233 Approximately 11% of genotype 1a viruses are estimated to harbor one of

these polymorphisms prior to taking elbasvir/grazoprevir regimen. In the presence of

one of the NS5A polymorphisms, ribavirin (weight-based) could be added to the

regimen and the treatment course extended to improve the SVR rates. Of note, the

polymorphisms do not affect the SVR rates in persons with genotype 1b virus

infection. The polymorphisms in the NS3 protein, especially the Q80L polymorphism

in genotype 1a virus, do not appear to affect treatment response and SVR rates. The

other difference between the NS5A and NS3 polymorphisms appears to be the long

persistence of the NS5A resistance mutations in the individuals after treatment.

Elbasvir/grazoprevir is overall well tolerated. From the large clinical trials, the

most common adverse effects were headache, fatigue and nausea.

233,234

Approximately 1% of patients developed late aminotransferase elevations >5 times

the upper limit of normal without associated bilirubin increases that resolved once

the regimen was stopped. Aminotransferase monitoring at baseline and at week 8 of

therapy (and at week 12, if the total duration is 16 weeks) is recommended.

232 The

regimen should be discontinued if aminotransferase elevations are accompanied by

other signs or symptoms of hepatic injury, such as jaundice, increased bilirubin, or

INR. The regimen is primarily metabolized through CYP3A, and grazoprevir is a

substrate of OATP1B1/3 transporters. The coadministration of elbasvir/grazoprevir

is contraindicated with potent inducers (e.g., rifampin, phenytoin, carbamazepine,

Saint-John’s-wort, cyclosporine), efavirenz and HIV protease inhibitors.

Furthermore, coadministration of the regimen is not recommended with ketoconazole,

nafcillin, modafinil and antiretrovirals (etravirine or cobicistat).

Ledipasvir/Sofosbuvir

Sofosbuvir (400 mg) is combined with ledipasvir (90 mg), a NS5A inhibitor, as a

fixed-dose combination (Harvoni) that is administered as a single tablet with or

without food.

213 The regimen is given with or without weight-based ribavirin,

depending on the patient population, and is active against HCV genotypes 1, 4, 5, and

6. The levels of sofosbuvir and its metabolite might accumulate in the setting of

severe renal impairment (eGFR >30 mL/minute/1.73 m2

); thus, the combination

should not be used until further data are available. Otherwise, no dose adjustment is

needed for mild or moderate renal impairment, or in the setting of moderate (ChildPugh class B) or severe (Child-Pugh class C) hepatic impairment.

Harvoni is well tolerated, and the common adverse effects include fatigue,

headache, nausea, and insomnia. With regard to drug interactions, ledipasvir is also a

substrate of the P-gp drug transporter. Similar to sofosbuvir, ledipasvir should not be

coadministered with potent intestinal P-gp inducers because its serum levels will

significantly decrease. Ledipasvir absorption is affected by gastric pH. The

coadministration of ledipasvir with acid-suppressing agents could increase the

gastric pH levels and decrease its absorption. If the regimen needs to be taken with

proton pump inhibitors, the proton pump inhibitor dose should not exceed a dose

comparable to omeprazole 20 mg daily. If the regimen is given with H2

receptor

antagonists, such as famotidine 40 mg or equivalent, both drugs should be

administered twelve hours apart.

226

The resistance profile of Harvoni has been associated with several NS5A

mutations that reduce the susceptibility to ledipasvir, such as Q30R, Y93H/N and

L31M in subtype 1a virus and Y93H in subtype 1b virus.

235 The presence of NS5A

mutations does not require adjustment of duration or dosing of the combination

regimen. Further data are warranted to make any clinical adjustments.

Sofosbuvir/Velpatasvir

Another fixed-dose combination regimen (Epclusa) comprises of sofosbuvir (400

mg) with velpatasvir (100 mg), a NS5A inhibitor. It is coformulated as a single tablet

and administered once daily for 12 weeks with or without ribavirin. The regimen is

active against all HCV genotypes. No dose adjustments are needed for mild-tomoderate renal impairment, or in the setting of moderate (Child-Pugh class B) or

severe (Child-Pugh class C) hepatic impairment. The same renal precautions apply to

this combination regimen because it contains sofosbuvir. The commonly reported

adverse effects include headache, fatigue, nausea, nasopharyngitis, and insomnia.

236

Similar to sofosbuvir, velpatasvir is a substrate of the P-gp drug transporter.

