissues and virus simultaneously, such as cryotherapy, laser, and podophyllin treatment of warts. Although effective, such measures are useful only for discrete or localized mucocutaneous infections.
Antivirals for Hepatitis B Virus Infections
Acute hepatitis B virus (HBV) infection ( Chapter 134 ) generally does not require antiviral treatment. Currently approved antivirals for chronic hepatitis B ( Chapter 135 ) include six nucleic acid analogues (adefovir, entecavir, lamivudine, telbivudine, tenofovir disoproxil fumarate, and tenofovir alafenamide), as well as two immune modulators (interferon-alfa-2b and pegylated [PEG]-interferon-alfa-2a) ( Tables 328-1 to 328-3 ). Treatment may be initiated with any approved antiviral medications, but tenofovir, tenofovir alafenamide, entecavir, and PEG-interferon-alfa-2a are generally the preferred agents. Tenofovir or entecavir is preferred for patients with compensated cirrhosis ( Chapter 139 ). The goal of antiviral treatment is to suppress HBV replication and reduce the progression of liver disease and its complications.
TABLE 328-1
ANTIVIRALS FOR HEPATITIS VIRUS INFECTIONS
| VIRAL INFECTION | DRUG | ROUTE | USUAL ADULT DOSAGE |
|---|---|---|---|
| Chronic hepatitis B | Tenofovir disoproxil fumarate | PO | 300 mg/day |
| Tenofovir alafenamide | PO | 25 mg/day | |
| Entecavir | |||
| Naïve virus | PO | 0.5 mg daily; optimal duration of therapy unknown | |
| Lamivudine-resistant virus | PO | 1 mg daily; optimal duration of therapy unknown | |
| Interferon-alfa-2b | SQ | 6 MU/m 2 (up to 10 MU) three times weekly for 16-24 wk | |
| PEG-interferon-alfa-2a | SQ | 180 µg weekly for 48 wk | |
| Adefovir | PO | 10 mg/day | |
| Lamivudine | PO | 100 mg/day | |
| Telbivudine | PO | 600 mg/day | |
| Chronic hepatitis C | Ledipasvir/sofosbuvir | PO | 90 mg/400 mg once daily for 8-24 wk |
| Sofosbuvir/velpatasvir | PO | 400 mg/100 mg/day for 12 wk | |
| Sofosbuvir/velpatasvir/voxilaprevir | PO | 400 mg/100 mg/100 mg/day for 12-24 wk | |
| Sofosbuvir/glecaprevir/pibrentasvir | PO | 400 mg/100 mg/40 mg once daily for 12-24 wk | |
| Daclatasvir/sofosbuvir | PO | 60 mg/400 mg/day for 12-24 wk | |
| Grazoprevir/elbasvir | PO | 100 mg/50 mg/day for 12-16 wk | |
| Glecaprevir/pibrentasvir | PO | 300 mg/120 mg/day for 8-16 wk | |
| Daclatasvir/asunaprevir | PO | 60 mg/400 mg/day for 24 wk | |
| Sofosbuvir | PO | 400 mg once daily for 12-24 wk | |
| PEG-interferon-alfa-2a | SQ | 180 µg weekly for 48 wk | |
|
SQ | 1.5 µg/kg weekly for 48 wk | |
|
PO | 800-1200 mg/day, depending on weight |
PO = orally; SQ = subcutaneously.
