Hepatitis C Treatment & Management

Updated: Mar 28, 2016
  • Author: Vinod K Dhawan, MD, FACP, FRCPC, FIDSA; Chief Editor: BS Anand, MD  more...
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Treatment

Approach Considerations

Patients with acute hepatitis C virus (HCV) infection appear to have an excellent chance of responding to 6 months of standard therapy with interferon (IFN). Because spontaneous resolution is common, no definitive timing of therapy initiation can be recommended; however, waiting 2-4 months after the onset of illness seems reasonable.

Treatment for chronic HCV is based on guidelines from the Infectious Diseases Society of America (IDSA) and the American Associations for the Study of Liver Diseases (AASLD), in collaboration with the International Antiviral Society-USA (IAS-USA). [50]  These guidelines are constantly being updated. For more information, see HCV Guidance: Recommendations for Testing, Managing, and Treating Hepatitis C.

The guidelines propose that because all patients cannot receive treatment immediately upon the approval of new agents, priority should be given to those with the most urgent need. The recommendations include the following [50] :

  • Patients with advanced fibrosis, those with compensated cirrhosis, liver transplant recipients, and those with severe extraheptic hepatitis are to be given the highest priority for treatment
  • Based on available resources, patients at high risk for liver-related complications and severe extrahepatic hepatitis C complications should be given high priority for treatment
  • Treatment decisions should balance the anticipated reduction in transmission versus the likelihood of reinfection in patients whose risk of HCV transmission is high and in whom HCV treatment may result in a reduction in transmission (eg, men who have high-risk sex with men, active injection drug users, incarcerated persons, and those on hemodialysis)

Initiating treatment earlier for patients with lower stage fibrosis may extend the benefits of sustained virologic response (SVR). In a long-term follow-up study, 820 patients with Metavir stage F0 or F1 fibrosis confirmed by biopsy were followed for up to 20 years. The 15-year survival rate was statistically significantly better for those who experienced SVR compared with those whose treatment had failed or for those who remained untreated (93%, 82%, and 88%, respectively; P =.003). [51]

Treatment of chronic HCV infection has 2 goals. The first is to achieve sustained eradication of HCV (ie, SVR), which is defined as the persistent absence of HCV RNA in serum 6 months or more after completing antiviral treatment. The second goal is to prevent progression to cirrhosis, hepatocellular carcinoma (HCC), and decompensated liver disease requiring liver transplantation.

Antiviral therapy for chronic hepatitis C should be determined on a case-by-case basis. However, treatment is widely recommended for patients with elevated serum alanine aminotransferase (ALT) levels who meet the following criteria [3] :

  • Age greater than 18 years
  • Positive HCV antibody and serum HCV RNA test results
  • Compensated liver disease (eg, no hepatic encephalopathy or ascites)
  • Acceptable hematologic and biochemical indices (hemoglobin at least 13 g/dL for men and 12 g/dL for women; neutrophil count >1500/mm 3, serum creatinine < 1.5 mg/dL)
  • Willingness to be treated and to adhere to treatment requirements
  • No contraindications for treatment

A further criterion is liver biopsy findings consistent with a diagnosis of chronic hepatitis. However, a pretreatment liver biopsy is not mandatory. It may be helpful in certain situations, such as in patients with normal transaminase levels, particularly those with a history of alcohol dependence, in whom little correlation may exist between liver enzyme levels and histologic findings.

Patients with normal liver enzyme levels and minimal histologic damage noted on liver biopsy may elect to defer treatment until more effective and less toxic medications become available, whereas patients with more advanced liver injury may prefer to initiate treatment sooner. Patients should be informed that the treatment of HCV infection in the setting of normal liver enzyme levels remains controversial.

Viral load suppression reduces risk of hepatitis C liver morbidity and mortality. In an observational study of Veterans Affairs (VA) HCV clinical registry data from 128,769 patients that spanned more than a decade, researchers found that those who achieved an undetectable HCV viral load had a decreased risk of subsequent liver morbidity and death. [52, 53] Viral load suppression reduced the risk for future liver events by 27% (eg, compensated/decompensated cirrhosis, hepatocellular carcinoma, or liver-related hospitalization) as well as reduced the risk of death by 45%, relative to patients who did not achieve viral load suppression. Among the entire study population, only 24% had been treated previously for HCV; of these patients, only 16% (4% of all patients) achieved an undetectable viral load. [52, 53]

Patient race/ethnicity and HCV genotypes also affected the risk of future liver events and death. The risk for all liver events and death was higher in white patients relative to black patients, and those with HCV genotype 3 had a higher risk for all study outcomes compared with patients who had HCV genotype 2 (lowest risk) or 1. [52, 53]

The treatment of hepatitis C has evolved over the years. Initial studies used IFN monotherapy. Subsequently, combination of ribavirin and IFN or of IFN to which polyethylene glycol (PEG) molecules have been added (ie, PEG-IFN) were used.

Protease inhibitors have emerged as a third feature of combination therapy. The first protease inhibitor indicated for use in HCV infection, boceprevir (Victrelis), was approved by the FDA in May 2011 followed by approval of telaprevir. However these two protease inhibitors are not recommended due to the more recent availability of more effective options. A third protease inhibitor, simeprevir (Olysio), was approved in November 2013 and is recommended as a part of combination therapy for chronic hepatitis C infection.

More recently, HCV NS5B polymerase inhibitor sofosbuvir (Sovaldi) was shown to result in suppression of HCV replication and has emerged as an important component of currently recommended regimens. In November 2014, the FDA approved an all oral regimen of simeprevir plus sofosbuvir for treatment-naïve or treatment-experienced patients. [54] The treatment duration is 12 weeks for patients without cirrhosis and 24 weeks for those with cirrhosis.

On December 19, 2014, the FDA approved the combination of ombitasvir/paritaprevir/ritonavir and dasabuvir (Viekira Pak ) for the treatment of genotype 1 chronic hepatitis C infection in adults, including patients with compensated cirrhosis. [55] This all-oral regimen can be used with or without ribavirin.

In the Viekira Pak, ombitasvir, paritaprevir, and ritonavir are combined as a fixed-dose tablet and the dasabuvir is a separate tablet. Ombitasvir is a NS5A inhibitor, paritaprevir is an inhibitor of the NS3/4A serine protease, and dasabuvir is a nonnucleoside NS5B polymerase inhibitor. Ritonavir is a potent inhibitor of CYP3A4 enzymes and is used as a pharmacologic booster for paritaprevir. Ritonavir does not have activity against HCV but significantly increases serum concentrations of paritaprevir. The recommended dosing regimen is the ombitasvir/paritaprevir/ritonavir fixed-dose combination 2 tablets once daily plus dasabuvir 1 tablet twice daily. [55]

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Interferons and Pegylated Interferons

The 2 most frequently used recombinant IFN preparations in clinical trials have been IFN alfa-2b (Intron-A) and IFN alfa-2a (Roferon-A), which differ from each other by only a single amino acid residue. IFN alfacon-1 (Infergen), or consensus IFN, is a genetically engineered compound synthesized by combining the most common amino acid sequences from all 12 naturally occurring IFNs. Roferon-A was discontinued from the market in 2007 and Infergen was discontinued from the market in 2013.

