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Treatment of Hepatitis C
Abbreviations
AASLD
American Association for the Study of Liver Diseases
AUC
area under the curve
CKD
chronic kidney disease
CYP3A
cytochrome P450 3A
DAA
direct-acting antiviral
DNA
deoxyribonucleic acid
DRESS
drug reaction, eosinophilia, systemic symptoms
ESRD
end-stage renal disease
GFR
glomerular filtration rate
HCC
hepatocellular carcinoma
HCV
hepatitis C virus
HIV
human immunodeficiency virus
IDSA
Infectious Diseases Society of America
IL-28B
interleukin-28B
P-gp
P-glycoprotein
Peg-IFN
pegylated interferon
PRO
patient-reported outcomes
RAV
resistance-associated variant
RBV
ribavirin
RNA
ribonucleic acid
SVR
sustained virologic response
SVR12
sustained virologic response 12 weeks after end of treatment
SVR24
sustained virologic response 24 weeks after end of treatment
Introduction
Treatment of hepatitis C virus (HCV) infection has undergone tremendous change since 2010 and reached heights that few could have anticipated in this timeframe. After 2 decades of regimens with the backbone of interferon-α, many patients with HCV infection have the opportunity to receive all-oral, well-tolerated, and highly effective therapies ( Fig. 30-1 ). A number of direct-acting antiviral (DAA) agents have been developed and are now administered in combination. The safety profile of these medications has expanded the populations of patients able to receive treatment. Access to these medicines varies throughout the world, and therefore diverse treatment options are currently being offered. Research continues with new agents in development to increase potency and shorten the duration of treatment.
The Evolution of Hepatitis C Virus Therapies
For more than 20 years, therapy for HCV infection was based on boosting or supporting the innate immune response of interferon-α. The limitations of interferon-α in both efficacy and adverse event profile led to the development of DAA compounds. As depicted in Fig. 30-2 , agents have been developed to target specific enzymes in the life cycle of HCV. Following viral entry and uncoating, the viral ribonucleic acid (RNA) is translated into a polyprotein that is then cleaved into the core protein, envelope proteins, and seven nonstructural proteins. The HCV protease is a complex of the NS3 and the NS4A cofactor, and the first generation of DAA agents targeted this enzyme. A replication complex is then formed and consists of the NS3, NS4A, NS4B, NS5A, and the NS5B RNA–dependent RNA polymerase. Viral replication then occurs, followed by viral assembly and release from the hepatocyte. DAA compounds have also been developed for the NS5A and the NS5B RNA–dependent RNA polymerase. Early studies determined that DAA monotherapy led to treatment failure and the development of resistance, and these compounds were initially given in combination with peginterferon-α and ribavirin (RBV), as outlined in Fig. 30-1 . Successful subsequent approaches have combined multiple DAA medicines in combination and have sometimes also required RBV. Other DAA compounds are in development but are expected to follow the approach outlined in Fig. 30-1 . Table 30-1 reviews key attributes of the different DAA classes, and Table 30-2 summarizes key attributes of the DAA regimens in clinical practice.