TABLE 328-2
MECHANISMS OF EXCRETION AND THRESHOLDS FOR DOSE ADJUSTMENT
| MAJOR ROUTE OF ELIMINATION | THRESHOLD FOR ADJUSTMENT IN RENAL INSUFFICIENCY OR FAILURE | ADJUSTMENT FOR HEPATIC FAILURE | SPECIAL ADJUSTMENT FOR ELDERLY | |
|---|---|---|---|---|
| Adefovir | Renal | CrCl <50 mL/min | No adjustment | |
| Entecavir | Renal | CrCl <50 mL/min | No adjustment | |
| Lamivudine | Renal | CrCl <50 mL/min | No adjustment | |
| Ledipasvir/sofosbuvir | Renal | CrCl <30 mL/min/1.73 m 2 | No adjustment | |
| Sofosbuvir/velpatasvir | Renal | CrCl <30 mL/min/1.73 m 2 | No adjustment | |
| Voxilaprevir | Hepatic | CrCl <30 mL/min | No adjustment | |
| Ribavirin | Renal | CrCl <50 mL/min | No adjustment | |
| PEG-interferon-alfa-2a | Renal | CrCl <50 mL/min | Progressive rise in alanine transaminase | >60 yr, consider reduction |
| Telbivudine | Renal | CrCl <50 mL/min | No adjustment | |
| Sofosbuvir | Renal | CrCl <50 mL/min | No adjustment | |
| Boceprevir | Hepatic | No adjustment | No adjustment | |
| Daclatasvir | Hepatic | No adjustment | No adjustment | |
| Asunaprevir | Hepatic | No adjustment | Contraindicated | |
| Glecaprevir/pibrentasvir | Hepatic | No adjustment | Contraindicated | |
| Grazoprevir/elbasvir | Hepatic | No adjustment | Contraindicated |
CrCl = creatinine clearance.
TABLE 328-3
SIGNIFICANT ADVERSE EFFECTS (U.S. FDA BLACK BOX WARNING)
| DRUG | BLACK BOX SYNOPSIS |
|---|---|
| Adefovir | Severe acute exacerbations of hepatitis B may occur with cessation of therapy Nephrotoxicity may occur in patients at risk for renal dysfunction Lactic acidosis and severe hepatomegaly with steatosis |
| Entecavir | Severe acute exacerbation of hepatitis B may occur with cessation of therapy Lactic acidosis and severe hepatomegaly with steatosis |
| Grazoprevir/elbasvir | Hepatitis B virus reactivation in patients with HCV and HBV |
| Interferon-alfa | May cause or aggravate neuropsychiatric, autoimmune, ischemic, and infectious disorders |
| Lamivudine | Severe acute exacerbations of hepatitis B may occur with cessation of therapy Lactic acidosis and severe hepatomegaly with steatosis |
| Ledipasvir/sofosbuvir | Hepatitis B virus reactivation in patients with HCV and HBV |
| Voxilaprevir | Hepatic failure in patients with decompensated liver cirrhosis |
| Glecaprevir/pibrentasvir | Hepatic failure in patients with decompensated liver cirrhosis |
| Ribavirin | Monotherapy is not effective Hemolytic anemia Teratogenic and embryocidal |
| Sofosbuvir | Life-threatening bradycardia when administered with amiodarone Hepatic failure in patients with decompensated liver cirrhosis |
| Telbivudine | Severe acute exacerbation of hepatitis B may occur with cessation of therapy Lactic acidosis and severe hepatomegaly with steatosis |
| Tenofovir or tenofovir alafenamide | Severe acute exacerbations of hepatitis B may occur with cessation of therapy |
HBV = hepatitis B virus; HCV = hepatitis C virus.
Patients with chronic hepatitis B (hepatitis B surface antigen [HBsAg]-positive for >6 months, detectable serum HBV DNA [>2000 IU/mL for hepatitis B e antigen (HBeAg)-negative patients, >20,000 IU/mL for HBeAg-positive patients, and >200,000 IU/mL for pregnant women], and an alanine aminotransferase level more than twice the normal level) should be evaluated for treatment. Patients with clinically decompensated hepatitis B (e.g., icterus or other signs) generally require antiviral treatment. Therapy in HBeAg-positive chronic hepatitis B should be continued until the patient has achieved HBeAg seroconversion and serum HBV DNA is undetectable, followed by at least 6 months of additional treatment after the appearance of anti-HBe. Therapy in HBeAg-negative chronic hepatitis B should continue for at least a year. Patients with decompensated cirrhosis or recurrent hepatitis B after liver transplantation should receive lifelong treatment.