The addition of propylene glycol (PEG) molecules to IFN has led to the development of long-lasting IFNs that have better sustained absorption, a slower rate of clearance, and a longer half-life than unmodified IFN, which permits more convenient once-weekly dosing. The FDA has approved PEG-IFNs for the treatment of chronic hepatitis C.

Two PEG-IFN preparations are available. PEG-IFN alfa-2b (PEG-Intron) consists of IFN alfa-2b attached to a single 12-kd PEG chain; it is excreted by the kidneys. PEG-IFN alfa-2a (Pegasys) consists of IFN alfa-2a attached to a 40-kd branched PEG molecule; it is metabolized predominantly by the liver.

IFN monotherapy in acute hepatitis C

Although the short courses of standard IFN monotherapy introduced in the 1980s by Hoofnagle et al, [56] Davis et al, [4] and Di Bisceglie et al [57] led to sustained improvement in liver disease and loss of virus in less than 10% of patients, these therapies were the first to cure chronic viral hepatitis. IFN monotherapy may play a role in the treatment of acute HCV infection.

Jaeckel et al reported that treatment with IFN alfa-2b prevented chronic infection in 98% of a group of 44 German patients with acute hepatitis C. [58] In this study, patients received 5 million U/day of IFN alfa-2b subcutaneously for 4 weeks and then 3 times per week for another 20 weeks; the IFN alfa-2b was well tolerated in all patients but one. [58] Because spontaneous resolution is common, no definitive timing of therapy can be recommended; however, waiting 2-4 months after the onset of illness seems reasonable.

PEG-IFN monotherapy

Several reports have documented improved SVR with PEG-IFN monotherapy. In a randomized study of patients with chronic hepatitis C, Zeuzem et al found that PEG-IFN alfa-2a at 180 mcg subcutaneously administered once per week was associated with a higher rate of virologic response than IFN alfa-2a at 6 million U subcutaneously administered 3 times per week for 12 weeks followed by 3 million U 3 times per week for 36 weeks. [59] Findings were 69% versus 28% at week 48 of therapy and 39% versus 19% at week 72 of therapy. [59]

In a controlled trial of persons with cirrhosis, Heathcote and colleagues reported an SVR rate of 30% after 48 weeks of therapy with PEG-IFN alfa-2a, compared with 8% for patients treated with standard IFN alfa. Adverse effects were not significantly higher with the pegylated product. [60]

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Interferons and Ribavirin

A major advance in the treatment of chronic hepatitis C was the addition of the oral nucleoside analogue ribavirin to the IFN regimen. As reported in the landmark 1998 studies by McHutchison et al [61] and Poynard et al, [62] IFN alfa-2b and ribavirin combination therapy for 6-12 months resulted in sustained eradication rates of 30-40%. However, patients with HCV genotype 1 who were treated for 12 months had a much less favorable response than patients infected with genotypes 2 and 3 who received a 6-month course of therapy.

PEG-IFN therapy with ribavirin

As with IFN alfa, the addition of ribavirin to PEG-IFN heralded a new era in the treatment of chronic HCV. The benefits of combination therapy were documented in 3 landmark trials: Manns et al from 2001, [63] Fried et al from 2002, [64] and Hadziyannis et al from 2004. [65]

Manns et al reported a significantly higher SVR rate in patients given higher-dose PEG-IFN alfa-2b plus ribavirin than in patients given lower-dose PEG-IFN alfa-2b plus ribavirin or given IFN alfa-2b plus ribavirin. [63] Adverse-effect profiles in the 3 treatment groups were similar. Secondary analyses identified body weight and HCV RNA viral load less than 1 million copies per milliliter as important predictors of SVR. (See the image below.)

Pegylated interferon alfa-2b plus ribavirin therap Pegylated interferon alfa-2b plus ribavirin therapy for chronic hepatitis C.

Fried at al found that patients who received PEG-IFN alfa-2a plus ribavirin had a significantly higher SVR rate than patients who received IFN alfa-2b plus ribavirin (56% vs 44%) or PEG-IFN alfa-2a alone (56% vs 29%). [64] The SVR rates for patients with HCV genotype 1 were 46%, 36%, and 21%, respectively, for the 3 regimens.

Hadziyannis et al reported that in patients infected with HCV genotype 1, 48 weeks of treatment was statistically superior to 24 weeks, and standard-dose ribavirin was statistically superior to low-dose ribavirin. [65] In this study, 1311 persons were randomized to PEG-IFN alfa-2a at 180 mcg/wk for 24 or 48 weeks plus a low dose (800 mg/day) or standard weight-based dose (1000 or 1200 mg/day) of ribavirin. [65] In patients with HCV genotypes 2 or 3, there were no statistically significant differences in SVR rates in the 4 treatment groups.

In a study of ribavirin in combination with either PEG-IFN alfa-2b or PEG-IFN alfa-2a for the treatment of chronic HCV infection, Ascione et al reported a higher SVR rate with PEG-IFN alfa-2a than with PEG-IFN alfa-2b (68% versus 54.4%). [66] SVR rates were not statistically different in patients with a baseline HCV RNA of 500,000 IU/mL or less or in those with cirrhosis. [66]

In a similar trial, Rumi et al reported that treatment with ribavirin plus PEG-IFN alfa-2a resulted in a significantly higher SVR rate than ribavirin plus PEG-IFN alfa-2b. The 2 regimens showed a similar safety profile. [67]

In a study of patients coinfected with HCV and HIV with compensated cirrhosis, Mira et al found that SVR to PEG-IFN plus ribavirin significantly reduced the incidence of liver-related decompensations and overall mortality. [68] The probability of hepatic decompensation was 0% at 1 year and 4% at 3 years for SVR patients, compared with 15% and 32%, respectively, for non-SVR patients. The probability of overall mortality was 0% at 1 year and 4% at 3 years for SVR patients, compared with 12% and 20%, respectively, for non-SVR patients.

