Disease-a-Month 60 (2014) 201–212
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Disease-a-Month journal homepage: www.elsevier.com/locate/disamonth
Hepatitis C Juliana Chan, PharmD, FCCP, BCACP
Introduction Hepatitis C is a common blood-borne infection that primarily affects the liver. Complications of the liver disease include cirrhosis and hepatocellular carcinoma (HCC), which have been the leading causes for a liver transplant in the United States. The treatment for hepatitis C has evolved over time with virological cure rates of less than 10% in the 1990s compared to about 90% in 2014. The purpose of this article is to review the risk factors for acquiring hepatitis C, natural history of the infection, diagnosis, and medical management of treatment-naïve patients infected with the hepatitis C virus (HCV).
Epidemiology There are approximately 150 million people worldwide infected with the hepatitis C virus (HCV).1–3 It is estimated that the overall incidence in the United States is 1.6%, which equates to approximately 3–5 million individuals.4 In certain high-risk groups, such as the incarcerated population, the incidence of HCV reported is higher compared to the general population, ranging between 23% and 41%.3,5 A survey conducted in 2000 of correctional facilities found that 79% had screened inmates, and of those sites, approximately 31% were positive for HCV.6 HCV is primarily transmitted through blood, thus those at highest risk of being infected are users of illicit intravenous drugs (IVD), especially those with a history of incarceration. A study documented that 27% of one state's correctional facility inmates had a documented history of IVD, and of these, there were 91% who tested positive for HCV.6 This is in line with the general population, where the prevalence of HCV via IVD is approximately 90%.7,8 Additional percutaneous exposure to HCV includes the transfusion of contaminated blood products and organ transplants prior to 1987 and 1992, respectively. Prior to this date, there was no effective screening to test for HCV antibodies in blood donors. Hemophiliacs or patients who received clotting factors before 1987 are also at risk for HCV. It is quite rare to transmit HCV with today's current standards in place for testing and inactivating HCV in blood and blood-related products.2,7 It is possible to transmit HCV through the use of needles in commercial tattoo parlors, although it is rare. There are exceptions though, such as inmates who received tattoos in the correctional setting through use of contaminated needles.9 HCV transmission through sexual http://dx.doi.org/10.1016/j.disamonth.2014.04.002 0011-5029/ Published by Mosby, Inc.
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Table 1 Recommendations for anti-HCV antibodies screening.4,10–12 Bureau of prison (BOP) for incarcerated population
Centers for disease control and prevention (CDC) for general population
Presence of certain clinical conditions (regardless of sentencing status) Chronic hemodialysis (screen ALT monthly and anti-HCV semiannually) Elevated ALT levels of unknown etiology Evidence of extrahepatic manifestations of HCV (e.g, mixed cryoglobulinemia, membranoproliferative glomerulonephritis, or porphyria cutanea tarda) Presence of hepatitis C risk factors (sentenced inmates only) Ever injected illegal drugs or shared equipment Received tattoos or body piercings while incarcerated HIV-infected or chronic HBV infection Received blood transfusion or organ transplant before 1992 or clotting factor transfusion prior to 1987 History of percutaneous exposure to blood Ever received hemodialysis
Test at least once in lifetime Any person born between 1945 and 1965 Injected illegal drugs Recipient of clotting factor before 1987 Recipient of blood transfusions or solid organ transplant before 1992 Received hemodialysis treatments Healthcare workers after needlesticks All HIV-infected persons Signs and symptoms of liver disease Children born to HCV-positive mothers Elevated liver function tests
intercourse is low (1–5%) among monogamous sexual relationships, yet the prevalence is higher for those with multiple sexual partners. Individuals born between 1945 and 1965 have also demonstrated a higher risk of exposure as there is a five times higher prevalence, 3.25%, of HCV compared to the general population.4,10 Other modes of transmission and those who should be recommended for HCV screening are listed in Table 1.4,10–12 Natural history of HCV infection Hepatitis C may present as an acute infection, as about 20% will clear the HCV spontaneously and 55–85% of patients progress to chronic disease. For individuals who remain untreated, progression to cirrhosis has shown to be slow, with incidence ranging between 5% and 25% for those who have been infected for 25–30 years. Factors increasing disease progression include alcohol intake, older age at infection, obesity, co-infections with human immunodeficiency virus (HIV) or hepatitis B virus (HBV), and male gender. For patients who develop cirrhosis, the risk of HCC is approximately 1–4% per year. Without antiviral treatment or liver transplantation, further hepatic deterioration may occur, leading to ESLD and death.7,8,12
Diagnosing hepatitis C Initial testing with a FDA-approved assay for HCV antibody (anti-HCV) should be obtained for individuals with risk factors (Table 1) for hepatitis C. If anti-HCV are positive, then it may indicate current infection or past infection that has resolved. Therefore to detect if the individual is currently infected, an assay for HCV RNA by nucleic acid testing (NAT) must be performed.13 Regardless of the HCV antibodies result, patients who are immunocompromised or suspected to have been exposed to HCV within the previous 6 months should be re-tested with an HCV RNA NAT assay.11,13 Following exposure, HCV RNA may be detectable as soon as 2–3 weeks and will likely appear prior to anti-HCV as it takes 4–10 weeks before being detected in blood. After exposure and seroconversion, the mean incubation prior to onset of symptoms is typically 4–12 weeks (range: 2–24 weeks).2 The majority, 80%, are asymptomatic and if patients do present with symptoms they may include jaundice, anorexia, nausea, or malaise.1,2 If the infection does not resolve spontaneously, it may progress to chronic HCV with fluctuating ALT levels and detectable HCV RNA levels.2,7,8 HCV is categorized based on genotype (genotypes 1–7), which has been used to determine the likelihood of response to antiviral therapy and the duration of therapy.7,8,14 The
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Table 2 Scoring systems used to evaluate stage of liver fibrosis.7 Stage IASL 0 1 2 3 4 5 6
No fibrosis Mild fibrosis Moderate fibrosis Severe fibrosis Cirrhosis
Batts–Ludwig
Metavir
Ishak
No fibrosis Fibrous portal expansion Rare bridges or septae Numerous bridges or septae Cirrhosis
No fibrosis Periportal fibrotic expansion Periportal septae
No fibrosis Fibrous expansion of some portal areas 7 short fibrous septa Fibrous expansion of most portal areas 7 short fibrous septa Fibrous expansion of most portal areas þ occasional portal to portal bridging Fibrous expansion of most portal areas þ marked bridging Marked bridging þ occasional nodules (incomplete cirrhosis) Cirrhosis
Porto-central septae Cirrhosis
most common genotype in the United States is genotype 1, which affects approximately 70% of HCV patients and is considered more difficult to treat when compared to genotype 2 and genotype 3.7,8 Liver biopsy is considered the “gold” standard for assessing the level of fibrosis. It also provides information to guide treatment decisions and reveal the presence of advanced fibrosis or cirrhosis that requires monitoring for HCC and/or varices.7 Liver biopsy reports the degree of inflammation, “grade,” and the degree of scaring or fibrosis, “stage.” There are numerous scoring systems available, with the most common listed in Table 2. The general recommendation is to initiate HCV treatment in those with a stage Z3.15,16 Although the information obtained can be useful, it is costly, invasive, requires expertise in interpretation, and may cause harm such as excessive bleeding or organ damage. Due to these potential risks, a liver biopsy may be unnecessary and should be considered if there is a need to evaluate prognosis, other underlying cause of liver disease or assist in determining a treatment decision.7,8 Less invasive methods to assess for liver inflammation and fibrosis are available. Evaluating blood tests (e.g., albumin, platelet count, and prothrombin time) are commonly used to rule out significant cirrhosis in clinical practice. The Aspartate aminotransferase-to-Platelet Ratio Index (APRI) is a simple calculation using AST, the upper limit of normal of AST level, and platelet counts to determine the severity of fibrosis. APRI is sensitive in detecting minimal fibrosis or cirrhosis and not specific in differentiating moderate liver disease. Other noninvasive tests are available to assess for fibrosis [e.g., FIB-4, FibroIndex, Forns index, HepaScore (also known as FibroScore), FibroSURE, FibroTest] and should be used with caution as the sensitivity and specificity for predicting or confirming cirrhosis is not specific without assessing other invasive or noninvasive markers of fibrosis.7,8 When deciding whether to perform a liver biopsy, the clinician should take into account if HCV treatment is being considered, the estimated duration of infection, signs of progressing disease, HCV genotype, and if the patient is willing to undergo the biopsy and begin treatment. Although helpful in making treatment decisions, it is not required to initiate HCV antiviral therapy.7,8,15,16
Treatment outcomes and definitions of viral response The goal of therapy is to eradicate the HCV infection to prevent the progression and development of liver complications including cirrhosis, HCC, and end-stage liver disease (ESLD). Additional treatment endpoints include normalization of hepatic aminotransferases, improvement of histology, and achieving undetectable HCV RNA levels defined as a sustained virologic response (SVR) at 12 or 24 weeks following treatment completion.7,8,15,16 More recently, Chen et al.17 examined the correlation between SVR at 12 weeks (SVR12) and SVR at 24 weeks (SVR24) and found a high concordance rate. With a sensitivity (99%) and specificity (98%), SVR12
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Table 3 Definitions of therapeutic milestones for treatment of hepatitis C.7,8 Virologic response