Therefore, coadministration of the regimen

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p. 1690

with potent intestinal P-gp inducers can decrease both sofosbuvir and velpatasvir

serum levels. The coadministration of Epclusa is contraindicated with

anticonvulsants, anti-tuberculosis drugs, and Saint-John’s-wort. Efavirenz can also

significantly reduce the serum levels of velpatasvir and should not be

coadministered. Velpatasvir is also an inhibitor of P-gp and thus may increase the

absorption of P-gp substrates. Similar to ledipasvir, velpatasvir requires an acid

gastric environment for optimal absorption. Proton pump inhibitors and H2

receptor

antagonists will increase the gastric pH levels, resulting in a decreased absorption of

velpatasvir. If used with proton pump inhibitors, sofosbuvir/velpatasvir should be

taken without food and 4 hours before omeprazole 20 mg or equivalent dose. The

coadministration of amiodarone and sofosbuvir/velpatasvir is contraindicated

because of severe bradycardia and cardiac arrest.

226

(See sofosbuvir section.)

Paritaprevir/Ritonavir/Ombitasvir plus Dasabuvir

The coformulated single tablet of paritaprevir/ritonavir/ombitasvir is given with

dasabuvir, an NS5B non-nucleoside polymerase inhibitor. The regimen is called

often referred to as PrOD (Viekira Pak, Viekira XR). PrOD can be taken with or

without weight-based ribavirin, depending on the patient population, for the treatment

of genotypes 1a and 1b without cirrhosis or with compensated cirrhosis. PrOD is

also indicated in combination with ribavirin in liver transplant patients with any

HCV genotype 1 subtype as long as hepatic function is normal and fibrosis is mild

(Metavir score ≤2).

237

In contrast, the combination of

paritaprevir/ritonavir/ombitasvir (Technivie) with ribavirin is approved for

genotype 4 infections without cirrhosis. Technivie does not contain dasabuvir.

Paritaprevir/ritonavir/ombitasvir, with or without dasabuvir, can be administered in

HCV-infected patients with renal impairment. The administration of these regimens

in patients with severe renal impairment (eGFR <30 mL/minute/1.73 m2

) has not

been studied.

237 Dose adjustment for the regimens is not warranted for patients with

mild (Child-Pugh class A) hepatic impairment. However, the regimens are

contraindicated in patients with moderate-to-severe (Child-Pugh classes B and C)

hepatic impairment. Hepatic decompensation was reported when the regimen is used,

with or without dasabuvir, in patients with underlying cirrhosis.

238 Most of the

reported cases occurred within 1 to 4 weeks of drug initiation, and some cases

resulted in the need for liver transplantation or death.

PrOD is available in immediate-release and extended-release oral formulations.

For the immediate-release formulation (Viekira Pak), two combination tablets (each

containing 12.5 mg ombitasvir, 75 mg paritaprevir, and 50 mg ritonavir) are

administered once daily. Dasabuvir is administered with the regimen as a single 250-

mg tablet twice daily. For the extended-release formulation (Viekira XR), three

tablets (each containing 8.33 mg ombitasvir, 50 mg paritaprevir, 33.33 mg ritonavir,

and 200 mg dasabuvir) are administered once daily with ribavirin (weight-based

dosing) in two divided doses with food. PrOD regimens should be taken with food

and are generally well tolerated. The most commonly reported adverse effects in the

trials that used the PrOD regimen with ribavirin included nausea, pruritus, insomnia,

diarrhea, and asthenia.

239,240 Fatigue and headache were the most common side effects

and may be attributable to the ribavirin component. Decreases in the hemoglobin

level, by 2 to 2.5 g/dL, were also observed in patients taking regimens with

ribavirin. The incidence of severe anemia (hemoglobin <8 g/dL) is uncommon.

239,240

The components of PrOD are both substrates and inhibitors of CYP450 enzymes.

The coadministration of paritaprevir/ritonavir/ombitasvir and dasabuvir is

contraindicated with anticonvulsants, rifampin, Saint-John’s-wort, oral

contraceptives containing ethinyl estradiol and salmeterol.

237 Close monitoring and

dose adjustments of certain drugs (e.g., HMG-CoAs, cyclosporine, tacrolimus, and

antiarrhythmics) are recommended when given with the PrOD regimen.

The use of paritaprevir, ombitasvir, and dasabuvir can select for resistance

mutations in NS3, NS5A, and NS5B, respectively, which will reduce the activity of a

particular antiviral agent. In the clinical trials, the common resistance mutations that

have emerged and/or caused treatment relapse among the genotype 1a infections were

D168V in NS3, M28A/T/V and Q30E/K/R in NS5A, and S556G/R in NS5B.