In conclusion, treatment with PEG-IFN alfa-2a and ribavirin may be individualized by genotype. Patients with HCV genotype 1 require treatment for 48 weeks and a standard dose of ribavirin; those with HCV genotype 2 or 3 seem to be adequately treated with a low dose of ribavirin for 24 weeks. [69]

Response to therapy of HCV genotype 1 (ie, achievement of SVR) can now be predicted by identifying the single neoceotide polymorphisms (SNPs) located in the region of interleukin (IL)-28B gene through genome-wide association studies. Patients with CC genotype of the IL-28B have much more favorable response as compared to CT or TT genotypr (70% vs 25-30%). Testing for IL-28B genotype is thus a useful tool in the managemet of patients. [70]

Adverse effects

Adverse effects are common with IFN and ribavirin combination therapy. Approximately 75% of patients experience one or more of adverse effects.

Adverse effects of IFN include the following:

  • Hematologic complications (ie, neutropenia, thrombocytopenia)
  • Neuropsychiatric complications (ie, memory and concentration disturbances, visual disturbances, headaches, depression, irritability)
  • Flu-like symptoms
  • Metabolic complications (ie, hypothyroidism, hyperthyroidism, low-grade fever)
  • Gastrointestinal complications (ie, nausea, vomiting, weight loss)
  • Dermatologic complications (ie, alopecia)
  • Pulmonary complications (ie, interstitial fibrosis)

Adverse effects of ribavirin include the following:

  • Hematologic complications (ie, hemolytic anemia)
  • Reproductive complications (ie, birth defects)
  • Metabolic complications (ie, gout)

Because of the risk of reproductive complications from ribavirin, recommend that patients and their spouses not become pregnant while either is on therapy and for 6 months after the completion of treatment.

Growth factors, such as granulocyte-stimulating factor (GSF) and erythropoietin, are frequently used to counteract the adverse hematologic effects of IFN and ribavirin, respectively. Despite the encouraging early results reported by Afdhal et al [71] and Van Thiel et al, [72] cost-effectiveness data supporting the routine use of these agents as a means of avoiding IFN and ribavirin dose reductions are insufficient.

In November 2012, the US Food and Drug Administration (FDA) approved eltrombopag (Promacta), an oral thrombopoietin agonist, for treatment of thrombocytopenia in patients with chronic hepatitis C to allow the initiation and maintenance of IFN-based therapy. The approval was based on results from the phase 3 ltrombopag to I itiate and Maintain Interferon ntiviral Treatment to enefit Subjects with Hepatitis C related iver Diseas (ENABLE) 1 and 2 trials, which showed eltrombopag significantly reduced the time to the first IFN dose reduction compared with placebo. [73, 74]

Because of this, a significant improvement in virologic response was observed in the eltrombopag group compared with placebo. These randomized, double-blind, placebo-controlled, multicenter studies collectively enrolled 1521 patients with platelet counts less than 75,000/mcL. ENABLE 1 utilized PEG-IFN alfa-2a plus ribavirin for antiviral treatment and ENABLE 2 utilized PEG-IFN alfa-2b plus ribavirin.

In patients who are at risk of depression or who develop depression during treatment, any antidepressant is better than none. Because available evidence suggests that all antidepressants will have an effect, Schaefer et al reported that treatment must be individualized on the basis of adverse effect profile, drug-to-drug interactions, and general considerations (eg, speed of onset, efficacy). [75]

Fatigue is common in patients with chronic hepatitis C but is poorly associated with biochemical parameters. Sustained response is accompanied by substantial improvement of fatigue. [76]

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Protease and Polymerase Inhibitors

Protease inhibitors

A new class of direct-acting antiviral agents (DAAs) targets specific enzymes involved in viral replication. The addition of these new protease inhibitors to pegylated interferon and ribavirin further improves the treatment responses.

Boceprevir (Victrelis) and telaprevir (Incivek) are HCV NS3/4A protease inhibitors and were approved by the US Food and Drug Administration (FDA) in May 2011. However, treatment with either of these agents is no longer recommended because of higher efficacy with regimens that contain sofosbuvir or simeprevir. In August 2014, Vertex Pharmaceuticals announced they will discontinue the sale and distribution of telaprevir in the United States by October 2014.

A third HCV NS3/4A protease inhibitor, simeprevir (Olysio), was approved in November 2013. Each of these is indicated for treatment of chronic HCV genotype 1 infection in combination with PEG-IFN alfa and ribavirin in adults with compensated liver disease, including cirrhosis, who are previously untreated or who have failed previous interferon and ribavirin therapy. In November 2014, the FDA approved an all-oral regimen of simeprevir plus sofosbuvir for treatment-naïve or treatment-experienced patients; the duration of treatment is 12 weeks for patients without cirrhosis and 24 weeks for those with cirrhosis. [54]

The approval for simeprevir plus sofosbuvir was based on the COSMOS study, an open-label, randomized phase II clinical trial. [54] For all patients (treatment-naïve and treatment-experienced, with or without cirrhosis), 93% achieved a sustained virologic response at treatment week 12 (SVR12) after 12 weeks of treatment, and 97% achieved SVR12 after 24 weeks of treatment. [54]

The QUEST 1 and QUEST 2 phase 3 trials assessed efficacy of simeprevir in 785 adult, treatment-naïve patients with chronic HCV genotype 1. Results showed that 80% and 81% of patients treated with simeprevir (plus peginterferon alfa and ribavirin) achieved SVR12 compared with the peginterferon alfa and ribavirin control groups (50%). [77]

In the PROMISE study, 393 patients who had previous relapse after completing HCV treatment with pegylated interferon and ribavirin, were randomized to receive either 150 mg of once-daily simeprevir for 12 weeks plus pegylated interferon and ribavirin for 24 or 48 weeks based on response guided treatment criteria (simeprevir group) or pegylated interferon and ribavirin alone for 48 weeks (control group). In this study, the SVR12 was 79% in the simeprevir treatment group compared with 37% with peginterferon and ribavirin alone. [77]

The presence of the Q80K HCV GT1a polymorphism (commonly found in GT1a patients in the United States) at baseline had a substantial impact on the efficacy of simeprevir. In the pooled trials, the differences in SVR12 rates in GT1a patients with the Q80K polymorphism were not statistically significant between the treatment (58%) and control (55%) groups. In HPC3007, the SVR12 rates for those with the Q80K polymorphism were 47% in the treatment group and 30% in the control group.