Abbreviation Definition
Rapid virologic response RVR Extended rapid virologic eRVR response Early virologic response EVR Complete early virologic response Partial early virologic response End-of-treatment response Sustained virologic response
cEVR pEVR ETR or EOT SVR
HCV RNA is undetectable after 4 weeks of treatment HCV RNA is undetectable at week 4 and remains undetectable at week 12 of treatment HCV RNA is undetectable after 12 weeks of treatment or reduced by at least 2 logs HCV RNA is undetectable after 12 weeks of treatment HCV RNA level decreases at least 2 logs but remains detectable after 12 weeks of therapy HCV RNA is undetectable at the end of treatment HCV RNA is undetectable at the end of treatment and 12 or 24 weeks after completion of treatment
is considered an acceptable primary efficacy endpoint by U.S. and European regulators.18,19 SVR corresponds with long-term clearance of HCV infection in 99% of cases; thus, a patient who achieves SVR is considered to be “virologically cured.”7,8,17 Cirrhotic patients achieving SVR are not free of liver complications; thus, it is important to initiate HCV treatment early. Other virologic responses have been defined according to the HCV RNA levels at certain time points during the course of therapy. This was important during the first-generation direct-acting antiviral agents (DAA) era. An undetectable HCV RNA level at week 4 of therapy, known as rapid virologic response (RVR), predicts a 90% probability of achieving SVR.7,8 Based on the HCV drug regimen and specific time point within therapy, treatment may be discontinued due to detectable HCV RNA; this is known as response-guided therapy (RGT). Following futility rules is necessary to prevent additional drug exposure that may result in HCV resistance. Additional virologic responses to hepatitis C treatment are summarized in Table 3. As newer agents become available for HCV, obtaining frequent HCV RNA levels during the course of treatment may not be necessary.20 It is important to identify the type of response patients had with prior hepatitis C treatment (Table 4). Patients with detectable HCV RNA without a 2-log drop are deemed nonresponders. Nonresponders are further subdivided as null responder and partial responder (Table 4). A relapser is one who has undetectable HCV RNA levels at the end of treatment (EOT; or end-oftreatment response, ETR) followed by detectable HCV RNA levels at any point after treatment discontinuation. Relapsers have shown to have a greater probability of SVR with first- and second-generation DAA therapy when compared to null responders.9,15,16 Treatment of chronic hepatitis C The treatment for hepatitis C has evolved over the past decades. Interferon (IFN) was the first agent approved in the 1990s with SVR rates of 5–30%. By the early 2000s, the approval of ribavirin (RBV) and pegylated IFN (PegIFN) revolutionized the treatment of HCV, making this combination regimen the standard-of-care (SOC) for more than a decade. When trials stratified subjects by genotype, SVR24 rates were approximately 40–60% for genotype 1 and 70–90% for genotypes 2 and 3.7,8 Until recently, the SOC therapy for genotypes 2 and 3 has been PegIFN administered subcutaneously once weekly with twice-daily oral RBV for 24 weeks.7,8 The SOC for genotype 1 changed in 2011 with the introduction of the first-generation DAA. Boceprevir (BOC) and telaprevir (TVR) are protease inhibitors, and when administered with PegIFN and RBV, they achieved SVR24 rates of 60–75% in treatment-naïve and treatment-experienced patients with compensated liver disease.8 First-generation triple therapy allowed for a shortened duration of treatment (e.g., 24 weeks) depending on the protease inhibitor selected.
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Table 4 Definitions of patient response to hepatitis C therapy.7,8 Response
Definition
Nonresponder Breakthrough Null responder Partial responder Relapser
Failing to achieve undetectable HCV RNA after 24 weeks of therapy HCV RNA level becomes detectable during treatment Failing to decrease HCV RNA level less than 2 logs after 24 weeks of therapy HCV RNA level decreased greater than 2 logs at week 12 but remains detectable at week 24 Achieved ETR while on HCV therapy, then HCV RNA level reappears once therapy has been discontinued
Despite higher SVR rates and potentially shorter duration of treatment with the firstgeneration DAAs, there are several disadvantages. Resistance-associated amino acid variants (RAVs) with BOC and TVR have been observed in days or weeks in all clinical trials and are associated with virologic failure and relapse, especially if administered as monotherapy.8 Other disadvantages of HCV treatments with BOC or TVR include complicated treatment regimens, high pill burden given three times daily with food (high-fat foods with TVR), increased rates of serious adverse events (e.g., anemia and rash), and numerous drug–drug interactions (e.g., CYP3A4). HCV-infected patients may continue to go untreated if they possess absolute or relative contraindications to or cannot tolerate IFN.15,16 The limitations to SOC therapies have prompted the need for newer, safer, and more effective HCV drugs. Simeprevir In November 2013, the FDA approved the oral HCV NS3/4A serine protease inhibitor, simeprevir (SMV), for the treatment of chronic HCV infection genotype 1 in combination with PegIFN and RBV. Simeprevir is taken once daily with food for 12 weeks combined with 24–48 weeks of PegIFN and RBV depending on the patient's prior history of HCV therapy and genotype (Table 5).21 Triple therapy with SMV also follows futility rules to minimize unnecessary drug exposure. Sofosbuvir Sofosbuvir (SOF), a NS5B polymerase inhibitor, is an oral DAA that was granted FDA approval in December 2013 for genotypes 1 and 4 in combination with PegIFN and RBV for 12 weeks.20 It is the first oral treatment regimen in combination with RBV for genotypes 2 and 3 administered for 12 and 24 weeks, respectively. The option of an interferon-free regimen opens treatment to patients who have contraindications to IFN such as those with psychiatric disorders or patients who prefer not to self-administer an injectable medication. Compared to SMV, SOF offers a Table 5 Duration of treatment with simeprevir, pegylated interferon, and ribavirin.21
Treatment-naïve and prior relapser patients including those with cirrhosis Prior nonresponder patients (including partial and null responders) including those with cirrhosis
Simeprevir þ PegIFN/RBVa
Treatment with PegIFN/RBV
Total treatment duration
First 12 weeks
Additional 12 weeks Additional 36 weeks
24 weeks
First 12 weeks
Stop all drugs if HCV RNA level is Z 25 IU/mL at either week 4, 12, or 24. a Futility rules for simeprevir, pegylated interferon, and ribavirin.
48 weeks
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shorter duration of therapy and a higher barrier to viral resistance with no virologic breakthrough to date.20 Treatment-naïve and relapsers Genotype 1 The recommended regimen for treatment-naïve patients with HCV genotype 1 of any subtype who are eligible to receive IFN is daily SOF and weight-based RBV plus weekly PegIFN for 12 weeks (Table 6).15 The phase 3 NEUTRINO trial evaluated a 12-week regimen of SOF plus PegIFN/RBV in 327 treatment-naïve patients with genotype 1, 4, 5, or 6 compared to historical controls.22 The overall SVR12 rate was 90%, with SVR12 of 89% for genotype 1 (genotype 1a, 92%, and genotype 1b, 82%). Similar SVR were observed in blacks (87%) and Hispanics/Latino (91%); however, subjects with cirrhosis had lower SVR12 at 80%. The recommended regimen for treatment-naïve patients with HCV genotype 1a or 1b who are not eligible to receive IFN is daily SOF plus SMV, with or without weight-based RBV for 12 weeks (Table 6).15 COSMOS, a phase 2a randomized, open-label clinical trial, evaluated SOF plus SMV with or without RBV for 12 or 24 week in 2 cohorts: cohort 1 included 80 prior null responders to PegIFN/RBV with a Metavir stage 0 or 2 and cohort 2 included 87 treatment-naïve patients or prior null responders with Metavir stage 3 or 4.23 Cohort 1 demonstrated SVR12 of 96% (n ¼ 27) and 93% (n ¼ 14) in patients treated with or without RBV, respectively, and SVR24 of 79% (n ¼ 24) and 93% (n ¼ 15), respectively. At present, SVR4 is 100% for all subjects enrolled in cohort 2 except the SOF/SMV/RBV arm with SVR4 at 96%. It is important to note that the COSMOS trial is still ongoing with only preliminary results and small sample size across all treatment arms, especially for cohort 2 (n ¼ 7–15 subjects).23 QUEST-1 and QUEST-2, two phase 3 trials, evaluated the efficacy and safety of SMV in combination with PegIFN/RBV in treatment-naïve genotype 1 patients.24,25 Subjects were randomized to receive either 12 weeks of placebo plus PegIFN/RBV followed by 36 weeks of PegIFN/RBV or 12 weeks of SMV plus PegIFN/RBV followed by 12 or 36 weeks of PegIFN/RBV using specific stopping rules. The overall SVR12 pooled analysis of the two trials for placebo was Table 6 Recommended and alternative treatment regimens, dosing, and duration for treatment-naïve patients with HCV genotype 1.15 Genotype Recommended
Alternative
Not recommendeda
1b or 1ab
IFN eligible: SMV 12 wks þ P þ R 24 wks IFN ineligiblec: SOF þ R 24 wks None SOF þ P þ R 12 wks IFN eligible: SMV 12 wks þ P þ R 24–48 wksd
P þ R 7 TVR or BOC
P þ R 48 wks
P þ R 7 TVR or BOC or SMV
2 3 4
5 or 6
IFN eligible: SOF þ P þ R 12 wks IFN ineligiblec: SOF þ SMV 7 R 12 wks SOF þ R 12 wks SOF þ R 24 wks IFN eligible: SOF þ P þ R 12 wks IFN ineligiblec: SOF þ R 24 wks SOF þ P þ R 12 wks
P þ R 7 TVR or BOC P þ R 7 TVR or BOC P þ R 7 TVR or BOC
IFN: interferon; SOF: sofosbuvir; P: pegylated interferon; R: ribavirin; SMV: simeprevir; wks: weeks; TVR: telaprevir; BOC: boceprevir; DAA: direct acting antiretroviral. a Monotherapy with P, R, or a DAA is not recommended for any genotype. b For genotype 1a, if NS3 Q80K polymorphism is present then SMV-based regimens should be avoided due to decreased rates of SVR. c Interferon ineligible: Intolerance to IFN, autoimmune hepatitis and other autoimmune disorders, hypersensitivity to PegIFN or any of its components, decompensated hepatic disease, history of depression, or clinical features consistent with depression, baseline neutrophil count below 1500/mL, platelet count below 90,000/mL, hemoglobin below 10 g/dL, and history of preexisting cardiac disease. d Futility rules for SMV þ P þ R: Stop ALL drugs if HCV RNA level is Z 25 IU/mL at either wk 4, 12, or 24.