239–242

In

contrast, there were not many virologic failures in patients with HCV genotype 1b

infection.

Future Treatment Options

243

Several agents are currently under investigation for HCV genotype 1 infection,

including voxilaprevir, ABT-493 plus ABT-530, and MK-3682 and MK-8408.

Voxilaprevir is an investigational NS3/4A protease inhibitor currently studied in a

coformulated combination with sofosbuvir-velpatasvir. This triple combination pill

is intended to be used as short-duration treatment and as salvage therapy for DAA

treatment failures.

The ABT-493 (NS3/4A protease inhibitor) plus ABT-530 (NS5A inhibitor)

coformulated combination has pangenotypic activity currently under study as both an

8-week regimen for genotype 1 patients without cirrhosis and a 12-week salvage

regimen for DAA-experienced patients.

The MK-3682 (NS5B inhibitor) plus MK-8408 (second generation NS5A

inhibitor) are being studied in a variety of triple combinations with either

grazoprevir or elbasvir as an 8-week regimen in genotype 1, 2, or 3 infection.

HEPATITIS D VIRUS

Virology and Epidemiology

HDV is a small, single-stranded circular RNA animal virus (36 nm) that is similar to

defective RNA plant viruses (Table 80-1).

244–246 Between 15 and 20 million persons

are infected with HDV globally, particularly in the Mediterranean basin, the Middle

East, Central and Northern Asia, West and Central Africa, the Amazon basin,

Colombia, Venezuela, Western Asia, and the South Pacific.

244–246 Vaccination for

HBV significantly reduces the incidence of HDV. However, immigration from

endemic areas, increased IV drug use, sexual practices, and body modification

procedures have resulted in an increase in HDV prevalence in some regions. In the

United States, an estimated 7,500 HDV cases occur annually.

247,248 The prevalence of

HDV is greatest among persons with percutaneous exposure (e.g., injection drug

users) and hemophiliacs (20%–53% and 48%–80%, respectively) and may be

affected by additional factors such as duration of infection.

247,248 The modes of

transmission of HDV are similar to those reported for HBV infection. Thus, HDV

clearly represents a potential infectious hazard to patients susceptible to HBV and

those who are chronic HBV carriers. Generally two major patterns of infection occur

with HBV: coinfection and superinfection. Because infection by HDV requires the

presence of active HBV, preventing HBV infection will prevent HDV infection in a

susceptible patient.

248,249

Pathogenesis

Limited data suggest that HDV antigen and HDV RNA are cytotoxic to hepatocytes;

however, the immune response may also be important.

248,249 Furthermore, several

autoantibodies associated with chronic HDV infection may play a role in propagating

liver disease and could partially explain the differences in disease severity observed

in patients with HDV plus HBV compared with those with HBV alone.

p. 1690

p. 1691

Diagnosis and Serology

Measuring HDV RNA (by RT-PCR) for HDV RNA confirms the presence of HDV

and is currently the most accurate diagnostic tool available.

248,249 ELISA and

radioimmunoassay tests for IgM anti-HDV are also commercially available.

Measurement of anti-HDV is generally not useful for early diagnosis because

detectable antibody levels are usually achieved late in the clinical course of the

infection. Anti-HDV IgM is detectable before anti-HDV IgG in acute HDV

coinfection and is diagnostic for acute HDV infection. Anti-HDV IgM levels are not

sustained in self-limiting HDV infection but may persist in patients with chronic

HDV infection. Also, anti-HDV IgM does not distinguish coinfection (HBV and HDV

acquired simultaneously) from superinfection (HDV acquired in chronic HBV

carrier).

Differentiation between coinfection and superinfection is made by the presence or

absence of anti-HBc IgM. In acute coinfection, serum anti-HDV IgM and HDV RNA

appear together with anti-HBc IgM, whereas in patients with superinfection, HDV

markers are present in the absence of anti-HBc IgM. The presence and titer level of

anti-HDV, in the case of persistent infection, also correlate with the severity of

disease. Titers of anti-HDV IgG greater than 1:1,000 indicate ongoing viral

replication.

HDV antigen is present in the serum in the late incubation period of acute infection

and lasts into the symptomatic phase in up to 20% of patients. Because this antigen is

transient, repeat testing may be required to detect its presence. HDV RNA is an early

marker of infection in patients with both acute and chronic HDV infection.

248,249 HDV

RNA is detectable in 90% of patients during the symptomatic phase of HDV

infection. HDV RNA levels are not detectable after symptomatic resolution but

remain elevated in chronic infection.