Simeprevir was approved by the FDA for the treatment of HCV genotype 4 monoinfected and HCV/HIV coinfected patients as a component of a combination antiviral treatment regimen that includes peginterferon and ribavirin. The open-label, single-arm study (RESTORE) included 107 patients with HCV GT4 infection. Treatment included simeprevir 150 mg once daily plus peginterferon and ribavirin for 12 weeks, followed by peginterferon and ribavirin alone (12 or 36 weeks, response guided). Overall, 65.4% of patients achieved SVR12 (82.9% treatment naïve; 86.4% prior relapsers; 60% prior partial responders; 40% prior null responders). In treatment-naïve and prior relapser patients fulfilling response-guided criteria for 24 weeks of treatment (88.6% and 90.9%), SVR12 rates were high: 93.5% and 95.0%, respectively. These results were similar to previous reports for HCV GT1. [78]

Newer approaches to hepatitis C therapy involve treatment with 2 direct-acting antiviral agents. In a preliminary study a combination of NS5A replication complex inhibitor daclatasvir (60 mg once daily) and the NS3 protease inhibitor asunaprevir (600 mg twice daily) resulted in a sustained virologic response in patients with HCV genotype 1 infection who had not responded to prior therapy with peginterferon and ribavirin. [79]

Polymerase inhibitors

HCV NS5B polymerase plays an essential role in HCV replication. Sofosbuvir (Sovaldi) is a NS5B polymerase inhibitor that results in suppression of HCV replication and life cycle. Sofosbuvir was approved by the FDA in December 2013 for treatment of CHC infection genotypes 1, 2, 3, and 4 as part of a combination antiviral regimen, including those with hepatocellular carcinoma meeting Milan criteria (awaiting liver transplantation) to prevent HCV recurrence and those with HCV/HIV-1 co-infection.

Sofosbuvir treatment regimens and duration are dependent on both viral genotype and patient population. Patients with genotype 1 or 4 are treated with sofosbuvir plus peginterferon alfa and ribavirin for 12 weeks. Those with genotype 2 or 3 are part of an all oral drug regimen consisting of sofosbuvir plus ribavirin for 12 or 24 weeks respectively.

Approval for sofosbuvir was supported by data from several Phase 3 studies that evaluated 12 or 16 weeks of treatment with the drug combined with either ribavirin or ribavirin plus peginterferon alfa. Three of these studies evaluated sofosbuvir plus ribavirin in genotype 2 or 3 patients who were either treatment-naïve, [80] treatment-experienced [81] or peginterferon intolerant, ineligible or unwilling. [81] The fourth study evaluated sofosbuvir in combination with peginterferon/ribavirin in treatment-naïve patients with genotypes 1, 4, 5 or 6. [80]

In these studies, sofosbuvir-based therapy was found to be superior to historical controls [80] or to placebo, [81] or noninferior to currently available treatment options [80] based on the proportion of patients who had a SVR12  after completing therapy. Patients who achieve SVR12 are considered cured of HCV. Trial participants taking sofosbuvir-based therapy achieved SVR12 rates of 50-90%.

During the FDA’s review, data from two additional Phase 3 studies were added to the NDA as a result of the Breakthrough Designation status. In the first study, patients with genotype 3 HCV infection were treated with sofosbuvir and ribavirin for 24 weeks. Eighty-four percent of patients in this trial achieved SVR12. [82] The second study evaluated sofosbuvir and ribavirin for 12 weeks in patients with genotype 2 HCV infection co-infected with HIV-1. [83]

In all Phase 3 studies, no viral resistance to sofosbuvir was detected among patients who relapsed following completion of therapy.

Harvoni is a combination oral product containing ledipasvir, an NS5A protein inhibitor, and sofosbuvir that was approved by the FDA in October 2014 for HCV genotype 1. Since its original approval in the United States, the indication has been expanded to include genotypes 1, 4, 5, and 6.  It is administered once daily and does not need to be administered with interferon. Some regimens may require ribavirin. Studies showed a high, sustained virologic response (94-99%) in all treatment groups (ie, treatment naïve or treatment experienced, with or without cirrhosis, and liver transplant recipients). [84, 85, 86]

This fixed-dose combination drug demonstrated efficacy in refractory cirrhotic hepatitis C. In a study of 154 patients with cirrhotic chronic HCV infection who had failed previous protease inhibitor–based therapy, treatment with the fixed-dose combination of ledipasvir and sofosbuvir (Harvoni) with or without ribavirin led to sustained viral response in the majority of patients. [87, 88]

Study subjects received either ledipasvir and sofosbuvir plus placebo for 24 weeks or placebo for 12 weeks followed by ledipasvir and sofosbuvir plus ribavirin for 12 weeks. Sustained viral response 12 weeks after treatment was seen in 96% of the 24-week combination group and 97% of the 12-week combination plus ribavirin group. Three patients in the 12-week group and two patients in the 24-week group experienced relapses. [87, 88]

Combination products

The fixed-dose HCV NS5A and NS3/4A protease inhibitor, elbasvir/grazoprevir (Zepatier) was approved in January 2016 for use with or without ribavirin for adults with HCV genotypes 1 or 4 infection. Elbasvir is an inhibitor of HCV NS5A, which is essential for viral RNA replication and virion assembly. Grazoprevir is an inhibitor of HCV NS3/4A protease, which is necessary for the proteolytic cleavage of the HCV-encoded polyprotein (into mature forms of the NS3, NS4A, NS4B, NS5A, and NS5B proteins) and is essential for viral replication.

Efficacy of elbasvir/grazoprevir was evaluated in clinical trials that included nearly 1,400 patients. The overall SVR rates ranged from 94% to 97% for genotype 1 and 97% to 100% for genotype 4 across trials. [89, 90] The approved dosage regimens are specific to the characteristics of the patient and their virus genotype. Prior to initiating therapy, patients should be tested for NS5A resistance in HCV genotype 1a–infected patients to determine the dosage regimen and duration.

On December 19, 2014, the FDA approved the combination of ombitasvir/paritaprevir/ritonavir and dasabuvir (Viekira Pak) for the treatment of genotype 1 chronic hepatitis C infection in adults, including patients with compensated cirrhosis. Studies were conducted using 2 tablets of ombitasvir/paritaprevir/ritonavir tablets once daily (in the morning) plus 1 tablet of dasabuvir 250 mg tablet twice daily (morning and evening) with a meal with ribavirin (up to 6 pills divided into 2 daily doses) for 12 weeks (no cirrhosis) or 24 weeks (compensated cirrhosis) with the cure rates summarized below. [91, 92, 93, 94, 95]

HCV genotype 1a infection cure rates for the ombitasvir/paritaprevir/ritonavir and dasabuvir combination included the following:

  • No cirrhosis - SVR12 rates were 95% for 12 weeks of treatment with ribavirin (SAPPHIRE-I Study); SVR12 was 97% for 12 weeks of treatment with ribavirin but 90% without ribavirin (PEARL-IV Study)
  • Cirrhosis - SVR12 rates were 89% in the 12-week arm and 95% in the 24-week arm; prior treatment null responders had lower SVR rates (TURQOUISE-II Study)

HCV genotype 1b infection cure rates for the ombitasvir/paritaprevir/ritonavir and dasabuvir combination included the following:

  • No cirrhosis - SVR12 rates were 99% for 12 weeks of treatment with ribavirin (PEARL-III Study)
  • Cirrhosis: SVR12 rates were 98.5% in the 12-week arm (with ribavirin) and 100 percent in the 24-week arm; prior treatment null responders had lower SVR rates (TURQOUISE-II Study)

The combination product ombitasvir/paritaprevir/ritonavir (Technivie) was FDA approved in July 2015 for treatment of genotype 4 chronic HCV without cirrhosis. [96] It is recommended to be used in conjunction with ribavirin.