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50% compared to 80% in the SMV arms. Interestingly, subgroup analysis revealed lower SVR12 in genotype 1a (71%) to genotype 1b (90%).24,25 The reduced efficacy of SMV may be due to the baseline presence of NS3 Q80K polymorphism, a naturally occurring variation in the HCV NS3/ 4A protease enzyme.26 Treatment naïve and relapsers' SVR rates with or without NS3 Q80K polymorphism were 43% and 84% compared to 24% and 78%, respectively.15 Baseline screening for the presence of NS3 Q80K polymorphism in genotype 1a patients is strongly recommended and alternative HCV therapy should be considered if tested positive for the viral polymorphism. An alternative regimen for treatment-naïve and IFN-eligible patients with genotype 1a or genotype 1b with undetectable Q80K polymorphism at baseline is daily SMV for 12 weeks and weight-based RBV plus weekly PegIFN for 24 weeks (Table 6).15 For treatment-naïve genotype 1 patients (of any subtype) who are not eligible to receive IFN, daily SOF and weight-based RBV for 24 weeks is an acceptable alternative regimen, but it should be recommended with caution since SVR rates may be lower.15 The QUANTUM, ELECTRON, and PHOTON-1 trials evaluated SOF plus daily weight-based RBV for either 12 or 24 weeks in treatment-naïve HCV genotype 1 patients. Results of the phase 2 and 3 trials demonstrated an SVR ranging from 50% to 84%.15 Previously utilized FDA-approved regimens of PegIFN/RBV with or without BOC or TVR are no longer recommended as these regimens are now considered inferior due to their many disadvantages.15
Genotype 2 or 3 The recommended regimen for treatment-naïve patients with HCV genotypes 2 and 3 is daily SOF and weight-based RBV for 12 and 24 weeks, respectively (Table 6).15 The FISSION trial was a randomized open-label study evaluating 12 weeks of SOF plus RBV versus 24 weeks of PegIFN/ RBV in treatment-naïve genotype 2 or genotype 3 patients.22 The overall SVR12 was 67% for both treatment arms, suggesting that SOF-based therapy was noninferior to SOC. When the data was stratified per genotype, genotype 2 resulted in higher SVR12 in the SOF group (97%) versus 78% with PegIFN/RBV. Meanwhile, SVR12 with SOF and PegIFN/RBV in genotype 3 patients were 56% and 63%, respectively.22 This suggests that genotype 3 is harder to treat than genotype 2. POSITRON was a randomized, placebo-blinded, controlled trial evaluating 12 weeks of SOF plus RBV that was compared to placebo in genotype 2 or 3 patients for whom IFN was not an option.27 The subjects in this trial had previously received IFN but had discontinued treatment due to underlying comorbidities, had experienced IFN adverse effects, or were unwilling to start therapy with IFN. No one achieved SVR in the placebo group. The overall SVR12 was 78% (genotype 2, 93% and genotype 3, 61%).27 VALENCE was a European trial evaluating the safety and efficacy of SOF and RBV in treatment-naïve and treatment-experienced genotypes 2 and 3 subjects.28 The initial study design was to treat for 12 weeks, however it was later changed to 24 weeks for only genotype 3 patients; data suggested this subgroup may benefit from treatment if it was administered beyond 12 weeks. Patients with genotype 2 treated with 12 weeks of SOF plus RBV achieved an overall SVR of 93%, whereas those with genotype 3 treated for 24 weeks achieved an SVR12 of 84%.27 Subjects with cirrhosis demonstrated overall lower SVR12, 61% compared to 81% with no cirrhosis, and it was significantly lower in genotype 3 (21%) versus genotype 2 (94%).28 In the FUSION trial, a 12- or 16-week regimen of SOF plus RBV was evaluated in genotype 2 or 3 treatment-experienced patients (relapsers and null responders) compared with historical controls.27 Patients receiving SOF and RBV for 12 weeks achieved an overall SVR12 of 50% (genotype 2, 86% and genotype 3, 30%), while those who received SOF and RBV for 16 weeks achieved an overall SVR12 of 73% (genotype 2, 94% and genotype 3, 62%). Overall, the SVR rates for genotype 3 patients achieved with 12- or 16-week regimens of SOF and RBV in the FISSION, POSITRON, and FUSION studies were lower than those compared to the 24-week regimen of SOF plus RBV in the VALENCE study.22,27,28 Thus, patients with genotype 3 are treated for a duration of 24 weeks. An alternative regimen for treatment-naïve patients
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with genotype 3 who are IFN eligible is daily SOF and weight-based RBV plus weekly PegIFN for 12 weeks (Table 6). Genotype 4, 5, or 6 Data regarding the treatment of HCV in patients with genotypes 4, 5, and 6 are limited and the following recommendations have been drawn from available data.15,16,22 In the NEUTRINO trial, 96% of patients with genotype 4 and all patients with genotype 5 (n ¼ 1) and 6 (n ¼ 6) achieved SVR12.22 The recommended regimen for treatment-naïve patients with genotype 4 who are IFN eligible is daily SOF and weight-based RBV for 12 weeks (Table 6).15 For genotype 4 patients who are not eligible for IFN, the recommended regimen is daily SOF plus weightbased RBV for 24 weeks. The RESTORE phase 3 clinical trial for genotype 4 patients comparing PegIFN/RBV for 48 weeks with a 12-week regimen of daily SMV and PegIFN/RBV followed by an additional 12 or 36 weeks of PegIFN/RBV alone is currently ongoing (Table 6).15,29 At present, the alternative regimen for treatment-naïve genotype 4 patients who are IFN eligible is daily SMV for 12 weeks and weight-based RBV plus weekly PegIFN for 24–48 weeks based on RGT.15 The recommended regimen for treatment-naïve patients with HCV genotype 5 or 6 is daily SOF and weight-based RBV plus weekly PegIFN for 12 weeks (Table 6).15 The combination of PegIFN and RBV for 48 weeks was the previously recommended regimen for patients with genotype 5 or 6 and is now the alternative regimen. The choice of treatment regimen should take into account the patient's HCV genotype, likely efficacy based on disease state and history of prior HCV treatment, duration of treatment, adverse effect profile and current health state to tolerate drug side effects. Medication adherence, social history, and financial factors must also be considered upon selecting the appropriate HCV regimen. Adverse effects and drug interactions of hepatitis C therapy The adverse effects associated with therapy contribute to the challenges of hepatitis C treatment, potentially impacting adherence and resulting in premature cessation of therapy. In registration trials of PegIFN/RBV, the discontinuation rates were 10–14%.7,8 The most common adverse events with PegIFN use are influenza-like (fatigue, headache, fever, and rigors) and psychiatric (depression, irritability, and insomnia) side effects. Thyroid disorders, diabetes, and hypertriglyceridemia are abnormalities that may result from PegIFN use and require laboratory surveillance. Hematological abnormalities arising from PegIFN include neutropenia, thrombocytopenia, and anemia. Hemolytic anemia and dermatological complaints (pruritus and rash) is the most common ribavirin adverse effects. Triple therapy with SOF is well tolerated with minimal adverse reactions beyond what is seen with PegIFN and RBV.20,22,27 The most common side effect with SMV and PegIFN/RBV include rash, photosensitivity, pruritus, and fatigue.21 The adverse effects of PegIFN, RBV, and DAAs are summarized in Table 7. In the era of DDA therapy, emerges another complication associated with HCV therapy, drug– drug interactions. Screening the patient's medication lists, including all prescription drugs, OTC drugs, and dietary supplements prior to initiating treatment is important as alterations in pharmacokinetic parameters may increase or decrease drug exposure given how DAAs are metabolized. Telaprevir and boceprevir are potent inhibitors of the cytochrome P450, or CYP, pathway—specifically, of the 3A4 isoenzyme. Drugs such as HMG-CoA reductase inhibitors, immunosuppressants, and antiretrovirals appear to be problematic. For the first-generation DAAs, drug that may interact with P-glycoprotein, or P-gp, may also be a concern, such as interactions with digoxin. SMV inhibits CYP1A2 and intestinal CYP3A4, with minimal effects of hepatic CYP3A4. Similar to TEL and BOC, SMV has some activity with P-gp, increasing plasma drug concentrations. Additionally, SMV inhibits OATP1B1/3, which may result in drug–drug interactions, specifically with HMG-CoA inhibitors. Unlike the approved HCV protease inhibitors, polymerase inhibitor, SOF has fewer drug interactions, yet it may still be significant. SOF is a
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Table 7 Adverse effects of hepatitis C treatment options.20,21,30,31 Pegylated interferon
Ribavirin
Simeprevir
Sofosbuvir
Influenza-like symptoms: Fatigue Headache Fever and chills Arthralgia and myalgia Injection site reaction Hematological abnormalities Neutropenia Thrombocytopenia Anemia Neuropsychiatric conditions: Depression Anxiety Irritability Thyroid disorders Diabetes Hypertriglyceridemia
Hemolytic anemia Rash Cough Gastrointestinal effects: Nausea Gastrointestinal upset Diarrhea Teratogenicity (pregnancy category X)
In combination with PegIFN plus RBV Rash Photosensitivity Pruritus Nausea Psychological
In combination with RBV Fatigue Headache In combination with PegIFN plus RBV Fatigue Headache Nausea Insomnia Anemia Psychological
substrate of P-gp in the intestines, therefore agents such as St. John's wort should not be administered with SOF to avoid decreasing drug concentrations. Interesting to note, SOF is metabolized to GS-331007, the active metabolite, which means drugs that inhibit P-gp may not affect GS-331007 plasma concentrations. Several anticonvulsants (carbamazepine and phenytoin), antimycobacterials (rifampin), and HIV protease inhibitors (tipranavir/ritonavir) should not be co-administered with SOF. For a summary of drug interactions with the DDAs, please refer to the manufactures package inserts.20,21,30–33
Management of hepatitis C therapy and telehealth For clinic sites with the available technology, patients diagnosed with hepatitis C may be referred to a telemedicine clinic to be further assessed for HCV treatment candidacy by a team of hepatitis specialists. One setting that has implemented this type of practice is the correctional facility. Patients who are approved to initiate therapy are counseled on the disease state and the potential outcomes from HCV treatment. A discussion of adverse effects, duration of treatment, importance of drug adherence, and avoidance of initiating over-the-counter (OTC) agents prior to consulting the HCV drug prescriber is performed to prevent premature cessation of HCV treatment and increase the likelihood of achieving SVR. A psychological clearance by a psychiatrist must be obtained prior to beginning IFN-based treatments. The patient's medication profile (e.g., prescription, dietary supplements, and OTC) is critically reviewed to identify and limit drug interactions. Patients who have started HCV treatment should schedule clinic visits every 2–4 weeks for approximately 20 min to assess for adverse effects and address any drug- or medical-related issues. Scheduled laboratory orders are drawn by the correctional facility at regular intervals (Table 8). Growth factors (e.g, erythropoietin, darbepoetin, and granulocyte colony-stimulating factors), thyroid supplements, hyperglycemics, and anti-hyperlipidemics may be added as needed to counter laboratory abnormalities arising from therapy. Should adverse effects become severe, the clinician may choose to reduce the dose or discontinue some or all of the HCV medications.