Natural History

Coinfection with HDV and HBV is correlated with a higher risk of severe or

fulminant liver disease.

249,250 The rate of chronic disease after coinfection with HDV

is similar to that of HBV infection alone, whereas superinfection with HDV is linked

to a high rate of chronicity; however, the clinical course may be variable.

Approximately 15% of patients superinfected with HDV develop rapidly progressive

disease with hepatic decompensation (e.g., cirrhosis) within 12 months of the

infection. Another 15% of patients have a benign course of illness. Most patients

(70%) have a slow progression to cirrhosis, depending on age, IV drug use, and level

of viral replication.

249 Finally, HBsAg-positive, HBeAg-positive patients who are

superinfected with HDV are more likely to develop fulminant disease compared with

those who are HBsAg-positive with anti-HBe and who are superinfected and

develop chronic disease.

249,250

Prevention

Hepatitis D virus replication is dependent on HBV replication; therefore, successful

immunization with HBV vaccine also prevents HDV infection.

244–246 No

immunoprophylactic therapies are available for patients with chronic HBV infection

who are also at risk for superinfection with HDV. Prevention of HDV superinfection

is based on behavioral modification, such as the use of condoms to prevent sexual

transmission and needle exchange programs to minimize transmission by IV drug use.

Treatment

The goal of treatment is to eradicate HDV along with HBV. HDV is eradicated when

both serum HDV RNA and HDV antigen in the liver become persistently

undetectable. Notably, it is only when HBsAg clearance has taken place that

complete clinical resolution occurs. Supportive care is the general strategy used to

treat HDV infection. Because the development of FHF is more frequent with HDV

infection, close monitoring for evidence of severe liver failure is warranted. Liver

transplantation is the treatment of choice for patients with fulminant or end-stage

liver disease after HDV infection. In patients with chronic HDV infection, antiviral

therapy has been disappointing.

251–254

In patients with decompensated cirrhosis caused by HDV, liver transplantation is

the most appropriate intervention because IFN may precipitate hepatic

decompensation.

251–254 The presence and amount of HBV DNA before transplantation

is the most significant outcome marker, often predicting the post-transplant

reinfection rate. Patients who receive a liver transplant for chronic HDV infection

have a lower incidence of post-transplant HBV infection than do those with HBV

infection alone (67% vs. 32%, respectively).

253,254 This is thought to be related to an

inhibitory effect of HDV on HBV replication. Furthermore, 3-year survival is higher

for patients with HDV cirrhosis than for patients undergoing transplantation for HBV

cirrhosis alone (88% vs. 44%, respectively) and is similar to patients having liver

transplantation for other indications.

117–119

HEPATITIS E VIRUS

Virology, Epidemiology, Transmission, and

Pathogenesis

HEV is an icosahedral, nonenveloped virus of the Hepeviridae family (Table 80-1).

The HEV genome is a single-stranded polyadenylated RNA and, unlike HAV, has an

RNA genome that encodes for NS proteins through overlapping open reading

frames.

255,256 HEV sequences have been classified into four genotypes (1, 2, 3, and 4).

Genotype 1 consists of epidemic strains in developing countries; genotype 2 has been

found in Mexico; genotype 3 has been associated with acute cases of hepatitis and

with domestic pigs in the United States, European countries, and Japan; and genotype

4 has been found in Asian countries.

257–260

HEV occurs in endemic areas such as Africa, Southeast and Central Asia, Mexico,

and Central and South America as both epidemic and sporadic infections.

258,259,261,262

Sporadic infections also occur in nonendemic areas and are usually associated with

travel into areas of endemicity. The attack rate (the percentage of exposed patients

who become infected) of HEV is low compared with HAV (1% vs. 10%,

respectively). In endemic areas, outbreaks usually occur between 5 and 10 years

apart and are often associated with times of heavy rainfall, after floods or monsoons,

or after the recession of flood waters.

260–262 The overall case fatality rate for the

general endemic population is 0.5% to 4%, whereas for reasons unknown, pregnant

women have a much greater case fatality rate of 20%.

263

In particular, the fetal

complication rate is increased, especially if the infection occurs in the third trimester

of pregnancy. The frequency of death in utero and immediately after birth is also

greater than that seen with acute hepatitis of other causes.

263

Transmission of HEV is via the fecal–oral route, and the most common source of

transmission is ingestion of fecally contaminated water.