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Treatment Recommendations for Chronic Hepatitis C Infection

The following recommendations are based on  guidelines from the American Association for the Study of Liver Diseases [AASLD], the Infectious Disease Society of America [ISDA], and the International Antiviral Society-USA [IAS-USA]. [50] They are available at http://www.hcvguidelines.org/full-report-view.

Treatment-naïve patients

HCV genotype 1a infection

In general, there are three options with similar efficacy recommended for treatment-naive patients with HCV genotype 1a infection, as follows:

  1. Daily fixed-dose combination of ledipasvir (90 mg)/sofosbuvir (400 mg) for 12 weeks
  2. Daily fixed-dose combination of paritaprevir (150 mg)/ritonavir (100 mg)/ombitasvir (25 mg) plus  twice-daily dasabuvir (250 mg) and weight-based ribavirin (RBV) (1000 mg [<75 kg] to 1200 mg [≥75 kg]) for 12 weeks (no cirrhosis) or 24 weeks (cirrhosis)
  3. Daily sofosbuvir (400 mg) plus simeprevir (150 mg), with or without weight-based RBV (1000 mg [<75 kg] to 1200 mg [≥75 kg]), for 12 weeks (no cirrhosis) or 24 weeks (cirrhosis without Q80 polymorphism)
  4. Daily daclatasvir (60 mg) and sofosbuvir (400 mg), for 12 weeks (no cirrhosis) or 24 weeks with or without ribavirin (cirrhosis)

HCV genotype 1b infection

There are generally three options with similar efficacy recommended for treatment-naive patients with HCV genotype 1b infection, as follows:

  1. Daily fixed-dose combination of ledipasvir (90 mg)/sofosbuvir (400 mg) for 12 weeks
  2. Daily fixed-dose combination of paritaprevir (150 mg)/ritonavir (100 mg)/ombitasvir (25 mg) plus twice-daily dasabuvir (250 mg) for 12 weeks. The addition of weight-based RBV (1000 mg [<75kg] to 1200 mg [≥75 kg]) is recommended in patients with cirrhosis.
  3. Daily sofosbuvir (400 mg) plus simeprevir (150 mg) for 12 weeks (no cirrhosis) or 24 weeks with or without weight-based RBV (cirrhosis)
  4. Daily daclatasvir (60 mg) plus sofosbuvir (400 mg) for 12 weeks (no cirrhosis) or 24 weeks, with or without weight-based ribavirin, (cirrhosis) for treatment-naive patients with HCV genotype 1b infection

HCV genotype 2 infection

  1. The recommended regimen is daily sofosbuvir (400 mg) and weight-based RBV (1000 mg [<75 kg] to 1200 mg [≥75 kg]) for 12 weeks (16 weeks in patients with cirrhosis); this regimen may be extended up to 16 weeks for treatment-naïve patients with cirrhosis
  2. Daily daclatasvir (60 mg) plus sofosbuvir (400 mg) for 12 weeks, in patients who cannot tolerate ribavirin

HCV genotype 3 infection

Daclatasvir (Daklinza), an NS5A inhibitor, was FDA approved in July 2015 for use with sofosbuvir for chronic HCV genotype 3 infection. [97] The dose is 60 mg PO once daily plus  sofosbuvir 400 mg once daily. In the ALLY-3 study, SVR at 12 weeks (SVR12) was achieved in 98% of treatment-naïve patients and 92% of treatment-experienced patients without cirrhosis. [98]  Patients with cirrhosis had reduced SVR, 58% and 69%, respectively, in treatment-naïve and treatment-experienced patients.

  1. Daily sofosbuvir 400 mg PO once per day plus  daily ribavirin for 12 weeks plus  weekly pegylated interferon for 24 weeks  (NOTE:  This regimen, described in the phase III VALENCE trial, may be utilized in both treatment-naïve patients and treatment-experienced patients [82] ; the SVR rate was 93% in treatment-naïve patients and 77% in treatment-experienced patients)
  2. Daily sofosbuvir (400 mg) plus weight-based ribavirin for 24 weeks who are IFN-ineligible
  3. Daily daclatasvir (60 mg) plus sofosbuvir (400 mg) for 12 weeks (no cirrhosis) or 24 weeks, with or without weight-based RBV (cirrhosis)

HCV genotype 4 infection

Several options with similar efficacy are recommended for treatment-naive patients with HCV genotype 4 infection, as follows:

  1. Daily fixed-dose combination of ledipasvir (90 mg)/sofosbuvir (400 mg) for 12 weeks
  2. Daily fixed-dose combination of paritaprevir (150 mg)/ritonavir (100 mg)/ombitasvir (25 mg) and weight-based RBV (1000 mg [<75 kg] to 1200 mg [≥75 kg]) for 12 weeks
  3. Daily sofosbuvir (400 mg) and weight-based RBV (1000 mg [<75 kg] to 1200 mg [≥75 kg]) for 24 weeks

Alternative regimens include the following:

  1. Daily sofosbuvir (400 mg) and  weight-based RBV (1000 mg [<75 kg] to 1200 mg [≥75 kg]) plus weekly PEG-IFN for 12 weeks
  2. Daily sofosbuvir (400 mg) plus simeprevir (150 mg), with or without weight-based RBV (1000 mg [<75 kg] to 1200 mg [≥75 kg]), for 12 weeks

The combination product ombitasvir/paritaprevir/ritonavir (Technivie) was FDA approved in July 2015. [96] It is indicated for treatment of genotype 4 chronic HCV infection without cirrhosis in patients who were either treatment naïve or did not achieve a virologic response with prior treatment with pegylated interferon/ribavirin (pegIFN/RBV). It is recommended to be used in combination with ribavirin, although it may be considered for treatment-naïve patients who cannot take or tolerate ribavirin. [96] In the PEARL-1 study, all patients who received Technivie with ribavirin achieved SVR12 compared with 91% of those who received Technivie without ribavirin. [99] Clinical trials did not include patients who were previously treated with direct-acting antivirals.