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Table 8 Example of monitoring parameters and time points during hepatitis C treatment. Week
Baseline
HCV RNAa CBC LFT BMP Lipid panel TSH Influenza-like symptoms Adverse effects
X X X X X X
a
24–48 h
X X
2
4
8
12
16/20
24
28/32
36
40/44
EOT
SVR12 or 24 weeks post-therapy
X X X
X X X
X X X
X X X
X X X X
X X X X
X X
X X X X X X X
X X X
X X
X X X X X X X
X X X
X X
X X X X X X X
X X
X X
X X
Based on HCV treatment regimen selected.20,21
Education is critical as the patient has vital responsibility in his or her HCV therapy. Psychological disturbances is common adverse effect with PegIFN; thus, patients must be counseled on the mental and emotional changes that may develop so they may seek psychiatric consultation in a timely manner. The patient is responsible for reporting any dermatological symptoms to the healthcare providers. If skin disturbances occur, the HCV specialist can assess the severity and order corticosteroids, lotions, and/or antihistamines to manage symptoms or make a decision to discontinue therapy. The patient is educated regarding appropriate premedications (e.g., acetaminophen prior to IFN), supportive care measures, and diet modifications. Most importantly, men and women of child-conceiving potential are counseled to use two forms of contraception during and 6 months post-treatment due to the teratogenicity of RBV. At 3–6 months upon completion of treatment, the patient returns for a blood draw and follow-up consultation to determine if the patient has achieved SVR. Patients who are “cured” are educated on lifestyle modifications as it is important to understand that they may become re-infected with HCV and SVR may be difficult to achieve in re-treatment. Additionally, patients who have cirrhosis, it is important for them to undergo serial surveillance for HCC and varices. Advantages and disadvantages of correctional setting hepatitis C management There have been varying levels of success for incarcerated patients with genotypes 1, 2, 3, and 4 achieving SVR, with studies reporting between 28% and 50%.34–37 However, these response rates were achieved with previous treatment regimens that only included PegIFN and RBV, which at present is not the current SOC for genotype 1.15,16 Based on more recent clinical trials,22–29 it should be expected that treatment involving SMV or SOF would achieve higher rates of SVR when or if used in the incarcerated population. A major barrier to initiating HCV therapy is the long treatment duration. It is typically recommended that patients who would like to be treated for HCV have at least 15–18 months of incarceration time prior to release since HCV treatment may last up to 48 weeks.7,8,12 If treatment is initiated and the inmate is discharged from the correctional facility prior to completing the course of therapy, then there is a high possibility of treatment failure, development of resistance, and lack of monitoring of adverse effects due to no laboratory or clinical follow-up upon release.12 However, with some of the newer regimens having treatment durations as low as 12 weeks, it may likely result in decreasing the required length of stay a patient is incarcerated to be eligible for HCV treatment. Other issues that remain as obstacles for successful HCV treatment include active drug abuse, alcohol abuse, re-infection, psychiatric illness, and poor adherence.37 Although hepatitis C treatment is expensive, studies have shown it to be cost-effective in the correctional facility setting.38 One study analyzing the cost-effectiveness of treating in the prison setting found overall treatment cost ranging from $25,000 to $189,000 depending on the
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genotype, stage of fibrosis, patient age, and if compensated cirrhosis was present. For patients not needing to undergo a liver biopsy, researchers found an overall cost savings of $11,000– $41,000 in those who received HCV treatment versus those who did not.38 Additionally, patients who were treated had a better quality of life measured by an increase of quality-adjusted life years (QALY) between 0.5 and 0.75.38 Of note, IFN/RBV was the SOC at the time the data was obtained.38 Even though only 10–20% of patients with HCV develop severe hepatic complications, the high incidence of incarcerated patients may result in a higher financial burden on the State and Federal prison system if more patients become eligible to receive treatment. Treating hepatitis C while patients are incarcerated does have a list of benefits other than potential cost savings. The option of beginning treatment may not be available to some inmates if it were not for being incarcerated. Patients may benefit from having close monitoring and follow-up due to their incarcerated status as well as decreasing the HCV burden and risk for HCV transmission to the community upon release.36 References 1. World Health Organization. Hepatitis C: WHO fact sheet N1 164. 〈http://www.who.int/mediacentre/factsheets/fs164/ en/index.html〉; 2013 Accessed 22.02.14. 2. Center for Disease Control. Hepatitis C FAQs for health professionals. 〈http://www.cdc.gov/hepatitis/HCV/HCVfaq. htm#section1〉; 2012 Accessed 22.02.14. 3. Chak E, Talal AH, Sherman KE, Schiff ER, Saab S. Hepatitis C virus infection in USA: an estimate of true prevalence. Liver Int. 2011;31(8):1090–1101. 4. Moyer VA. Screening for hepatitis C virus infection in adults: US preventive services task force recommendation statement. Ann Intern Med. 2013;159(5):349–357. 5. Weinbaum C, Lyerla R, Margolis HS. Prevention and control of infections with hepatitis viruses in correctional settings. Centers for Disease Control and Prevention. MMWR Recomm Rep. 2003;52(RR-1):1–36. 6. Beck AJ, Maruschak LM. Hepatitis testing and treatment in state prisons. US Department of Justice, Office of Justice Programs, Bureau of Statistics. 〈http://www.bjs.gov/content/pub/pdf/httsp.pdf〉; 2004 Accessed 22.02.14. 7. Ghany MG, Strader DB, Thomas DL, Seeff LB. Diagnosis, management, and treatment of hepatitis C: an update. Hepatology. 2009;49(4):1335–1374. 8. Ghany MG, Nelson DR, Strader DB, Thomas DL, Seeff LB. An update on treatment of genotype 1 chronic hepatitis C virus infection: 2011 practice guideline by the American Association for the study of liver diseases. Hepatology. 2011;54(4):1433–1444. 9. Klevens RM, Hu DJ, Jiles R, Holmberg SD. Evolving epidemiology of hepatitis C virus in the United States. Clin Infect Dis. 2012;55(suppl 1):S3–S9. 10. Smith BD, Morgan RL, Beckett GA, et al. Recommendations for the identification of chronic hepatitis C virus infection among persons born during 1945–1965. MMWR Recomm Rep. 2012;61(RR-4):1–32. 11. Mahajan R, Liu SJ, Klevens RM, Holmberg SD. Indications for testing among reported cases of HCV infection from enhanced hepatitis surveillance sites in the United States, 2004–2010. Am J Public Health. 2013;103(8):1445–1449. 12. Federal Bureau of Prisons. Evaluation and treatment of hepatitis C and cirrhosis. Clinical practice guidelines. 〈http:// www.hepcassoc.org/pdf/2012/mar-federal-guidlines.pdf〉; 2012 Accessed 22.02.14. 13. Centers for Disease Control and Prevention (CDC). Testing for HCV infection: an update of guidance for clinicians and laboratorians. MMWR Morb Mortal Wkly Rep. 2013;62(18):362–365. 14. Smith DB, Bukh J, Kuiken C, et al. Expanded classification of hepatitis C virus into 7 genotypes and 67 subtypes: updated criteria and genotype assignment web resource. Hepatology. 2014;59(1):318–327. 15. American Association for the Study of Liver Diseases and Infectious Diseases Society of America. Recommendations for testing, managing, and treating hepatitis C. Initial treatment of HCV infection in patients starting treatment. 〈http:// www.hcvguidelines.org/full-report/initial-treatment-hcv-infection-patients-starting-treatment〉 Accessed 22.02.14. 16. American Association for the Study of Liver Diseases and Infectious Diseases Society of America. Recommendations for testing, managing, and treating hepatitis C. Retreatment of persons in whom prior therapy has failed. 〈http://www. hcvguidelines.org/full-report/retreatment-persons-whom-prior-therapy-has-failed〉; Accessed 22.02.14. 17. Chen J, Florian J, Carter W, et al. Earlier sustained virologic response end points for regulatory approval and dose selection of hepatitis C therapies. Gastroenterology. 2013;144(7):1450–1455. 18. U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research. Guidance for industry chronic hepatitis C virus infection: developing direct-acting antiviral drugs for treatment. Draft guidance. 〈http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ UCM225333.pdf〉; 2013 Accessed 22.02.14. 19. European Association of the Study of the Liver. EASL clinical practice guidelines: management of hepatitis C virus infection. J Hepatol. 2014;60(2):392–420. 20. Sovaldi [package insert]. Foster City, CA: Gilead Sciences; 2013. 21. Olysio [package insert]. Titusville, NJ: Janssen Therapeutics; 2013. 22. Lawitz E, Mangia A, Wyles D, et al. Sofosbuvir for previously untreated chronic hepatitis C infection. N Engl J Med. 2013;368(20):1878–1887.