TABLE 30-1
Direct Acting Antiviral Class Attributes
| Protease Inhibitors | NS5B POLYMERASE INHIBITORS | NS5A Inhibitors | ||
|---|---|---|---|---|
| Nucleoside Inhibitors | Nonnucleoside Inhibitors | |||
| Potency | High | Intermediate | Intermediate | High |
| Genotype coverage | Multiple genotypes | Pangenotypic | Limited genotypes | Multiple genotypes |
| Barrier to resistance | Low-intermediate | High | Low | Low-intermediate |
| Drug-drug interactions | Many | Few | Moderate | Moderate |
Table 30-2
Hepatitis C Virus Regimens in 2015
| Peginterferon + Sofosbuvir + RBV | Sofosbuvir + RBV | Simeprevir + Sofosbuvir | Ledipasvir + Sofosbuvir | Ombitasvir/Paritaprevir/Ritonavir + Dasabuvir | Daclatasvir + Sofosbuvir | |
|---|---|---|---|---|---|---|
| FDA approval year | 2013 | 2013 | 2013 | 2014 | 2014 | 2015 |
| FDA indications | HCV and HIV/HCV Genotype 2, 3 |
HCV and HIV/HCV Genotype 2, 3 |
HCV genotype 1 | HCV genotype 1 | HCV genotype 1 and 4 (without dasabuvir) | Genotype 3 |
| AASLD/IDSA guidance indications | ||||||
| Treatment naïve | Genotype 3. Alternative option for genotype 4, 5, 6 |
Genotype 2, 4 Alternative option for genotype 3 |
Genotype 1 | Genotype 1, 4, 5, 6 | Genotype 1 Genotype 4 (without dasabuvir) |
Genotype 1, 2, 3 |
| Treatment experienced | Genotype 3, 4, Alternative option for genotype 2, 5, 6 |
Genotype 2, 3, 4 | Genotype 1 | Genotype 1, 4, 5, 6 | Genotype 1 Genotype 4 (without dasabuvir) |
Genotype 1,2, 3 |
| Protease inhibitor failures | Not recommended | Not recommended | Not recommended | Recommended | Not recommended | Recommended |
| Sofosbuvir + RBV failures (± peginterferon) | Genotype 2, 3 | Genotype 1 | Genotype 2, 3 | |||
| RBV | Yes | Yes | Optional | Optional for 12-week regimen with cirrhosis | With genotype 1a or 4. | Optional for 1 and 3 but recommended for genotype 3 cirrhosis |
| Pill burden | 1 + RBV | 1 + RBV | 2 ± RBV | 1 | 1a: 4 + RBV 1b: 4 4: 2 + RBV |
2 |
| Frequency | Twice daily | Twice daily | Once daily (twice daily if RBV) | Once daily (twice daily if RBV) | Twice daily | Once daily |
| Duration | 12 weeks | 12-24 weeks | 12-24 weeks | 8-24 weeks | 12-24 weeks | 12-24 weeks |
| Food effect | None | None | Take with food | None | Take with food | None |
| Renal impairment | Not recommended if GFR < 30 mL/min or ESRD | Not recommended if GFR < 30 mL/min or ESRD | Simeprevir: no dose adjustment with mild, moderate or severe renal impairment. Sofosbuvir: not recommended if GFR < 30 mL/min or ESRD | Not recommended if GFR < 30 mL/min or ESRD | No dosage adjustment with mild, moderate or severe renal impairment. Refer to RBV package insert for dosing if used. | Sofosbuvir: not recommended if GFR < 30 mL/min or ESRD |
| Hepatic impairment | Peginterferon not routinely recommended in Child-Pugh B, C | No dose adjustment required | Simeprevir: no dose adjustment for Child-Pugh A; no dose recommended for Child-Pugh B; not recommended for Child-Pugh C. | No dose adjustment for Child-Pugh A, B, C | No dosage adjustment for Child-Pugh A; not recommended Child-Pugh B; contraindicated in Child-Pugh C. | No dose adjustment for Child-Pugh A, B, C |
| Drug interactions | Amiodarone P-gp inducers Includes St. John's wort, rifampin, anticonvulsants tipranavir |
Amiodarone P-gp inducers (St. John's wort, rifampin) Anticonvulsants Tipranavir |
Simeprevir: moderate or strong inducers or inhibitors of CYP3A | Amiodarone P-gp inducers Includes St. John's wort, rifampin, anticonvulsants, HIV regimens with tenofovir, tipranavir. PPI doses equivalent to omeprazole 20 mg or less. |
Substrates of CYP3A, UGT1A1, BCRP, OATP1B1 or OATP1B3. Discontinue ethinyl estradiol-containing medications before treatment. Tacrolimus & cyclosporine levels increased. HIV antiretrovirals. |
Strong inducers of CYP3A4 and P-gp, includes St. John's wort, rifampin, anticonvulsants. Daclatasvir: dose adjustment with HIV antiretrovirals. |
| Pregnancy | Category B. Contraindicated because of RBV teratogenicity |
Category B. Contraindicated because of RBV teratogenicity |
Simeprevir: C Sofosbuvir; B RBV contraindicated |
Category B | Category B RBV contraindicated |
Pending |
AASLD, American Association for the Study of Liver Diseases; ESRD, end-stage renal disease; FDA, United States Food and Drug Administration; GFR, glomerular filtration rate; HCV, hepatitis C virus; HIV, human immunodeficiency virus; IDSA, Infectious Diseases Society of America; PPI, proton pump inhibitors.