261,262 Poor climactic

conditions in conjunction with inadequate personal hygiene and sanitation have led to

epidemics of HEV infection. Additional routes of transmission include consuming

raw or undercooked meat of infected animals such as boar or deer and domestic

animals such as pigs, vertical, and bloodborne transmission.

258,259

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p. 1692

Interference with the production of cellular macromolecules, alteration of cellular

membranes, and alteration of lysosomal permeability are some of the proposed

mechanisms of hepatic injury.

257,259

In addition, immune-mediated mechanisms are

believed to be responsible for lysis of virally infected hepatocytes by direct

lymphocyte cytotoxicity or antibody-mediated cytotoxicity.

Diagnosis

Initial assays for detection of anti-HEV used electron microscopy to detect HEV

antigen on the surface of HEV particles in stool and serum and immunohistochemistry

to detect the antigen in liver tissue.

257,259,260 Fluorescent antibody-blocking assay is

currently used to detect anti-HEV reacting to HEV antigen in serum, but although

highly specific, this assay lacks sensitivity (50%) in acute HEV infection.

257,259,260

Additional cloning and sequencing of HEV has led to the development of Western

blot assays and ELISA that detect anti-HEV by using recombinant expressed proteins

from the structural region of the virus. RT-PCR has also been used to confirm the

diagnosis of HEV by detecting HEV RNA from serum, liver, or stool.

257,259,260

Clinically, HEV is a diagnosis of exclusion.

Clinical Manifestations and Natural History

Typical HEV clinical symptoms include jaundice, dark urine, tender and enlarged

liver, elevated liver enzymes, abdominal pain, nausea, vomiting, and fever.

Protracted coagulopathy and cholestasis have also been reported in more severe

cases, possibly related to genotype 4.

257–259 Two phases of illness exist, including a

prodromal and preicteric phase. Peak serum aminotransferase levels reflect the onset

of the icteric phase and generally return to baseline by 6 weeks.

257–259 Stool is often

positive for HEV RNA at the onset of the icteric phase and persists for an additional

10 days beyond this period. Viral shedding may occur for up to 52 days after the

onset of icterus. Detection in the serum occurs during the preicteric phase, before

detection of virus in the stool, and becomes undetectable after the peak in

aminotransferase activity. Because HEV RNA is not detectable in the serum during

symptoms, diagnostic tests using HEV RNA have limited utility, and a correlation

between PCR detection and infectivity has not been observed. Serologically, HEV

IgM becomes detectable before the peak rise in ALT, whereas antibody titers peak

with peak ALT levels and subsequently decline. In most patients, HEV IgM is present

for 5 to 6 months after the onset of illness. HEV IgG appears after HEV IgM and

remains detectable for up to 14 years after acute infection; however, the duration of

protective immunity has not been fully elucidated.

257–260

In nonfatal cases, acute HEV hepatitis is followed by complete recovery without

any chronic complications. There is protection from reinfection; however, the

duration of protection is variable.

Prevention and Treatment

No immunoprophylactic measures exist for HEV disease, and effective prevention

strategies are dependent on improved sanitation in endemic areas. Travelers going to

endemic areas should be educated regarding the risks of drinking water, eating ice, or

eating uncooked shellfish or uncooked and peeled fruits and vegetables. Drinking

water should be boiled to inactivate HEV. No vaccines or postexposure prophylaxis

treatments are currently available to prevent HEV infection.

SUMMARY

Viral hepatitis continues to be a significant worldwide infectious disease. To date,

prevention strategies through universal vaccination are the most efficient methods for

minimizing the incidence of HAV, HBV, and HDV coinfected with HBV. Patient

education with respect to the common ways of spreading these infections may also

result in behavioral modifications that reduce the overall incidence of infection.

Once HBV and HCV progress to chronic infection, more efficacious and better-

tolerated antiviral therapies are needed to treat these infections. Similarly,

therapeutic modalities that reduce the progression of these diseases are necessary to

prevent end-stage liver disease and the development of additional complications

(encephalopathy, intractable ascites, coagulation disorders, and HCC). As a better

understanding of viral replication is established, as well as appropriate models for

study, new therapeutic agents are becoming available. Furthermore, viral kinetics and

genomic-based approaches may optimize responses to drug therapies, especially in

HCV-infected patients. The economic impact and quality of life of these patients

remain to be fully elucidated.

KEY REFERENCES AND WEBSITES

A full list of references for this chapter can be found at

http://thepoint.lww.com/AT11e. Below are the key references and website for this

chapter, with the corresponding reference number in this chapter found in parentheses

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