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23. Jacobson I, Ghalib RM, Rodriguez-Torres M, et al. SVR results of a once-daily regimen of simeprevir (TMC435) plus sofosbuvir (GS-7977) with or without ribavirin in cirrhotic and non-cirrhotic HCV genotype 1 treatment-naïve and prior null responder patients: the COSMOS study. Hepatology. 2013;58:1379A. 24. Jacobson I, Dore GJ, Foster GR, et al. Simeprevir (TMC435) with peginterferon/ribavirin for chronic HCV genotype-1 infection in treatment-naïve patients: results from QUEST-1, a phase III trial. J Hepatol. 2013;58:1425A. 25. Manns M, Marcellin P, Fred Poordad FP, et al. Simeprevir (TMC435) with peginterferon/ribavirin for treatment of chronic HCV genotype-1 infection in treatment-naïve patients: results from QUEST-2, a phase III trial. J Hepatol. 2013;58:1413A. 26. Lenz O, Verbinnen T, Lin TI, et al. In vitro resistance profile of the hepatitis C virus NS3/4A protease inhibitor TMC435. Antimicrob Agents Chemother. 2010;54(5):1878–1887. 27. Jacobson IM, Gordon SC, Kowdley KV, et al. Sofosbuvir for hepatitis C genotype 2 or 3 in patients without treatment options. N Engl J Med. 2013;368(20):1867–1877. 28. Zeuzem S, Dusheiko GM, Salupere R. Sofosbuvir and ribavirin for 12 or 24 weeks for patients with HCV genotype 2 or 3: the VALENCE trial. Hepatology. 2013;58:1085A. 29. Moreno C, Hezode C, Marcellin P, et al. Simeprevir with peginterferon/ribavirin in treatment-naive or -experienced patients with chronic HCV genotype 4 infection: a phase III study. 14th European AIDS Conference;2013 [Abstract PS9/6]. 30. Pegasys [package insert]. San Francisco, CA: Genentech USA, Inc; 2013. 31. Copegus [package insert]. San Francisco, CA: Genentech USA, Inc; 2013. 32. Incivek [package insert]. Cambridge, MA: Vertex; 2013. 33. Victrelis [package insert]. Whitehouse Station, NJ; 2014. 34. Rice JP, Burnett D, Tsotsis H, et al. Comparison of hepatitis C virus treatment between incarcerated and community patients. Hepatology. 2012;56(4):1252–1260. 35. Allen SA, Spaulding AC, Osei AM, Taylor LE, Cabral AM, Rich JD. Treatment of chronic hepatitis C in a state correctional facility. Ann Intern Med. 2003;138(3):187–190. 36. Chew KW, Allen SA, Taylor LE, Rich JD, Feller E. Treatment outcomes with pegylated interferon and ribavirin for male prisoners with chronic hepatitis C. J Clin Gastroenterol. 2009;43(7):686–691. 37. Iacomi F, Iannicelli G, Franceschini A, et al. HCV infected prisoners: should they be still considered a difficult to treat population? BMC Infect Dis. 2013;13:1–7. 38. Tan JA, Joseph TA, Saab S. Treating hepatitis C in the prison population is cost‐saving. Hepatology. 2008;48(5): 1387–1395.
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Disease-a-Month journal homepage: www.elsevier.com/locate/disamonth
Hepatitis C Juliana Chan, PharmD, FCCP, BCACP
Introduction Hepatitis C is a common blood-borne infection that primarily affects the liver. Complications of the liver disease include cirrhosis and hepatocellular carcinoma (HCC), which have been the leading causes for a liver transplant in the United States. The treatment for hepatitis C has evolved over time with virological cure rates of less than 10% in the 1990s compared to about 90% in 2014. The purpose of this article is to review the risk factors for acquiring hepatitis C, natural history of the infection, diagnosis, and medical management of treatment-naïve patients infected with the hepatitis C virus (HCV).
Epidemiology There are approximately 150 million people worldwide infected with the hepatitis C virus (HCV).1–3 It is estimated that the overall incidence in the United States is 1.6%, which equates to approximately 3–5 million individuals.4 In certain high-risk groups, such as the incarcerated population, the incidence of HCV reported is higher compared to the general population, ranging between 23% and 41%.3,5 A survey conducted in 2000 of correctional facilities found that 79% had screened inmates, and of those sites, approximately 31% were positive for HCV.6 HCV is primarily transmitted through blood, thus those at highest risk of being infected are users of illicit intravenous drugs (IVD), especially those with a history of incarceration. A study documented that 27% of one state's correctional facility inmates had a documented history of IVD, and of these, there were 91% who tested positive for HCV.6 This is in line with the general population, where the prevalence of HCV via IVD is approximately 90%.7,8 Additional percutaneous exposure to HCV includes the transfusion of contaminated blood products and organ transplants prior to 1987 and 1992, respectively. Prior to this date, there was no effective screening to test for HCV antibodies in blood donors. Hemophiliacs or patients who received clotting factors before 1987 are also at risk for HCV. It is quite rare to transmit HCV with today's current standards in place for testing and inactivating HCV in blood and blood-related products.2,7 It is possible to transmit HCV through the use of needles in commercial tattoo parlors, although it is rare. There are exceptions though, such as inmates who received tattoos in the correctional setting through use of contaminated needles.9 HCV transmission through sexual http://dx.doi.org/10.1016/j.disamonth.2014.04.002 0011-5029/ Published by Mosby, Inc.
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Table 1 Recommendations for anti-HCV antibodies screening.4,10–12 Bureau of prison (BOP) for incarcerated population
Centers for disease control and prevention (CDC) for general population
Presence of certain clinical conditions (regardless of sentencing status) Chronic hemodialysis (screen ALT monthly and anti-HCV semiannually) Elevated ALT levels of unknown etiology Evidence of extrahepatic manifestations of HCV (e.g, mixed cryoglobulinemia, membranoproliferative glomerulonephritis, or porphyria cutanea tarda) Presence of hepatitis C risk factors (sentenced inmates only) Ever injected illegal drugs or shared equipment Received tattoos or body piercings while incarcerated HIV-infected or chronic HBV infection Received blood transfusion or organ transplant before 1992 or clotting factor transfusion prior to 1987 History of percutaneous exposure to blood Ever received hemodialysis
Test at least once in lifetime Any person born between 1945 and 1965 Injected illegal drugs Recipient of clotting factor before 1987 Recipient of blood transfusions or solid organ transplant before 1992 Received hemodialysis treatments Healthcare workers after needlesticks All HIV-infected persons Signs and symptoms of liver disease Children born to HCV-positive mothers Elevated liver function tests
intercourse is low (1–5%) among monogamous sexual relationships, yet the prevalence is higher for those with multiple sexual partners. Individuals born between 1945 and 1965 have also demonstrated a higher risk of exposure as there is a five times higher prevalence, 3.25%, of HCV compared to the general population.4,10 Other modes of transmission and those who should be recommended for HCV screening are listed in Table 1.4,10–12 Natural history of HCV infection Hepatitis C may present as an acute infection, as about 20% will clear the HCV spontaneously and 55–85% of patients progress to chronic disease. For individuals who remain untreated, progression to cirrhosis has shown to be slow, with incidence ranging between 5% and 25% for those who have been infected for 25–30 years. Factors increasing disease progression include alcohol intake, older age at infection, obesity, co-infections with human immunodeficiency virus (HIV) or hepatitis B virus (HBV), and male gender. For patients who develop cirrhosis, the risk of HCC is approximately 1–4% per year. Without antiviral treatment or liver transplantation, further hepatic deterioration may occur, leading to ESLD and death.7,8,12
Diagnosing hepatitis C Initial testing with a FDA-approved assay for HCV antibody (anti-HCV) should be obtained for individuals with risk factors (Table 1) for hepatitis C. If anti-HCV are positive, then it may indicate current infection or past infection that has resolved. Therefore to detect if the individual is currently infected, an assay for HCV RNA by nucleic acid testing (NAT) must be performed.13 Regardless of the HCV antibodies result, patients who are immunocompromised or suspected to have been exposed to HCV within the previous 6 months should be re-tested with an HCV RNA NAT assay.11,13 Following exposure, HCV RNA may be detectable as soon as 2–3 weeks and will likely appear prior to anti-HCV as it takes 4–10 weeks before being detected in blood. After exposure and seroconversion, the mean incubation prior to onset of symptoms is typically 4–12 weeks (range: 2–24 weeks).2 The majority, 80%, are asymptomatic and if patients do present with symptoms they may include jaundice, anorexia, nausea, or malaise.1,2 If the infection does not resolve spontaneously, it may progress to chronic HCV with fluctuating ALT levels and detectable HCV RNA levels.2,7,8 HCV is categorized based on genotype (genotypes 1–7), which has been used to determine the likelihood of response to antiviral therapy and the duration of therapy.7,8,14 The
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Table 2 Scoring systems used to evaluate stage of liver fibrosis.7 Stage IASL 0 1 2 3 4 5 6
No fibrosis Mild fibrosis Moderate fibrosis Severe fibrosis Cirrhosis
Batts–Ludwig
Metavir
Ishak
No fibrosis Fibrous portal expansion Rare bridges or septae Numerous bridges or septae Cirrhosis
No fibrosis Periportal fibrotic expansion Periportal septae
No fibrosis Fibrous expansion of some portal areas 7 short fibrous septa Fibrous expansion of most portal areas 7 short fibrous septa Fibrous expansion of most portal areas þ occasional portal to portal bridging Fibrous expansion of most portal areas þ marked bridging Marked bridging þ occasional nodules (incomplete cirrhosis) Cirrhosis
Porto-central septae Cirrhosis