Interferon-α
As a component of the innate antiviral immune response, interferon-α was used to treat “non-A, non-B hepatitis” before the identification of HCV in 1989. Improved response rates were observed through the addition of RBV and the pegylation of interferon to extend the half-life. The generally low response rates and the adverse event profile led to the development of the DAA compounds.
Ribavirin
This guanosine analog was originally approved for treatment of respiratory syncytial virus infection but has broad activity against several RNA and deoxyribonucleic acid (DNA) viruses. Although not effective as a single agent, RBV did improve outcomes with interferon-α. The mechanism of action of RBV in HCV infection has remained elusive. Potential mechanisms that have been explored include some degree of direct antiviral effect against the HCV RNA–dependent RNA polymerase, inhibition of inosine monophosphate dehydrogenase, induction of misincorporation of nucleotides by the viral RNA polymerase (leading to less fit or lethal variants), and an immunomodulatory effect shifting the response from the T helper cytokine balance from a Th2 profile to a more antiviral Th1 profile. Although the mechanism remains unclear, some interferon-free regimens of potent DAAs gain benefit from its addition. Its renal clearance, hemolytic anemia, and teratogenic potential have led to efforts to find RBV-free regimens.
Protease Inhibitors
These agents inhibit the NS3/4A serine protease that is involved in posttranslational processing and replication of HCV. Some agents block the NS3 catalytic site, whereas others disrupt the NS3/NS4A interaction. The first-generation protease inhibitors, boceprevir and telaprevir, had activity against genotype 1 and were approved in 2011 in combination with peginterferon-α and RBV. Although these agents increased sustained virologic response (SVR) rates to greater than 70%, the use of these agents was challenging with a low barrier to resistance, two to three times daily dosing, increased risk of anemia, and drug-drug interactions related to metabolism by the CYP 3A4/5 enzymes. Telaprevir carried a risk of severe rash including drug reaction, eosinophilia, systemic symptoms (DRESS), and Stevens-Johnson syndrome. Greater concern emerged with reports that patients with cirrhosis had increased morbidity and mortality when treated with boceprevir and telaprevir in combination with peginterferon-α and RBV. In the initial report of a French cohort of 674 patients, 40% experienced a serious adverse event and 6.4% died or developed a major complication (severe infection or hepatic decompensation). The next generation of protease inhibitors include simeprevir, asunaprevir, paritaprevir, and grazoprevir. These agents have broader genotypic coverage and more favorable side-effect profiles and dosing schedules. They still have a relatively low barrier to resistance, and patients who fail treatment with one protease inhibitor are not recommended to receive treatment with another. The Q80K variant in the NS3/4A protease was present in approximately 30% of genotype-1a patients at baseline in studies of simeprevir with peginterferon-α and RBV from the United States and Europe and was associated with lower response rate. Testing for this variant should be considered in genotype-1a patients considering simeprevir. These second-generation protease inhibitors have been developed into potent interferon-free combinations for genotypes 1, 4, and 6. Ongoing research for the next generation of protease inhibitors seeks pangenotypic coverage for this class of compounds.