Simeprevir was approved by the FDA for the treatment of HCV genotype 4 monoinfected and HCV/HIV coinfected patients as a component of a combination antiviral treatment regimen that includes peginterferon and ribavirin. [78]

HCV Genotypes 5 or 6 infection

The recommended regimen is daily fixed-dose combination of ledipasvir (90 mg)/sofosbuvir (400 mg) for 12 weeks.

An alternative regimen is the following:

  • Daily sofosbuvir (400 mg) and  weight-based RBV (1000 mg [<75 kg] to 1200 mg [≥75 kg]) plus weekly PEG-IFN for 12 weeks

Treatment-experienced patients with previous treatment failure

Patients with HCV genotype 1a infection who do not have cirrhosis, in whom prior PEG-IFN and RBV treatment has failed

The recommended regimens are as follows:

  1. Daily fixed-dose combination of ledipasvir (90 mg)/sofosbuvir (400 mg) for 12 weeks
  2. Daily fixed-dose combination of paritaprevir (150 mg)/ritonavir (100 mg)/ombitasvir (25 mg) plus twice-daily dasabuvir (250 mg) for 12 weeks
  3. Daily sofosbuvir (400 mg) plus simeprevir (150 mg) for 12 weeks
  4. Daily daclatasvir (60 mg) plus sofosbuvir (400 mg) for 12 weeks

Patients with HCV genotype 1b infection who do not have cirrhosis, in whom prior PEG-IFN and RBV treatment has failed

The recommended regimens are as follows:

  1. Daily fixed-dose combination of ledipasvir (90 mg)/sofosbuvir (400 mg) for 12 weeks
  2. Daily fixed-dose combination of paritaprevir (150 mg)/ritonavir (100 mg)/ombitasvir (25 mg) plus twice-daily dasabuvir (250 mg) for 12 weeks
  3. Daily sofosbuvir (400 mg) plus simeprevir (150 mg) for 12 weeks
  4. Daily daclatasvir (60 mg) plus sofosbuvir (400 mg) for 12 weeks

Patients with HCV genotype 1a or 1b infection who have compensated cirrhosis, in whom prior PEG-IFN and RBV treatment has failed

The recommended regimens are as follows:

  1. Daily fixed-dose combination of ledipasvir (90 mg)/sofosbuvir (400 mg) for 24 weeks
  2. Daily fixed-dose combination of ledipasvir (90 mg)/sofosbuvir (400 mg) plus weight-based RBV (1000 mg [< 75 kg] to 1200 mg [≥75 kg]) for 12 weeks
  3. Daily fixed-dose combination of paritaprevir (150 mg)/ritonavir (100 mg)/ombitasvir (25 mg) plus  twice-daily dasabuvir (250 mg) and weight-based RBV (1000 mg [<75 kg] to 1200 mg [≥75 kg]) for 24 weeks (HCV genotype 1a infection) or for 12 weeks (HCV genotype 1b infection)
  4. Daily sofosbuvir (400 mg) plus simeprevir (150 mg), with or without weight-based RBV (1000 mg [<75 kg] to 1200 mg [≥75 kg]), for 24 weeks (HCV genotype 1a infection negative for Q80K variant and HCV genotype 1b)
  5. Genotype 1a only: Daily daclatasvir (60 mg) plus sofosbuvir (400 mg) for 12 weeks

Patients without advanced fibrosis, in whom a previous sofosbuvir plus RBV with or without PEG-INF treatment has failed

Patients with cirrhosis: The recommended regimen is daily fixed-dose combination of ledipasvir (90 mg)/sofosbuvir (400 mg) with weight-based RBV (1000 mg [<75 kg] to 1200 mg [≥75 kg]) for 24 weeks.

Patients with no cirrhosis: The recommended regimen is daily fixed-dose combination ledipasvir (90 mg)/sofosbuvir (400 mg) with RBV for 12 weeks.

Patients without cirrhosis who have HCV genotype 1 infection, regardless of subtype, in whom a prior treatment with an HCV NS3 protease inhibitor plus PEG-IFN and RBV has failed or simeprevir plus sofosbuvir has failed (no prior NS5A treatment)

The recommended regimens are as follows:

  1. Daily fixed-dose combination ledipasvir (90 mg)/sofosbuvir (400 mg) for 12 weeks
  2. Patients without cirrhosis in whom prior treatment with simeprevir plus sofosbuvir has failed: Daily fixed-dose combination ledipasvir (90 mg)/sofosbuvir (400 mg) plus weight-based RBV (1000 mg [<75 kg] to 1200 mg [≥75 kg]) for 12 weeks
  3. Daily daclatasvir (60 mg) plus sofosbuvir (400 mg) for 24 weeks with or without ribavirin

Patients with HCV genotype 2 infection, in whom prior PEG-IFN and RBV treatment has failed

The recommended regimen is daily sofosbuvir (400 mg) and weight-based RBV (1000 mg [<75 kg] to 1200 mg [≥75 kg]) for 12 to 16 weeks

An alternative regimen for patients in whom previous PEG-IFN and RBV treatment failed, who have HCV genotype 2 infection, and are who are eligible to receive IFN is as follows:

  • Retreatment with daily sofosbuvir (400 mg) and  weight-based RBV (1000 mg [<75 kg] to 1200 mg [≥75 kg]) plus weekly PEG-IFN for 12 weeks

Patients with HCV genotype 3 infection in whom prior PEG-IFN and RBV treatment has failed

Patients without cirrhosis:

  1. Daily sofosbuvir (400 mg) plus  weight-based ribavirin plus weekly pegylated interferon for 12 weeks
  2. Daily daclatasvir (60 mg) plus sofosbuvir (400 mg) for 12 weeks

Patients with cirrhosis:

  1. Daily sofosbuvir (400 mg) plus weight-based ribavirin plus weekly pegylated interferon for 12 weeks
  2. Daily daclatasvir (60 mg) plus  sofosbuvir (400 mg) plus weight-based ribavirin for 24 weeks

Recommended regimens are as follows for patients with sofosbuvir and RBV treatment failures

  1. Daily sofosbuvir (400 mg) plus  weight-based ribavirin plus weekly pegylated interferon for 12 weeks
  2. Daily daclatasvir (60 mg) plus  sofosbuvir (400 mg) plus  weight-based ribavirin for 24 weeks 

Patients with HCV genotype 4 infection, in whom prior PEG-IFN and RBV treatment has failed

The recommended regimens are as follows:

  1. Daily fixed-dose combination of ledipasvir (90 mg)/sofosbuvir (400 mg) for 12 weeks
  2. Daily sofosbuvir (400 mg) plus weight-based ribavirin plus weekly pegylated interferon for 12 weeks

The combination product ombitasvir/paritaprevir/ritonavir (Technivie) was FDA approved in July 2015. [96] It is indicated for treatment of genotype 4 chronic HCV infection without cirrhosis in patients who were either treatment naïve or did not achieve a virologic response with prior treatment with pegylated interferon/ribavirin (pegIFN/RBV). It is recommended to be used in combination with ribavirin, although it may be considered for treatment-naïve patients who cannot take or tolerate ribavirin. [96] In the PEARL-1 study, all patients who received Technivie with ribavirin achieved SVR12 compared with 91% of those who received Technivie without ribavirin. [99] Clinical trials did not include patients who were previously treated with direct-acting antivirals.