Tenofovir Disoproxil Fumarate
Tenofovir, a nucleotide analogue of adenosine monophosphate, was first approved for the treatment of HIV infection. Tenofovir disoproxil fumarate is an ester prodrug of tenofovir, with an effective tenofovir bioavailability of 25%. Administration following a high-fat meal increases the oral bioavailability.
Clinical Uses
Tenofovir is approved for the treatment of chronic hepatitis B in adults with evidence of active viral replication and either persistent elevations in serum aminotransferase levels or histologically active disease. Treatment with tenofovir is more effective than adefovir or entecavir for producing histologic improvement and viral suppression in patients with HBeAg-negative or HBeAg-positive chronic hepatitis B. Tenofovir also has demonstrated efficacy in patients with lamivudine-resistant hepatitis B.
Toxicity
Tenofovir is generally safe and well tolerated for up to 5 years. The most common side effects are nausea, diarrhea, vomiting, and anorexia. Lactic acidosis with hepatic steatosis has been reported, primarily when it is used in combination with other nucleoside analogues. Acute exacerbations of hepatitis B have been reported after discontinuation of tenofovir in patients who are coinfected with HIV and hepatitis B.
Antiviral Resistance
Mutations in hepatitis B polymerase that confer reduced susceptibility to tenofovir occur during prolonged use (>12 months). In vitro studies showed that adefovir-resistant hepatitis B mutations are associated with three- to five-fold decrease in response to tenofovir, though clinical implications are not known.
Tenofovir Alafenamide
Tenofovir alafenamide, which is a prodrug of tenofovir, is a successor of tenofovir disoproxil fumarate. Tenofovir alafenamide is converted intracellularly to tenofovir. Its active diphosphate metabolite is targeted at the RNA-dependent DNA polymerase of either hepatitis B or HIV. Tenofovir alafenamide is also licensed to treat hepatitis B infection. Tenofovir alafenamide accumulates in lymphatic tissue and in the liver, and it enters cells more efficiently than tenofovir disoproxil fumarate. For these reasons, tenofovir alafenamide can be given at a lower dose, thereby resulting in lower plasma tenofovir levels and a much lower risk for kidney toxicity or bone density changes.
Clinical Uses
In clinical trials, tenofovir alafenamide was noninferior to tenofovir disoproxil fumarate in achieving HBV DNA levels below 29 IU/mL. Tenofovir alafenamide–treated patients had significantly smaller decreases in bone mineral density at the hip and spine in both HBeAg-positive and HBeAg-negative patients, and HBeAg-positive patients also had smaller mean increases in serum creatinine levels. Patients treated with tenofovir disoproxil fumarate for 96 weeks and then switched to tenofovir alafenamide had improvements in renal function and bone mineral density 24 weeks after switching.
Toxicity
Compared with tenofovir disoproxil fumarate, tenofovir alafenamide has less adverse effects on kidney (glomerular and tubular) function and bone mineral (spine, hip) density.
Antiviral Resistance
Tenofovir alafenamide leads to little or negligible emergence of drug resistance (to tenofovir). Clinical observations show a very low incidence of hepatitis B genotype resistance in treatment-naïve patients treated either with tenofovir alafenamide or tenofovir disoproxil fumarate. In patients treated with elvitegravir, cobicistat, and emtricitabine combined with either tenofovir alafenamide or tenofovir disoproxil fumarate, emergence of drug resistance did not exceed 1% for either HIV and hepatitis B.
Entecavir
Entecavir, which is a deoxyguanosine nucleoside analogue with specific antiviral activity for hepadnaviruses, is more potent than lamivudine and retains some activity against lamivudine-resistant hepatitis B variants. It is well absorbed after oral administration, and its prolonged half-life (128 to 149 hours) allows once-daily dosing.