Polymerase Inhibitors
NS5B is an RNA-dependent RNA polymerase required for viral replication. The polymerase inhibitors target the NS5B polymerase and are divided into the nucleoside/nucleotide analogs and nonnucleoside agents. Nucleotide inhibitors are phosphorylated within the hepatocyte to nucleoside triphosphate that then competes with nucleotides and leads to chain termination during viral replication. The nucleotide polymerase inhibitors are an attractive class with their high barrier to resistance and pangenotypic activity. Sofosbuvir, however, is the only nucleotide polymerase inhibitor successfully developed to date, and the use of other agents has been halted because of toxicity. Sofosbuvir is a first-line agent for genotypes 2 and 3 in combination with RBV and with ledipasvir in a fixed-dose combination for genotypes 1, 4, and 6. The nonnucleoside polymerase inhibitors bind to one of four allosteric sites referred to as thumb domains 1 and 2 and palm domains 1 and 2 . The nonnucleoside polymerase inhibitors have a low to moderate barrier to resistance and are genotype specific. Dasabuvir was the first nonnucleoside polymerase inhibitor approved in 2014 for genotype 1 in combination with ombitasvir and ritonavir-boosted paritaprevir.
NS5A Inhibitors
Although the exact mechanism of action for these compounds is unknown, the NS5A inhibitors have effects on viral replication and assembly. They have a moderate barrier to resistance, and baseline resistance-associated variants (RAVs) may influence treatment responses but this is a topic of ongoing research. This class is active against all genotypes, but not all first-generation agents were sufficiently potent and developed as pangenotypic compounds. Daclatasvir was the first NS5A inhibitor approved in 2014 in Japan in combination with the protease inhibitor asunaprevir for genotype-1b infection. Daclatasvir was then approved in Europe and the United States for combination therapy with sofosbuvir. Several other NS5A inhibitors have been developed in fixed-dose combination regimens with other DAA compounds: ledipasvir with sofosbuvir, ombitasvir with paritaprevir/ritonavir, and elbasvir with grazoprevir. Of the first wave of NS5A inhibitors, only daclatasvir could be described as pangenotypic, and its activity against genotype 3 in combination with sofosbuvir provided an alternative to the initial interferon-free regimen of sofosbuvir and RBV. NS5A inhibitors in development (e.g., velpatasvir) seek to be pangenotypic in potent interferon-free combinations.
Goals of Hepatitis C Virus Treatment
When reviewing clinical trials in the HCV literature, the accepted endpoint of treatment is the sustained virologic response (SVR), which was originally defined as undetectable HCV RNA 24 weeks after the end of treatment. If the patient had undetectable HCV RNA 12 weeks after treatment ended, relapse was noted to be extremely rare, and so SVR12 also became an accepted endpoint. SVR was determined to be durable and allowed clinicians to use the word cure with patients. In a cohort study of 1243 patients with HCV and 100 patients with human immunodeficiency virus (HIV) and HCV from nine trials in which SVR was followed for a mean of 3.9 years (range 0.8-7.1 years), HCV RNA was again positive in 0.9% of patients. Patients treated for HCV are at risk for reinfection, and viral sequencing established that reinfection had occurred rather than late relapse.
HCV infection affects morbidity and mortality of patients, especially with the development of cirrhosis and the complications of portal hypertension and hepatocellular carcinoma (HCC). Removal of the virus from the patient is therefore only meaningful if the natural history of HCV infection is altered. An important study from five hospitals in Europe and Canada evaluated this issue in patients with advanced fibrosis or cirrhosis. The cohort included 530 patients with and without SVR following treatment with interferon-containing regimens. Patients were followed for a median of 8.4 years. Fig. 30-3 demonstrates the substantial reduction in liver-related mortality and HCC in those achieving SVR. The study also found a reduction in the 10-year cumulative incidence of all-cause mortality from 26% in those without SVR to 8.9% in those with SVR. A similar analysis examined the impact of HCV treatment in routine clinical practice in the United States Veterans Affairs medical centers. The study cohorts included 12,166 genotype-1, 2904 genotype-2, and 1794 genotype-3 patients treated with interferon-containing regimens with median follow-up of 3.8 years. Multivariate survival models determined that SVR was associated with reduced risk of mortality for each genotype (genotype-1 hazard ratio, 0.70, p < 0.0001; genotype-2 hazard ratio, 0.64, p = 0.006; genotype-3 hazard ratio, 0.51, p = 0.0002). Multiple studies in diverse populations have therefore demonstrated benefits in liver-related outcomes and all-cause mortality with eradication of HCV infection.