Patients with HCV genotypes 5 or 6 infection in whom prior treatment has failed

The recommended regimen is daily fixed-dose combination ledipasvir (90 mg)/sofosbuvir (400 mg) for 12 weeks

An alternative regimen for IFN eligible patients with HCV genotypes 5 or 6 infection in whom prior treatment has failed is the following:

  • IFN eligible: The recommended regimen is daily sofosbuvir (400 mg) and weight-based RBV (1000 mg [<75 kg] to 1200 mg [≥75 kg]) plus weekly PEG-IFN for 12 weeks
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HIV-HCV Coinfection

HIV/HCV-coinfected persons should be treated and retreated the same as persons without HIV infection. Antiretroviral treatment interruption to allow HCV therapy is NOT recommended. However, several important points related to drug interactions with antiretroviral medications need to be emphasized, as follows:

  • Fixed-dose combination of ledipasvir (90 mg)/sofosbuvir (400 mg): Because ledipasvir increases tenofovir levels, concomitant use of these agents mandates consideration of the creatinine clearance (CrCl) rate; avoid their use in those with CrCl below 60 mL/min. Because potentiation of this effect is expected when tenofovir is used with ritonavir-boosted HIV protease inhibitors, avoid using ledipasvir with this combination unless the antiretroviral regimen cannot be changed and the urgency of treatment is high.
  • For combination agents expected to increase tenofovir levels, baseline and ongoing assessment for tenofovir nephrotoxicity is recommended.
  • Paritaprevir/ritonavir/ombitasvir plus dasabuvir should be used with antiretroviral drugs with which they do not have substantial interactions, such as raltegravir (and probably dolutegravir), enfuvirtide, tenofovir, emtricitabine, lamivudine, and atazanavir.
  • The dose of ritonavir used for boosting of HIV protease inhibitors may need to be adjusted (or held) when administered with paritaprevir/ritonavir/ombitasvir plus dasabuvir; restore the dose when the HCV treatment is completed. The HIV protease inhibitor should be administered at the same time as the fixed-dose HCV combination.
  • Simeprevir should only be used with antiretroviral drugs with which it does not have clinically significant interactions, such as raltegravir (and probably dolutegravir), rilpivirine, maraviroc, enfuvirtide, tenofovir, emtricitabine, lamivudine, and abacavir.
  • Avoid use of the fixed-dose combination of ledipasvir (90 mg)/sofosbuvir (400 mg) with cobicistat and elvitegravir.
  • Avoid use of sofosbuvir or ledipasvir/sofosbuvir with tipranavir.
  • Avoid use of the fixed-dose combination of paritaprevir (150 mg)/ritonavir (100 mg)/ombitasvir (25 mg) plus twice-daily dosed dasabuvir (250 mg) with efavirenz, rilpivirine, darunavir, or ritonavir-boosted lopinavir.
  • Avoid use of paritaprevir/ritonavir/ombitasvir, with or without dasabuvir, in HIV/HCV-coinfected individuals who are not taking antiretroviral therapy.
  • Avoid use of simeprevir with efavirenz, etravirine, nevirapine, cobicistat, or any HIV protease inhibitors.
  • Avoid use of ribavirin with didanosine, stavudine, or zidovudine.
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Hepatitis C and B Coinfection

Coinfection with HCV and hepatitis B virus (HBV), in the absence of HIV infection, is relatively uncommon in the United States, and optimal treatment regimens have not been established. However, 2 important studies are worth mentioning.

Villa et al reported that 9 million U of standard IFN 3 times weekly for 3 months could clear HCV in 31% of patients with HCV-HBV coinfection. [100] Liu et al used standard IFN and ribavirin and discovered that sustained HCV eradication was achieved at rates comparable to those in patients with HCV alone and, interestingly, up to 21% of their patients lost the hepatitis B surface antigen. [101]

Given the superior efficacy of PEG-IFN over standard IFN, Liu et al subsequently conducted a multicenter study using PEG-IFN and ribavirin in HVC-HBC coinfected patients. This regimen proved equally effective in patients with HCV monoinfection and in those with chronic HCV-HBV infection. [102]

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Interferon Response in Specific Populations

Several small studies have reported a lower response rate to IFN alfa in black patients with chronic hepatitis C infection than in white patients. The increased prevalence of infection with HCV genotype 1, which is associated with a lower response rate than other genotypes, has been suggested as the cause.

However, in a study that enrolled equal proportions of black and non-Hispanic white patients with chronic hepatitis from HCV genotype 1, Muir et al reported that the SVR rate was significantly higher among non-Hispanic white patients (52%) than among black patients (19%) after treatment with PEG-IFN alfa-2b and ribavirin for 48 weeks. [103] Multivariate analyses examining sociodemographic and clinical characteristics found that black race was the only variable significantly associated with the difference in response rates.

Hepburn et al analyzed data from 661 patients in 2 multicenter trials and found that compared with white patients, Asians were more likely to respond to treatment, and Hispanics and blacks were less likely to respond. [104] The role of ethnicity in predicting successful viral eradication emerged after multiple logistic regression analyses adjusted for factors known to impact outcome (eg, genotype).

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Nonresponse or Relapse

For patients who do not achieve an SVR after a full course of PEG-IFN plus ribavirin, retreatment is recommended with regimens listed above. Patients who do not respond to antiviral therapy and who have advanced fibrosis should be screened for hepatocellular carcinoma (HCC) and varices and should be evaluated for liver transplantation if they are appropriate candidates. Patients with mild fibrosis should be monitored without treatment. [105]

Hayashi and Kasahara noted that exposure to IFN, irrespective of HCV eradication status, was associated with a reduced incidence of HCC. [106] An important randomized study by Kubo et al, first conducted in 1996 with follow-up in 2002, also demonstrated that the administration of IFN to patients undergoing liver resection for HCC was associated with reduced tumor recurrence and improved survival. [107] Although IFN may have a role in reducing the incidence of HCC, it remains unclear as to which subgroup of HCV patients are most likely to benefit.