Clinical Uses
Entecavir is approved for the treatment of chronic hepatitis B in adults with evidence of active viral replication and either persistent elevations in serum aminotransferases or histologically active disease. Compared with lamivudine or telbivudine, entecavir is more efficacious in reducing hepatitis B DNA levels and normalizing serum aminotransferases, as well as in improving histologic abnormalities. Like tenofovir, entecavir can be used for lamivudine-resistant HBV infections, but higher doses and longer durations of therapy are needed.
Toxicity
Adverse effects reported during entecavir therapy include headache, fatigue, dizziness, nausea, abdominal pain, rhinitis, fever, diarrhea, cough, and myalgia. Lactic acidosis and severe hepatomegaly with steatosis have been reported. Severe exacerbations of hepatitis B have been observed after cessation of therapy.
Antiviral Resistance
Virologic breakthrough can occur in up to 4% of patients but is usually not indicative of resistant virus. True entecavir resistance, which is caused by specific mutations in hepatitis B polymerase, is uncommon (1.2% after 5 years of treatment). In vitro studies show that entecavir-resistant mutations are susceptible to adefovir and tenofovir, but there are very few supportive clinical data.
Interferons
Interferons are glycoprotein cytokines with a complex array of antiviral, immunomodulating, and antineoplastic properties. Interferons are currently classified as α, β, or γ. The natural sources of these classes in general are leukocytes, fibroblasts, and lymphocytes, but they now can be produced by recombinant DNA technology. Although the full mechanism of interferon’s action is not defined, interferons generally induce synthesis of new cellular RNA and proteins that mediate antiviral effects through multiple different mechanisms.
Interferons generally must be administered daily or several times per week. However, the combination of interferon with polyethylene glycol to form PEG-interferon significantly prolongs absorption and provides higher, more sustained plasma levels that enable once-weekly administration.
Clinical Uses
In chronic active hepatitis B, treatment with interferon-alfa leads to loss of HBV DNA and biochemical and histologic improvement in about 25 to 40% of patients. Administration of PEG-interferon-alfa-2a or PEG-interferon-alfa-2b for 48 weeks converts about 30% of patients to seronegative status after 6 months of treatment. Whether combination therapy with interferons and antivirals confers an additional benefit compared with monotherapy for treating chronic hepatitis B is not known.
Adefovir
Adefovir, an acyclic analogue of adenosine monophosphate, is administered orally as a prodrug, adefovir dipivoxil, which is rapidly converted enzymatically to adefovir in intestinal epithelium.
Clinical Uses
In chronic hepatitis B, prolonged administration of adefovir is effective in improving histologic abnormalities of the liver, decreasing HBV DNA levels, and normalizing biochemical markers (e.g., alanine aminotransferase) in patients with HBeAg-positive and HBeAg-negative chronic hepatitis B. Adefovir is a slightly weaker antiviral and therefore not considered first-line therapy, but it is useful for resistant viruses (effective against chronic hepatitis B resistant to lamivudine) and HIV/HBV coinfection (see later).
Toxicity
The major adverse effect is nephrotoxicity, which is manifested by increased serum creatinine levels and sometimes hypophosphatemia, both of which are usually reversible with discontinuation of the drug. Common side effects include asthenia, headache, nausea, vomiting, and diarrhea. In addition, severe exacerbations of hepatitis B have been observed after cessation of therapy.
Antiviral Resistance
Adefovir resistance due to point mutations in HBV polymerase develops in about 6% of patients after 3 years of therapy. Lamivudine generally retains activity against adefovir-resistant variants.
Lamivudine
Lamivudine is a deoxycytidine nucleoside analogue active against retroviruses and hepadnaviruses. The triphosphate inhibits HBV polymerase, and its incorporation into viral DNA results in termination of the DNA chain.