In addition to the clinical outcomes, patient-reported outcomes (PRO) have been studied with HCV treatments. For the years with only interferon-containing regimens, patients had to balance the risk of adverse events and impaired health-related quality of life with the benefits of treatment success. A systematic review determined that interferon-free regimens were superior to the interferon-containing regimens in terms of patient experience with improved PRO scores as early as 2 weeks into treatment. These regimens have resulted in lower discontinuation rates because of adverse events and given more patients the opportunity to achieve SVR. Long-term studies are needed to understand the effect of HCV treatment and SVR on PRO measures, particularly in patients with early-stage disease at low risk of complications from HCV.
Candidacy for Antiviral Therapy and Pretreatment Assessments
When considering a patient for HCV therapy ( Table 30-3 ), three important pieces of information are needed to guide the treatment plan for all patients: genotype, prior treatment history, and stage of liver disease. The HCV genotype will influence the specific selection of DAA medications. The prior treatment history will determine DAA selection and duration of treatment. Some of the available regimens contain a protease inhibitor (simeprevir, paritaprevir, asunaprevir, and grazoprevir). There is risk of the development of RAVs when exposed to a protease inhibitor again, and previous treatment with one of these medicines or one of the earlier protease inhibitors (e.g., boceprevir or telaprevir) should lead to the selection of a regimen without a protease inhibitor. The development of resistant variants to the nucleotide polymerase inhibitor sofosbuvir is exceedingly rare and is associated with a significant reduction in viral fitness. Patients who have failed sofosbuvir have been successfully treated again with a sofosbuvir-containing regimen. As new medicines like the NS5A inhibitors emerge in clinical practice, the impact of prior treatment and the risk of resistance will be important to understand. It is unclear if failure with an NS5A inhibitor–containing regimen impacts response to a future NS5A-containing regimen. The stage of liver disease also impacts treatment selection and duration. At the initial encounter, the clinician will ask about complications of portal hypertension (ascites, gastroesophageal varices, and hepatic encephalopathy) or HCC in the history and then look for stigmata of portal hypertension on physical examination, including ascites, splenomegaly, gynecomastia, and spider angiomata. If the patient has no signs or symptoms of cirrhosis or portal hypertension, an assessment of fibrosis should be performed. Although liver biopsy was routinely performed in the past, noninvasive tests for fibrosis have been studied extensively in HCV patients and can be considered. In general, these noninvasive tests group patients well into early-stage fibrosis (F0-F1) and significant fibrosis (F2-F4) or cirrhosis (F4). These tests do not differentiate one stage from another with the clarity of histology, and results may be falsely elevated if the patient has significant inflammatory activity, but they have high provider and patient acceptability. Noninvasive test options include serologic panels and radiologic tests. Radiologic tests of elastography using ultrasound and MRI assess liver stiffness, and the ultrasound-based technologies are available in many parts of the world. The serologic tests include commercial assays of serum markers (e.g., Fibrospect, Prometheus Laboratories, San Diego, CA; FibroTest/FibroSure, LabCorp, Burlington, NC; Hepascore, Quest, San Juan Capistrano, CA) and formulas derived through routine laboratory tests. The aspartate aminotransferase to platelet ratio (APRI) uses just those two tests, and the FIB-4 also requires the age and alanine aminotransferase. Online calculators and applications are available for these tests.