The aim of treating decompensated cirrhotic patients is to achieve sustained viral eradication before liver transplantation in an attempt to prevent recurrent HCV infection. However, this intervention is not recommended outside of clinical trials because the risks of treatment can outweigh the benefits. [108] Although viral titers may decrease during treatment and possibly diminish the severity of recurrent HCV infection, complications and successful eradication are less likely in patients with more advanced liver disease. [109]

Recurrence after liver transplantation

Recurrent HCV infection is universal after liver transplantation, can lead to cirrhosis in 30% of patients within 5 years, and is emerging as the most common cause of retransplantation in the United States. [110] IFN is contraindicated after organ transplantation because of its high risk of precipitating rejection, in part due to upregulation of the human leukocyte antigen (HLA) system by IFN. Liver transplantation is a possible exception, however, as allograft rejection is uncommon in liver transplant recipients with recurrent HCV infection who are treated with IFN-based therapies.

SOF-based therapy is now recommended for patients with recurrent hepatitis C after liver transplantation; first-line regimens are as follows: for genotype 1, SOF plus SMV with or without RBV for 12 to 24 weeks; for genotypes 2 and 3, SOF plus RBV for 24 weeks

Patients with normal liver eEnzyme levels

The treatment for these patients remains controversial, because previous studies have demonstrated that they frequently have mild liver disease, do not tolerate therapy, or can develop new elevations in liver chemistry parameters after starting treatment. Liver biopsy can be valuable in these cases. Hui et al reported that ALT levels and histologic findings are not well correlated and patients can have advanced fibrosis or cirrhosis in the presence of normal liver enzyme levels. [111]

Jacobson et al reported that sustained HCV eradication rates in patients with HCV infection and normal ALT values were comparable to those in patients with elevated liver enzyme levels. [112] However, the authors used both high-dose (5 million U) and low-dose (3 million U) IFN with ribavirin in their study, and only 1 patient had cirrhosis. [112]

In addition, Jacobson et al did not investigate the role of previous alcohol use on liver injury, although all patients abstained from alcohol for at least 12 months. Future trials will most likely evaluate PEG-IFN with ribavirin in this cohort of patients, and the hope is they will adjust for confounders, such as alcohol use.

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Patients Using Alcohol or Injection Drugs

In 1998, Wiley et al reported that significant alcohol use (>40 g alcohol/d in women and >60 g of alcohol/day in men for >5 y) in HCV-infected patients resulted in a twofold to threefold greater risk of liver cirrhosis and decompensated liver disease. In addition, cirrhosis developed more rapidly in alcohol users. [113] Because of the risk that alcohol use poses for rapid liver fibrosis, hepatoma, and deleterious effects on treatment response, complete alcohol abstinence is recommended during treatment.

Practice guidelines from the American Association for the Study of Liver Diseases recommend that HCV treatment not be withheld from patients who use illicit drugs or are on a methadone maintenance program, provided they are willing to maintain close monitoring, including practicing contraception. [114] However, the guidelines note that "it is important to consider the individual issues that may affect the risks and benefits of treatment of HCV infection in persons who use illicit drugs, rather than to make categorical recommendations." [105]

The complexity of HCV treatment in these patients is aided by a multidisciplinary team approach composed of physicians, nurses, and substance abuse and mental health professionals.

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Deterrence/Prevention

Currently, no products are available to prevent HCV infection. The development of immunoprophylaxis for this disease is proving difficult; an effective neutralizing immune response has not been demonstrated.

Patients with hepatitis C should be advised to abstain from alcohol use; they should also be advised to use barrier protection during sexual intercourse. Screening high-risk patients and initiating appropriate treatment may decrease the prevalence of cirrhosis and HCC.

In an ongoing prospective study of prevention of HCV infection in injection-drug users, researchers recommended 6 measures that can be used to prevent the spread of hepatitis C [115, 116] :

  • Reducing risk from shared ancillary drug preparation equipment, such as containers, rinse water, and filters, in addition to shared syringes
  • Using a new rapid test at the point of care that offers results in 20 minutes can detect infection before seroconversion occurs and, combined with counseling, can help to stem transmission
  • Addressing social and relational contexts of injecting can encourage uninfected individuals to take precautions when injecting drugs with infected sex partners
  • Encouraging "taking a break" from injecting drugs
  • Developing models to guide delivery of new prevention strategies, including already-available approaches such as increasing syringe availability and future strategies such as direct-acting antivirals that can be used prophylactically, as well as vaccines
  • Combining interventions in synergistic ways, such as needle exchange and methadone maintenance programs
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Consultations and Long-Term Monitoring

Consultation with a gastroenterologist and hepatologist is recommended in the treatment of HCV infection. Consultation with a psychiatrist may be helpful before and during treatment in patients at risk of depression or other psychiatric illnesses. Consultation with a surgeon may be necessary for patients in whom hepatic resection for HCC or liver transplantation is being considered.

At week 12 of treatment, the patient should be evaluated for an early virologic response by repeating the quantitative HCV RNA and IFN-associated thyroid dysfunction screening. If the HCV RNA level is undetectable or if a greater than 2-log-fold reduction in HCV RNA level is present, therapy should be continued because, according to Fried et al, up to 65% of patients go on to develop an SVR. [64]

Conversely, if an early virologic response is not present, treatment should be stopped, because the chance of developing a sustained response of HCV eradication is less than 3%. Poynard et al reported that the one exception is in the context of clinical trials or treatment of recurrent HCV infection in liver transplant recipients [117] ; improved fibrosis scores have been reported in patients in whom the virus has not been eradicated, thus identifying a subgroup of patients who may benefit from maintenance therapy.

The HCV RNA level should be rechecked 6 months after the completion of treatment; if HCV RNA is detectable, the patient has had a relapse of disease and an alternative treatment should therefore be considered. If HCV RNA is undetectable and test results remain negative, the patient has developed an SVR.

Patients with HCV infection should be monitored closely for adverse effects as well as response to therapy. Tests to help monitor drug toxicity include the following:

  • Complete blood count with differential
  • Renal function testing
  • Liver function tests (including alanine aminotransferase [ALT] level)
  • Thyrotropin level

While measurement of ALT levels is useful for monitoring the effectiveness of therapy for HCV infection, ALT levels can fluctuate. Consequently, a single value in the reference range does not rule out active infection, progressive liver disease, or cirrhosis. ALT normalization with therapy is not proof of cure.

Patients with cirrhosis should be screened for HCC and esophageal varices. They should also be monitored for the development of decompensated liver disease. Vaccination against hepatitis A virus (HAV) and HBV before or after completing HCV treatment has been recommended. [118] Patients should be offered vaccination for HAV and HBV before they develop decompensated liver disease, after which they may be less likely to mount an immune response.

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