Clinical Uses
Lamivudine suppresses hepatitis B viral replication, improves histologic abnormalities of the liver, reduces progression of fibrosis, and decreases the risk for late complications. Monotherapy with lamivudine appears to be inferior to the newer antivirals, as well as monotherapy with interferon, for sustained control of HBV replication. Combination therapy with lamivudine and interferon has shown inconsistent benefit compared with either drug alone. The dosing for HBV is lower than for HIV.
Toxicity
Adverse effects of lamivudine include diarrhea, headache, and elevated liver enzymes. Severe post-treatment exacerbations of hepatitis B, including fatalities, have occurred after discontinuation of lamivudine, especially in patients who are coinfected with HBV and HIV.
Antiviral Resistance
Lamivudine resistance caused by mutations in HBV polymerase is common during prolonged treatment of hepatitis B and emerges in about 20% of treated patients annually. Resistance is associated with increases in viral replication and aminotransferases.
Telbivudine
Telbivudine is a synthetic thymidine nucleoside analogue with activity against HBV, including some lamivudine-resistant variants. The triphosphate form competitively inhibits the HBV DNA polymerase (reverse transcriptase).
Clinical Uses
In comparative trials against lamivudine or adefovir, telbivudine demonstrated greater virologic response at week 52 (60 vs. 40% of subjects had HBV DNA negative by polymerase chain reaction analysis). The development of resistance with telbivudine is up to 5% after 1 year and 25% after 2 years. Telbivudine-resistant viruses are cross-resistant with lamivudine. Owing to the high development of resistance and cross-resistance, telbivudine is not considered a first-line treatment for hepatitis B.
Toxicity
Common side effects include headache, nausea, and vomiting. Severe acute exacerbations of hepatitis B have been reported in patients who have discontinued anti-HBV therapy. Myopathy, manifested by muscle aches or weakness with increased serum creatine kinase levels, has rarely been reported.
Special Considerations—HIV/HBV Coinfection
Lamivudine, entecavir, tenofovir, and tenofovir alafenamide have activity against both HIV and HBV. Monotherapy treatment of HBV with these agents should not be used in HIV coinfected patients, owing to the development of HIV resistance. Emtricitabine is licensed only for the treatment of HIV but is also weakly active against HBV. Withdrawal of this medication, like withdrawal of tenofovir or lamivudine, may cause acute, sometimes fulminant, exacerbations of hepatitis B in HIV/HBV coinfected patients.
If concurrent treatment of hepatitis B and HIV is warranted, tenofovir plus emtricitabine, tenofovir plus lamivudine, or tenofovir alafenamide plus emtricitabine should be considered as the nucleoside backbone of a fully suppressive antiretroviral regimen. If tenofovir or tenofovir alafenamide cannot be used, entecavir is an alternative as part of an antiretroviral regimen. In coinfected patients who require treatment for HBV but not HIV or who are already well controlled on anti-HIV viral therapy but now need hepatitis B treatment, PEG-interferon-alfa-2a monotherapy should be considered. If the antiretroviral regimen must be changed owing to HIV virologic failure and the HBV is adequately suppressed, antiviral drugs active against HBV should be continued for HBV treatment.
Antivirals for Hepatitis C Virus Infections
Treatment of acute hepatitis C remains symptomatic, and antiviral therapy generally is not indicated. For chronic hepatitis C ( Chapter 135 ), however, the goal of therapy is sustained virologic response (absence of hepatitis C virus [HCV] RNA for at least 12 weeks after completion of therapy) to prevent the morbidity and mortality associated with liver disease and long-term complications, such as hepatocellular carcinoma, liver failure, transplantation, and death. Treatment has been shown to decrease liver inflammation and cirrhosis as well as reduce the risk for hepatocellular carcinoma.