TABLE 30-3
Checklist for Hepatitis C Virus Therapy
| Component | Comments |
|---|---|
|
Confirms infection Guides duration for some regimens |
|
Guides regimen selection |
|
Prior interferon or DAA treatment guides choice of DAA regimen |
|
Guides duration for some regimens History and physical to rule out decompensated cirrhosis. In compensated patients, options include serum panels, elastography, and liver biopsy. |
|
HIV needs to be well controlled before HCV treatment with consideration of drug-drug interactions with HIV antiretrovirals. |
|
DAAs have specific drug-drug interactions included in package inserts and available in online applications. Key current issues include impact on HIV antiretroviral regimens for many regimens and amiodarone induced bradycardia with sofosbuvir. Use of herbal preparations must be reviewed because of drug-drug interactions with St. John's wort and milk thistle |
|
Interferon-containing regimens contraindicated if uncontrolled mental illness, decompensated cirrhosis, solid organ transplant other than liver, autoimmune conditions, severe medical illness. |
|
Pregnant patients should not take RBV. RBV is a teratogen and warrants two forms of birth control. Ability to tolerate hemolytic anemia should be considered for patients with reduced GFR, low baseline hemoglobin or comorbidities including hemoglobinopathies, cardiac, or pulmonary disease. |
|
RBV has renal clearance and should be avoided or dosed cautiously in CKD. Sofosbuvir has renal clearance and no dose established if GFR < 30 mL/min or on dialysis. All new DAAs need review of renal clearance and dosing recommendations. |
|
Pregnant women and their male partners and those attempting to conceive should delay treatment. |
|
See interferon and RBV eligibility. Seizure disorders warrant caution and review of drug-drug interactions. |
|
Patients must be ready and supported to take daily medications to maximize treatment success and avoid resistance. |
|
Iron studies (if RBV) Prothrombin time Hepatitis B surface antigen Thyroid-stimulating hormone (if interferon) |
CKD, Chronic kidney disease; DAA, direct-acting antiviral; GFR, glomerular filtration rate; HCV, hepatitis C virus; HIV, human immunodeficiency virus.
If the patients have comorbidities, these will need to be considered in the selection of treatment. When all regimens contained interferon-α, clinicians spent considerable time in the assessment of candidacy for antiviral treatment. Interferon-α had known complications and contraindications, and these are listed in Table 30-3 . RBV is renally cleared and is therefore challenging to dose in patients with chronic kidney disease (CKD) and end-stage renal disease (ESRD) on dialysis. RBV causes hemolytic anemia that is exacerbated by bone marrow suppression when paired with interferon-α. Patients with hemoglobinopathies and those with cardiac or pulmonary disorders exacerbated by anemia are therefore not good candidates for RBV-containing regimens. RBV is a known teratogen and should not therefore be given to women or their male partners during conception or pregnancy. All women and men of childbearing potential should be counseled on the need for two effective forms of birth control, and women need monthly pregnancy tests on treatment. The DAA medications have generally been developed with the expectation that they needed to be well tolerated by a broader population. Sofosbuvir is currently a component of treatment for many patients, and there no recommended dose in patients with advanced CKD and ESRD because of build-up of the active metabolite. Drug-drug interactions need to be considered for all patients, and various online tools and applications are available in addition to the information provided in package inserts. The review of potential drug-drug interactions should include herbal preparations; for example, St. John's wort reduces the exposure to multiple DAAs whereas milk thistle increases exposure to simeprevir. Key medications are substrates of the cytochrome P450 3A (CYP3A) and P-glycoprotein (P-gp) transporters. HIV medications need to be reviewed and may impact HCV treatment selection. Ledipasvir/sofosbuvir leads to elevated levels of tenofovir, a drug common in HIV regimens. Ritonavir is a component of the ombitasvir/paritaprevir/dasabuvir regimen, and boosted HIV protease inhibitors are not recommended. For all potential drug-drug interactions, clinicians will need to determine if medications can be held or switched or if another HCV regimen should be selected. The use of updated or online tools will be important for these medication considerations in the event that new interactions are determined. Such an example occurred following the approval of sofosbuvir when cases of serous symptomatic bradycardia were reported in patients on amiodarone. This combination is therefore no longer recommended.
Hepatitis C Virus Treatment Regimens
The field of HCV treatment has undergone tremendous change in recent years. The first-generation protease inhibitors, boceprevir and telaprevir, entered clinical practice in 2011 and were no longer in use by 2014. They were replaced by interferon-free options with better efficacy and fewer side effects. Three interferon-free combination regimens for genotype-1 infection were available by 2014, and multiple other regimens are expected to enter clinical practice within the next 2 years. Any discussion of specific treatment recommendations therefore is a snapshot in time in this fast-changing field.