most common genotype in the United States is genotype 1, which affects approximately 70% of HCV patients and is considered more difficult to treat when compared to genotype 2 and genotype 3.7,8 Liver biopsy is considered the “gold” standard for assessing the level of fibrosis. It also provides information to guide treatment decisions and reveal the presence of advanced fibrosis or cirrhosis that requires monitoring for HCC and/or varices.7 Liver biopsy reports the degree of inflammation, “grade,” and the degree of scaring or fibrosis, “stage.” There are numerous scoring systems available, with the most common listed in Table 2. The general recommendation is to initiate HCV treatment in those with a stage Z3.15,16 Although the information obtained can be useful, it is costly, invasive, requires expertise in interpretation, and may cause harm such as excessive bleeding or organ damage. Due to these potential risks, a liver biopsy may be unnecessary and should be considered if there is a need to evaluate prognosis, other underlying cause of liver disease or assist in determining a treatment decision.7,8 Less invasive methods to assess for liver inflammation and fibrosis are available. Evaluating blood tests (e.g., albumin, platelet count, and prothrombin time) are commonly used to rule out significant cirrhosis in clinical practice. The Aspartate aminotransferase-to-Platelet Ratio Index (APRI) is a simple calculation using AST, the upper limit of normal of AST level, and platelet counts to determine the severity of fibrosis. APRI is sensitive in detecting minimal fibrosis or cirrhosis and not specific in differentiating moderate liver disease. Other noninvasive tests are available to assess for fibrosis [e.g., FIB-4, FibroIndex, Forns index, HepaScore (also known as FibroScore), FibroSURE, FibroTest] and should be used with caution as the sensitivity and specificity for predicting or confirming cirrhosis is not specific without assessing other invasive or noninvasive markers of fibrosis.7,8 When deciding whether to perform a liver biopsy, the clinician should take into account if HCV treatment is being considered, the estimated duration of infection, signs of progressing disease, HCV genotype, and if the patient is willing to undergo the biopsy and begin treatment. Although helpful in making treatment decisions, it is not required to initiate HCV antiviral therapy.7,8,15,16
Treatment outcomes and definitions of viral response The goal of therapy is to eradicate the HCV infection to prevent the progression and development of liver complications including cirrhosis, HCC, and end-stage liver disease (ESLD). Additional treatment endpoints include normalization of hepatic aminotransferases, improvement of histology, and achieving undetectable HCV RNA levels defined as a sustained virologic response (SVR) at 12 or 24 weeks following treatment completion.7,8,15,16 More recently, Chen et al.17 examined the correlation between SVR at 12 weeks (SVR12) and SVR at 24 weeks (SVR24) and found a high concordance rate. With a sensitivity (99%) and specificity (98%), SVR12
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Table 3 Definitions of therapeutic milestones for treatment of hepatitis C.7,8 Virologic response
Abbreviation Definition
Rapid virologic response RVR Extended rapid virologic eRVR response Early virologic response EVR Complete early virologic response Partial early virologic response End-of-treatment response Sustained virologic response
cEVR pEVR ETR or EOT SVR
HCV RNA is undetectable after 4 weeks of treatment HCV RNA is undetectable at week 4 and remains undetectable at week 12 of treatment HCV RNA is undetectable after 12 weeks of treatment or reduced by at least 2 logs HCV RNA is undetectable after 12 weeks of treatment HCV RNA level decreases at least 2 logs but remains detectable after 12 weeks of therapy HCV RNA is undetectable at the end of treatment HCV RNA is undetectable at the end of treatment and 12 or 24 weeks after completion of treatment
is considered an acceptable primary efficacy endpoint by U.S. and European regulators.18,19 SVR corresponds with long-term clearance of HCV infection in 99% of cases; thus, a patient who achieves SVR is considered to be “virologically cured.”7,8,17 Cirrhotic patients achieving SVR are not free of liver complications; thus, it is important to initiate HCV treatment early. Other virologic responses have been defined according to the HCV RNA levels at certain time points during the course of therapy. This was important during the first-generation direct-acting antiviral agents (DAA) era. An undetectable HCV RNA level at week 4 of therapy, known as rapid virologic response (RVR), predicts a 90% probability of achieving SVR.7,8 Based on the HCV drug regimen and specific time point within therapy, treatment may be discontinued due to detectable HCV RNA; this is known as response-guided therapy (RGT). Following futility rules is necessary to prevent additional drug exposure that may result in HCV resistance. Additional virologic responses to hepatitis C treatment are summarized in Table 3. As newer agents become available for HCV, obtaining frequent HCV RNA levels during the course of treatment may not be necessary.20 It is important to identify the type of response patients had with prior hepatitis C treatment (Table 4). Patients with detectable HCV RNA without a 2-log drop are deemed nonresponders. Nonresponders are further subdivided as null responder and partial responder (Table 4). A relapser is one who has undetectable HCV RNA levels at the end of treatment (EOT; or end-oftreatment response, ETR) followed by detectable HCV RNA levels at any point after treatment discontinuation. Relapsers have shown to have a greater probability of SVR with first- and second-generation DAA therapy when compared to null responders.9,15,16 Treatment of chronic hepatitis C The treatment for hepatitis C has evolved over the past decades. Interferon (IFN) was the first agent approved in the 1990s with SVR rates of 5–30%. By the early 2000s, the approval of ribavirin (RBV) and pegylated IFN (PegIFN) revolutionized the treatment of HCV, making this combination regimen the standard-of-care (SOC) for more than a decade. When trials stratified subjects by genotype, SVR24 rates were approximately 40–60% for genotype 1 and 70–90% for genotypes 2 and 3.7,8 Until recently, the SOC therapy for genotypes 2 and 3 has been PegIFN administered subcutaneously once weekly with twice-daily oral RBV for 24 weeks.7,8 The SOC for genotype 1 changed in 2011 with the introduction of the first-generation DAA. Boceprevir (BOC) and telaprevir (TVR) are protease inhibitors, and when administered with PegIFN and RBV, they achieved SVR24 rates of 60–75% in treatment-naïve and treatment-experienced patients with compensated liver disease.8 First-generation triple therapy allowed for a shortened duration of treatment (e.g., 24 weeks) depending on the protease inhibitor selected.
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Table 4 Definitions of patient response to hepatitis C therapy.7,8 Response
Definition
Nonresponder Breakthrough Null responder Partial responder Relapser
Failing to achieve undetectable HCV RNA after 24 weeks of therapy HCV RNA level becomes detectable during treatment Failing to decrease HCV RNA level less than 2 logs after 24 weeks of therapy HCV RNA level decreased greater than 2 logs at week 12 but remains detectable at week 24 Achieved ETR while on HCV therapy, then HCV RNA level reappears once therapy has been discontinued
Despite higher SVR rates and potentially shorter duration of treatment with the firstgeneration DAAs, there are several disadvantages. Resistance-associated amino acid variants (RAVs) with BOC and TVR have been observed in days or weeks in all clinical trials and are associated with virologic failure and relapse, especially if administered as monotherapy.8 Other disadvantages of HCV treatments with BOC or TVR include complicated treatment regimens, high pill burden given three times daily with food (high-fat foods with TVR), increased rates of serious adverse events (e.g., anemia and rash), and numerous drug–drug interactions (e.g., CYP3A4). HCV-infected patients may continue to go untreated if they possess absolute or relative contraindications to or cannot tolerate IFN.15,16 The limitations to SOC therapies have prompted the need for newer, safer, and more effective HCV drugs. Simeprevir In November 2013, the FDA approved the oral HCV NS3/4A serine protease inhibitor, simeprevir (SMV), for the treatment of chronic HCV infection genotype 1 in combination with PegIFN and RBV. Simeprevir is taken once daily with food for 12 weeks combined with 24–48 weeks of PegIFN and RBV depending on the patient's prior history of HCV therapy and genotype (Table 5).21 Triple therapy with SMV also follows futility rules to minimize unnecessary drug exposure. Sofosbuvir Sofosbuvir (SOF), a NS5B polymerase inhibitor, is an oral DAA that was granted FDA approval in December 2013 for genotypes 1 and 4 in combination with PegIFN and RBV for 12 weeks.20 It is the first oral treatment regimen in combination with RBV for genotypes 2 and 3 administered for 12 and 24 weeks, respectively. The option of an interferon-free regimen opens treatment to patients who have contraindications to IFN such as those with psychiatric disorders or patients who prefer not to self-administer an injectable medication. Compared to SMV, SOF offers a Table 5 Duration of treatment with simeprevir, pegylated interferon, and ribavirin.21
Treatment-naïve and prior relapser patients including those with cirrhosis Prior nonresponder patients (including partial and null responders) including those with cirrhosis
Simeprevir þ PegIFN/RBVa
Treatment with PegIFN/RBV
Total treatment duration
First 12 weeks
Additional 12 weeks Additional 36 weeks
24 weeks
First 12 weeks
Stop all drugs if HCV RNA level is Z 25 IU/mL at either week 4, 12, or 24. a Futility rules for simeprevir, pegylated interferon, and ribavirin.