Although some specific drugs are more effective for specific HCV genotypes, current therapy is based on pangenotypic oral combinations ( Table 135-5 ), guided by whether or not patients have cirrhosis. Interferon-free regimens are preferred over interferon-based regimens (see Table 135-5 in Chapter 135 and Tables 328-1 to 328-3 ). Direct-acting antiviral agents are highly active oral medications available to treat all genotypes of HCV. Sofosbuvir/velpatasvir glecaprevir/pibrentasvir with or without sofosbuvir, and sofosbuvir/daclatasvir are considered primary regimens for HCV regardless of genotype. Retreatment after failure of the initial regimen generally requires expert consultation.
Ledipasvir/Sofosbuvir
Ledipasvir is an HCV NS5A inhibitor. Sofosbuvir is a nucleotide prodrug that, when triphosphorylated, inhibits HCV NS5B, an RNA-dependent RNA polymerase. Both NS5A and NS5B are important for HCV viral replication. Ledipasvir/sofosbuvir is available as a combination fixed-dose once-daily oral tablet.
Clinical Uses
Ledipasvir/sofosbuvir is currently licensed in the treatment of genotypes 1, 4, 5, and 6 chronic HCV without decompensated cirrhosis and genotypes 1 and 4 with decompensated cirrhosis. For treatment-naïve patients with or without cirrhosis, treatment should continue for 12 weeks. This regimen has been associated with a sustained virologic response of 99% at 12 weeks, and the duration of treatment can be safely reduced to as low as 8 weeks in selected patients with baseline HCV RNA levels <6 million IU/mL.
Toxicity
The most common side effects are headaches and fatigue. Significant drug interactions may occur with P-glycoprotein–inducing medications such as rifampin or St. John’s wort. Ledipasvir/sofosbuvir should not be given to patients who are taking amiodarone because of the risk of bradycardia.
Resistance
Resistance to the individual component drug may occur but is rare. Ledipasvir is active against sofosbuvir-resistant viruses, and sofosbuvir retains activity against ledipasvir-resistant viruses, so the clinical significance of resistance mutations is not known.
Sofosbuvir/Velpatasvir
Velpatasvir is a potent pangenotypic HCV NS5A inhibitor that is approved to treat hepatitis C patients in combination with sofosbuvir, an NS5B inhibitor. Sofosbuvir/velpatasvir is available as a combination in a fixed-dose, once-daily, oral tablet.
Clinical Uses
Sofosbuvir/velpatasvir is currently licensed in the treatment of adult patients with chronic hepatitis C genotype 1, 2, 3, 4, 5, or 6 infection with any degree of liver damage, including decompensated cirrhosis. The addition of ribavirin is recommended when treating patients with decompensated cirrhosis. The duration of treatment is 12 weeks, which is associated with sustained virologic response in more than 99% of patients in real-world situations.
Toxicity
The most common adverse reactions associated with 12 weeks of sofosbuvir/velpatasvir treatment are fatigue and headaches. Significant drug interactions may occur with P-glycoprotein–inducing medications (e.g., rifampin, St. John’s wort) and cytochrome P-450–inducing medications (e.g., rifampin, phenytoin). Concomitant use of sofosbuvir/velpatasvir with amiodarone is contraindicated because of the risk of bradycardia.
Antiviral Resistance
Preexisting NS5A mutants do not seem to influence the outcome of sofosbuvir/velpatasvir treatment. NS5A-resistant variants that confer in vitro resistance to velpatasvir have been isolated from the blood of the few patients who relapse. The significance of these mutants is not completely understood.
Sofosbuvir/Velpatasvir/Voxilaprevir
Velpatasvir is a potent pangenotypic HCV NS5A inhibitor to treat hepatitis C patients in combination with sofosbuvir, an NS5B inhibitor. Voxilaprevir is a second-generation HCV serine protease inhibitor. A single fixed-dose combination tablet of sofosbuvir, velpatasvir, and voxilaprevir is approved by the U.S. Food and Drug Administration (FDA) for treatment of HCV patients who have been previously treated with other direct-acting antivirals.