To help guide clinicians with the rapid pace of change in HCV treatment, a joint committee of members of the American Association for the Study of Liver Diseases (AASLD) and the Infectious Diseases Society of America (IDSA) was formed to meet regularly and provide updated guidance that reflected the latest research and included the entry of new agents and regimens. As of the time of this writing in 2015, the current recommendations for genotype 1 are summarized in Table 30-4 and for genotypes 2 through 6 in Table 30-5 .
TABLE 30-4
American Association for the Study of Liver Diseases/Infectious Diseases Society of America Recommendations for Genotype-1 Treatment
| Ledipasvir/Sofosbuvir | Ombitasvir/Paritaprevir/Ritonavir + Dasabuvir | Simeprevir + Sofosbuvir | Daclastasvir + Sofosbuvir | |
|---|---|---|---|---|
| Treatment Naïve | ||||
| Genotype 1a, no cirrhosis | 12 weeks | 12 weeks with RBV | 12 weeks | 12 weeks |
| Genotype 1a, cirrhosis | 12 weeks | 24 weeks with RBV | 24 weeks ± RBV |
24 weeks ± RBV |
| Genotype 1b, no cirrhosis | 12 weeks | 12 weeks | 12 weeks | 12 weeks |
| Genotype 1b, cirrhosis | 12 weeks | 12 weeks | 24 weeks ± RBV |
24 weeks ± RBV |
| Treatment Experienced (Peginterferon-α + RBV) | ||||
| Genotype 1a, no cirrhosis | 12 weeks | 12 weeks with RBV | 12 weeks | 12 weeks |
| Genotype 1a, cirrhosis | 24 weeks or 12 weeks with RBV |
24 weeks with RBV | 24 weeks ± RBV |
24 weeks ± RBV |
| Genotype 1b, no cirrhosis | 12 weeks | 12 weeks | 12 weeks | 12 weeks |
| Genotype 1b, cirrhosis | 24 weeks or 12 weeks with RBV |
12 weeks | 24 weeks ± RBV |
24 weeks ± RBV |
| Treatment Experienced (Peginterferon-α + RBV + Protease Inhibitor) | ||||
| Genotype 1a/1b, no cirrhosis | 12 weeks | Not recommended | Not recommended | 12 weeks |
| Genotype 1a/1b, cirrhosis | 24 weeks or 12 weeks with RBV |
Not recommended | Not recommended | 24 weeks ± RBV |
| Treatment Experienced (Sofosbuvir + RBV Failures ± Peginterferon) | ||||
| Genotype 1a/1b, no cirrhosis | 12 weeks with RBV | |||
| Genotype 1a/1b, cirrhosis | 24 weeks with RBV | |||
RBV, Ribavirin.
TABLE 30-5
American Association for the Study of Liver Diseases/Infectious Diseases Society of America 2015 Treatment Recommendations for Genotypes 2 Through 6
| Genotype and Treatment History | Peginterferon + Sofosbuvir + RBV | Sofosbuvir + RBV | Ledipasvir + Sofosbuvir | Ombitasvir/Paritaprevir/Ritonavir | Daclatasvir + Sofosbuvir |
|---|---|---|---|---|---|
| 2, naïve | Recommended 12 weeks Cirrhosis: 16 weeks |
Recommended 12 weeks | |||
| 2, experienced | Alternative 12 weeks |
Recommended 16-24 weeks |
|||
| 2, sofosbuvir failure | Recommended 12 weeks |
Recommended 24 weeks ± RBV |
|||
| 3, naïve | Recommended 12 weeks |
Alternative 24 weeks |
Recommended 12 weeks Cirrhosis: 24 weeks ± RBV |
||
| 3, experienced | Recommended 12 weeks |
Recommended 12 weeks Cirrhosis: 24 weeks + RBV |
|||
| 4, naïve | Alternative 12 weeks |
Recommended 24 weeks |
Recommended 12 weeks |
Recommended 12 weeks |
|
| 4, experienced | Recommended 12 weeks |
Recommended 24 weeks |
Recommended 12 weeks |
Recommended 12 weeks |
|
| 5, naïve | Alternative 12 weeks |
Recommended 12 weeks |
|||
| 5, experienced | Alternative 12 weeks |
Recommended 12 weeks |
|||
| 6, naïve | Alternative 12 weeks |
Recommended 12 weeks |
|||
| 6, experienced | Alternative 12 weeks |
Recommended 12 weeks |
RBV, Ribavirin.