48 weeks
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shorter duration of therapy and a higher barrier to viral resistance with no virologic breakthrough to date.20 Treatment-naïve and relapsers Genotype 1 The recommended regimen for treatment-naïve patients with HCV genotype 1 of any subtype who are eligible to receive IFN is daily SOF and weight-based RBV plus weekly PegIFN for 12 weeks (Table 6).15 The phase 3 NEUTRINO trial evaluated a 12-week regimen of SOF plus PegIFN/RBV in 327 treatment-naïve patients with genotype 1, 4, 5, or 6 compared to historical controls.22 The overall SVR12 rate was 90%, with SVR12 of 89% for genotype 1 (genotype 1a, 92%, and genotype 1b, 82%). Similar SVR were observed in blacks (87%) and Hispanics/Latino (91%); however, subjects with cirrhosis had lower SVR12 at 80%. The recommended regimen for treatment-naïve patients with HCV genotype 1a or 1b who are not eligible to receive IFN is daily SOF plus SMV, with or without weight-based RBV for 12 weeks (Table 6).15 COSMOS, a phase 2a randomized, open-label clinical trial, evaluated SOF plus SMV with or without RBV for 12 or 24 week in 2 cohorts: cohort 1 included 80 prior null responders to PegIFN/RBV with a Metavir stage 0 or 2 and cohort 2 included 87 treatment-naïve patients or prior null responders with Metavir stage 3 or 4.23 Cohort 1 demonstrated SVR12 of 96% (n ¼ 27) and 93% (n ¼ 14) in patients treated with or without RBV, respectively, and SVR24 of 79% (n ¼ 24) and 93% (n ¼ 15), respectively. At present, SVR4 is 100% for all subjects enrolled in cohort 2 except the SOF/SMV/RBV arm with SVR4 at 96%. It is important to note that the COSMOS trial is still ongoing with only preliminary results and small sample size across all treatment arms, especially for cohort 2 (n ¼ 7–15 subjects).23 QUEST-1 and QUEST-2, two phase 3 trials, evaluated the efficacy and safety of SMV in combination with PegIFN/RBV in treatment-naïve genotype 1 patients.24,25 Subjects were randomized to receive either 12 weeks of placebo plus PegIFN/RBV followed by 36 weeks of PegIFN/RBV or 12 weeks of SMV plus PegIFN/RBV followed by 12 or 36 weeks of PegIFN/RBV using specific stopping rules. The overall SVR12 pooled analysis of the two trials for placebo was Table 6 Recommended and alternative treatment regimens, dosing, and duration for treatment-naïve patients with HCV genotype 1.15 Genotype Recommended
Alternative
Not recommendeda
1b or 1ab
IFN eligible: SMV 12 wks þ P þ R 24 wks IFN ineligiblec: SOF þ R 24 wks None SOF þ P þ R 12 wks IFN eligible: SMV 12 wks þ P þ R 24–48 wksd
P þ R 7 TVR or BOC
P þ R 48 wks
P þ R 7 TVR or BOC or SMV
2 3 4
5 or 6
IFN eligible: SOF þ P þ R 12 wks IFN ineligiblec: SOF þ SMV 7 R 12 wks SOF þ R 12 wks SOF þ R 24 wks IFN eligible: SOF þ P þ R 12 wks IFN ineligiblec: SOF þ R 24 wks SOF þ P þ R 12 wks
P þ R 7 TVR or BOC P þ R 7 TVR or BOC P þ R 7 TVR or BOC
IFN: interferon; SOF: sofosbuvir; P: pegylated interferon; R: ribavirin; SMV: simeprevir; wks: weeks; TVR: telaprevir; BOC: boceprevir; DAA: direct acting antiretroviral. a Monotherapy with P, R, or a DAA is not recommended for any genotype. b For genotype 1a, if NS3 Q80K polymorphism is present then SMV-based regimens should be avoided due to decreased rates of SVR. c Interferon ineligible: Intolerance to IFN, autoimmune hepatitis and other autoimmune disorders, hypersensitivity to PegIFN or any of its components, decompensated hepatic disease, history of depression, or clinical features consistent with depression, baseline neutrophil count below 1500/mL, platelet count below 90,000/mL, hemoglobin below 10 g/dL, and history of preexisting cardiac disease. d Futility rules for SMV þ P þ R: Stop ALL drugs if HCV RNA level is Z 25 IU/mL at either wk 4, 12, or 24.
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50% compared to 80% in the SMV arms. Interestingly, subgroup analysis revealed lower SVR12 in genotype 1a (71%) to genotype 1b (90%).24,25 The reduced efficacy of SMV may be due to the baseline presence of NS3 Q80K polymorphism, a naturally occurring variation in the HCV NS3/ 4A protease enzyme.26 Treatment naïve and relapsers' SVR rates with or without NS3 Q80K polymorphism were 43% and 84% compared to 24% and 78%, respectively.15 Baseline screening for the presence of NS3 Q80K polymorphism in genotype 1a patients is strongly recommended and alternative HCV therapy should be considered if tested positive for the viral polymorphism. An alternative regimen for treatment-naïve and IFN-eligible patients with genotype 1a or genotype 1b with undetectable Q80K polymorphism at baseline is daily SMV for 12 weeks and weight-based RBV plus weekly PegIFN for 24 weeks (Table 6).15 For treatment-naïve genotype 1 patients (of any subtype) who are not eligible to receive IFN, daily SOF and weight-based RBV for 24 weeks is an acceptable alternative regimen, but it should be recommended with caution since SVR rates may be lower.15 The QUANTUM, ELECTRON, and PHOTON-1 trials evaluated SOF plus daily weight-based RBV for either 12 or 24 weeks in treatment-naïve HCV genotype 1 patients. Results of the phase 2 and 3 trials demonstrated an SVR ranging from 50% to 84%.15 Previously utilized FDA-approved regimens of PegIFN/RBV with or without BOC or TVR are no longer recommended as these regimens are now considered inferior due to their many disadvantages.15
Genotype 2 or 3 The recommended regimen for treatment-naïve patients with HCV genotypes 2 and 3 is daily SOF and weight-based RBV for 12 and 24 weeks, respectively (Table 6).15 The FISSION trial was a randomized open-label study evaluating 12 weeks of SOF plus RBV versus 24 weeks of PegIFN/ RBV in treatment-naïve genotype 2 or genotype 3 patients.22 The overall SVR12 was 67% for both treatment arms, suggesting that SOF-based therapy was noninferior to SOC. When the data was stratified per genotype, genotype 2 resulted in higher SVR12 in the SOF group (97%) versus 78% with PegIFN/RBV. Meanwhile, SVR12 with SOF and PegIFN/RBV in genotype 3 patients were 56% and 63%, respectively.22 This suggests that genotype 3 is harder to treat than genotype 2. POSITRON was a randomized, placebo-blinded, controlled trial evaluating 12 weeks of SOF plus RBV that was compared to placebo in genotype 2 or 3 patients for whom IFN was not an option.27 The subjects in this trial had previously received IFN but had discontinued treatment due to underlying comorbidities, had experienced IFN adverse effects, or were unwilling to start therapy with IFN. No one achieved SVR in the placebo group. The overall SVR12 was 78% (genotype 2, 93% and genotype 3, 61%).27 VALENCE was a European trial evaluating the safety and efficacy of SOF and RBV in treatment-naïve and treatment-experienced genotypes 2 and 3 subjects.28 The initial study design was to treat for 12 weeks, however it was later changed to 24 weeks for only genotype 3 patients; data suggested this subgroup may benefit from treatment if it was administered beyond 12 weeks. Patients with genotype 2 treated with 12 weeks of SOF plus RBV achieved an overall SVR of 93%, whereas those with genotype 3 treated for 24 weeks achieved an SVR12 of 84%.27 Subjects with cirrhosis demonstrated overall lower SVR12, 61% compared to 81% with no cirrhosis, and it was significantly lower in genotype 3 (21%) versus genotype 2 (94%).28 In the FUSION trial, a 12- or 16-week regimen of SOF plus RBV was evaluated in genotype 2 or 3 treatment-experienced patients (relapsers and null responders) compared with historical controls.27 Patients receiving SOF and RBV for 12 weeks achieved an overall SVR12 of 50% (genotype 2, 86% and genotype 3, 30%), while those who received SOF and RBV for 16 weeks achieved an overall SVR12 of 73% (genotype 2, 94% and genotype 3, 62%). Overall, the SVR rates for genotype 3 patients achieved with 12- or 16-week regimens of SOF and RBV in the FISSION, POSITRON, and FUSION studies were lower than those compared to the 24-week regimen of SOF plus RBV in the VALENCE study.22,27,28 Thus, patients with genotype 3 are treated for a duration of 24 weeks. An alternative regimen for treatment-naïve patients
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with genotype 3 who are IFN eligible is daily SOF and weight-based RBV plus weekly PegIFN for 12 weeks (Table 6). Genotype 4, 5, or 6 Data regarding the treatment of HCV in patients with genotypes 4, 5, and 6 are limited and the following recommendations have been drawn from available data.15,16,22 In the NEUTRINO trial, 96% of patients with genotype 4 and all patients with genotype 5 (n ¼ 1) and 6 (n ¼ 6) achieved SVR12.22 The recommended regimen for treatment-naïve patients with genotype 4 who are IFN eligible is daily SOF and weight-based RBV for 12 weeks (Table 6).15 For genotype 4 patients who are not eligible for IFN, the recommended regimen is daily SOF plus weightbased RBV for 24 weeks. The RESTORE phase 3 clinical trial for genotype 4 patients comparing PegIFN/RBV for 48 weeks with a 12-week regimen of daily SMV and PegIFN/RBV followed by an additional 12 or 36 weeks of PegIFN/RBV alone is currently ongoing (Table 6).15,29 At present, the alternative regimen for treatment-naïve genotype 4 patients who are IFN eligible is daily SMV for 12 weeks and weight-based RBV plus weekly PegIFN for 24–48 weeks based on RGT.15 The recommended regimen for treatment-naïve patients with HCV genotype 5 or 6 is daily SOF and weight-based RBV plus weekly PegIFN for 12 weeks (Table 6).15 The combination of PegIFN and RBV for 48 weeks was the previously recommended regimen for patients with genotype 5 or 6 and is