Clinical Uses
Sofosbuvir/velpatasvir/voxilaprevir is currently licensed in the treatment of adult patients who have chronic hepatitis C genotype 1, 2, 3, 4, 5, or 6 infection with any degree of liver damage without cirrhosis or compensated cirrhosis and who previously have been treated with an HCV direct-acting antiviral agent regimen. The duration of treatment is 12 weeks, which is associated with sustained virologic response in more than 99% of patients.
Toxicity
The most common adverse reactions associated with 12 weeks of sofosbuvir/velpatasvir/voxilaprevir treatment are fatigue, headaches, nausea, and diarrhea. Significant drug interactions may occur with P-glycoprotein–inducing medications (e.g., rifampin or St. John’s wort) and cytochrome P-450–inducing medications (e.g., phenytoin, rifampin). Significant bradycardia can occur with concomitant use of sofosbuvir/velpatasvir/voxilaprevir and amiodarone, which is contraindicated.
Antiviral Resistance
Preexisting NS5A or NS3 mutants do not seem to influence the outcome of sofosbuvir/velpatasvir/voxilaprevir treatment. NS5A-resistant variants that confer in vitro resistance to velpatasvir have been isolated from the blood of few patients who relapse. The significance of these mutants is not completely understood.
Glecaprevir/Pibrentasvir
A fixed-dose combination tablet of glecaprevir, an NS3/4A protease inhibitor, and pibrentasvir, an NS5A inhibitor, is approved for the treatment of patients with chronic HCV genotype 1, 2, 3, 4, 5, or 6 infection without cirrhosis and with compensated cirrhosis (Child-Pugh A).
Clinical Uses
Glecaprevir/pibrentasvir is currently licensed in the treatment of adult patients with chronic hepatitis C genotype 1, 2, 3, 4, 5, or 6 infection with all degrees of liver damage without cirrhosis or compensated cirrhosis (Child-Pugh A). The duration of treatment, which is 8 weeks for those without cirrhosis and 12 weeks for those with cirrhosis, is associated with sustained virologic response in more than 99% of patients. The combination pill is also indicated for the treatment of adult patients who have HCV genotype 1 infection and who previously have been treated with a regimen containing an HCV NS5A inhibitor or an NS3/4A protease inhibitor but not for those who failed both. For treatment-experienced genotype 1 patients who have failed a previous NS5A inhibitor (but not NS3)-containing HCV regimen, 16 weeks of treatment is recommended. For treatment-experienced genotype 1 patients who have failed a previous NS3 inhibitor (but not NS5A) containing HCV regimen, 12 weeks of treatment is recommended. For HCV genotype 1, 2, 4, 5, or 6 patients who have failed previous HCV regimens that did not include either an NS3 or NS5A inhibitor, either 8 weeks (those without cirrhosis) or 12 weeks (with cirrhosis) is recommended. For HCV genotype 3 patients who have failed previous HCV regimens that did not include either an NS3 or NS5A inhibitor, 16 weeks is recommended. Glecaprevir/pibrentasvir is the preferred interferon-free regimen shown to be effective in patients with stage 4 or 5 chronic kidney disease and all genotypes of HCV.
Toxicity
The most common adverse reactions associated with 12 weeks of glecaprevir/pibrentasvir treatment are fatigue and headaches in about 10% of all patients. Carbamazepine, efavirenz, and St. John’s wort may decrease concentrations of glecaprevir and pibrentasvir, so coadministration of these medications is not recommended.
Antiviral Resistance
Preexisting NS5A or NS3 mutants do not seem to influence the outcome of glecaprevir/pibrentasvir treatment. NS5A- and NS3-resistant variants that confer in vitro resistance to both drugs have been isolated from the blood of few patients who relapse. The significance of these mutants is not completely understood.
Daclatasvir
Daclatasvir is an NS5A inhibitor that can be used in combination with either sofosbuvir or asunaprevir for treatment of hepatitis C infection.
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