Genotype-1 Regimens
Ledipasvir and Sofosbuvir
This regimen combines the NS5A inhibitor, ledipasvir, with the nucleotide polymerase inhibitor, sofosbuvir, in a fixed-dose combination tablet. Findings from key studies with ledipasvir and sofosbuvir are included in Fig. 30-4 . The ION studies were large phase-3 clinical trials for this regimen. The studies for treatment-naïve patients were ION-1 and ION-3. ION-1 enrolled 865 genotype-1 patients with compensated liver disease, including cirrhosis. They were randomized to receive ledipasvir and sofosbuvir in a fixed-dose combination tablet once daily for 12 weeks or 24 weeks, with and without RBV. The SVR12 rates in these groups ranged from 97% to 99%, with no differences observed in subgroup analyses examining the presence of compensated cirrhosis or genotype 1a versus 1b. This study concluded that ledipasvir and sofosbuvir for 12 weeks without RBV was effective in treatment-naïve patients. The ION-3 study evaluated shorter duration therapy in treatment-naïve genotype-1 patients without cirrhosis. This study randomized 647 patients to ledipasvir and sofosbuvir for 8 weeks, ledipasvir and sofosbuvir plus RBV for 8 weeks, or ledipasvir and sofosbuvir for 12 weeks. The SVR12 rates were 93% to 95% for the three treatment groups, and the regimens were determined to be noninferior. An analysis of ION-3 by the U.S. Food and Drug Administration (FDA) found that the relapse rate in the 8-week regimen was 10% (9/92) in patients with HCV RNA greater than 6 million IU/mL and 2% (2/123) if less than this threshold. This analysis was the basis for the FDA recommendation to consider 8 weeks of treatment only for genotype-1, treatment-naïve patients without cirrhosis and with HCV RNA of less than 6 million IU/mL. The ION-2 study evaluated this regimen in genotype-1 treatment-experienced patients with compensated liver disease, including cirrhosis. Patients had previously failed treatment with peginterferon-α and RBV. Importantly, these prior treatment regimens could have included a protease inhibitor. The study enrolled 440 patients who were randomized to receive ledipasvir and sofosbuvir once daily for 12 weeks, ledipasvir and sofosbuvir plus RBV once daily for 12 weeks, ledipasvir and sofosbuvir once daily for 24 weeks, or ledipasvir and sofosbuvir plus RBV once daily for 24 weeks. SVR12 rates were 94% and 96% in the 12-week groups with and without RBV and 99% in both 24-week groups. The lower treatment responses in the 12-week groups were attributed to the outcomes in patients in cirrhosis with SVR in 19/22 (86%) without RBV and 18/22 (82%) with RBV. The SVR rates for the 24-week groups were 100% in patients with cirrhosis. These findings led to the recommendation to offer 24 weeks of therapy to treatment-experienced patients with cirrhosis. However, the SIRIUS study offered an alternative to patients with cirrhosis. This study evaluated patients with compensated cirrhosis and treatment failure from a peginterferon-α, RBV, and protease inhibitor regimen. Patients were randomized to ledipasvir and sofosbuvir for 24 weeks or ledipasvir, sofosbuvir, and RBV for 12 weeks. Of the 155 patients randomized, SVR12 rates were 96% with 24 weeks without RBV and 97% with 12 weeks with RBV. For the patient eligible for RBV therapy, the 12-week regimen offers a substantial reduction in the duration of treatment.
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