now the alternative regimen. The choice of treatment regimen should take into account the patient's HCV genotype, likely efficacy based on disease state and history of prior HCV treatment, duration of treatment, adverse effect profile and current health state to tolerate drug side effects. Medication adherence, social history, and financial factors must also be considered upon selecting the appropriate HCV regimen. Adverse effects and drug interactions of hepatitis C therapy The adverse effects associated with therapy contribute to the challenges of hepatitis C treatment, potentially impacting adherence and resulting in premature cessation of therapy. In registration trials of PegIFN/RBV, the discontinuation rates were 10–14%.7,8 The most common adverse events with PegIFN use are influenza-like (fatigue, headache, fever, and rigors) and psychiatric (depression, irritability, and insomnia) side effects. Thyroid disorders, diabetes, and hypertriglyceridemia are abnormalities that may result from PegIFN use and require laboratory surveillance. Hematological abnormalities arising from PegIFN include neutropenia, thrombocytopenia, and anemia. Hemolytic anemia and dermatological complaints (pruritus and rash) is the most common ribavirin adverse effects. Triple therapy with SOF is well tolerated with minimal adverse reactions beyond what is seen with PegIFN and RBV.20,22,27 The most common side effect with SMV and PegIFN/RBV include rash, photosensitivity, pruritus, and fatigue.21 The adverse effects of PegIFN, RBV, and DAAs are summarized in Table 7. In the era of DDA therapy, emerges another complication associated with HCV therapy, drug– drug interactions. Screening the patient's medication lists, including all prescription drugs, OTC drugs, and dietary supplements prior to initiating treatment is important as alterations in pharmacokinetic parameters may increase or decrease drug exposure given how DAAs are metabolized. Telaprevir and boceprevir are potent inhibitors of the cytochrome P450, or CYP, pathway—specifically, of the 3A4 isoenzyme. Drugs such as HMG-CoA reductase inhibitors, immunosuppressants, and antiretrovirals appear to be problematic. For the first-generation DAAs, drug that may interact with P-glycoprotein, or P-gp, may also be a concern, such as interactions with digoxin. SMV inhibits CYP1A2 and intestinal CYP3A4, with minimal effects of hepatic CYP3A4. Similar to TEL and BOC, SMV has some activity with P-gp, increasing plasma drug concentrations. Additionally, SMV inhibits OATP1B1/3, which may result in drug–drug interactions, specifically with HMG-CoA inhibitors. Unlike the approved HCV protease inhibitors, polymerase inhibitor, SOF has fewer drug interactions, yet it may still be significant. SOF is a
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Table 7 Adverse effects of hepatitis C treatment options.20,21,30,31 Pegylated interferon
Ribavirin
Simeprevir
Sofosbuvir
Influenza-like symptoms: Fatigue Headache Fever and chills Arthralgia and myalgia Injection site reaction Hematological abnormalities Neutropenia Thrombocytopenia Anemia Neuropsychiatric conditions: Depression Anxiety Irritability Thyroid disorders Diabetes Hypertriglyceridemia
Hemolytic anemia Rash Cough Gastrointestinal effects: Nausea Gastrointestinal upset Diarrhea Teratogenicity (pregnancy category X)
In combination with PegIFN plus RBV Rash Photosensitivity Pruritus Nausea Psychological
In combination with RBV Fatigue Headache In combination with PegIFN plus RBV Fatigue Headache Nausea Insomnia Anemia Psychological
substrate of P-gp in the intestines, therefore agents such as St. John's wort should not be administered with SOF to avoid decreasing drug concentrations. Interesting to note, SOF is metabolized to GS-331007, the active metabolite, which means drugs that inhibit P-gp may not affect GS-331007 plasma concentrations. Several anticonvulsants (carbamazepine and phenytoin), antimycobacterials (rifampin), and HIV protease inhibitors (tipranavir/ritonavir) should not be co-administered with SOF. For a summary of drug interactions with the DDAs, please refer to the manufactures package inserts.20,21,30–33
Management of hepatitis C therapy and telehealth For clinic sites with the available technology, patients diagnosed with hepatitis C may be referred to a telemedicine clinic to be further assessed for HCV treatment candidacy by a team of hepatitis specialists. One setting that has implemented this type of practice is the correctional facility. Patients who are approved to initiate therapy are counseled on the disease state and the potential outcomes from HCV treatment. A discussion of adverse effects, duration of treatment, importance of drug adherence, and avoidance of initiating over-the-counter (OTC) agents prior to consulting the HCV drug prescriber is performed to prevent premature cessation of HCV treatment and increase the likelihood of achieving SVR. A psychological clearance by a psychiatrist must be obtained prior to beginning IFN-based treatments. The patient's medication profile (e.g., prescription, dietary supplements, and OTC) is critically reviewed to identify and limit drug interactions. Patients who have started HCV treatment should schedule clinic visits every 2–4 weeks for approximately 20 min to assess for adverse effects and address any drug- or medical-related issues. Scheduled laboratory orders are drawn by the correctional facility at regular intervals (Table 8). Growth factors (e.g, erythropoietin, darbepoetin, and granulocyte colony-stimulating factors), thyroid supplements, hyperglycemics, and anti-hyperlipidemics may be added as needed to counter laboratory abnormalities arising from therapy. Should adverse effects become severe, the clinician may choose to reduce the dose or discontinue some or all of the HCV medications.
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Table 8 Example of monitoring parameters and time points during hepatitis C treatment. Week
Baseline
HCV RNAa CBC LFT BMP Lipid panel TSH Influenza-like symptoms Adverse effects
X X X X X X
a
24–48 h
X X
2
4
8
12
16/20
24
28/32
36
40/44
EOT
SVR12 or 24 weeks post-therapy
X X X
X X X
X X X
X X X
X X X X
X X X X
X X
X X X X X X X
X X X
X X
X X X X X X X
X X X
X X
X X X X X X X
X X
X X
X X
Based on HCV treatment regimen selected.20,21
Education is critical as the patient has vital responsibility in his or her HCV therapy. Psychological disturbances is common adverse effect with PegIFN; thus, patients must be counseled on the mental and emotional changes that may develop so they may seek psychiatric consultation in a timely manner. The patient is responsible for reporting any dermatological symptoms to the healthcare providers. If skin disturbances occur, the HCV specialist can assess the severity and order corticosteroids, lotions, and/or antihistamines to manage symptoms or make a decision to discontinue therapy. The patient is educated regarding appropriate premedications (e.g., acetaminophen prior to IFN), supportive care measures, and diet modifications. Most importantly, men and women of child-conceiving potential are counseled to use two forms of contraception during and 6 months post-treatment due to the teratogenicity of RBV. At 3–6 months upon completion of treatment, the patient returns for a blood draw and follow-up consultation to determine if the patient has achieved SVR. Patients who are “cured” are educated on lifestyle modifications as it is important to understand that they may become re-infected with HCV and SVR may be difficult to achieve in re-treatment. Additionally, patients who have cirrhosis, it is important for them to undergo serial surveillance for HCC and varices. Advantages and disadvantages of correctional setting hepatitis C management There have been varying levels of success for incarcerated patients with genotypes 1, 2, 3, and 4 achieving SVR, with studies reporting between 28% and 50%.34–37 However, these response rates were achieved with previous treatment regimens that only included PegIFN and RBV, which at present is not the current SOC for genotype 1.15,16 Based on more recent clinical trials,22–29 it should be expected that treatment involving SMV or SOF would achieve higher rates of SVR when or if used in the incarcerated population. A major barrier to initiating HCV therapy is the long treatment duration. It is typically recommended that patients who would like to be treated for HCV have at least 15–18 months of incarceration time prior to release since HCV treatment may last up to 48 weeks.7,8,12 If treatment is initiated and the inmate is discharged from the correctional facility prior to completing the course of therapy, then there is a high possibility of treatment failure, development of resistance, and lack of monitoring of adverse effects due to no laboratory or clinical follow-up upon release.12 However, with some of the newer regimens having treatment durations as low as 12 weeks, it may likely result in decreasing the required length of stay a patient is incarcerated to be eligible for HCV treatment. Other issues that remain as obstacles for successful HCV treatment include active drug abuse, alcohol abuse, re-infection, psychiatric illness, and poor adherence.37 Although hepatitis C treatment is expensive, studies have shown it to be cost-effective in the correctional facility setting.38 One study analyzing the cost-effectiveness of treating in the prison setting found overall treatment cost ranging from $25,000 to $189,000 depending on the
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genotype, stage of fibrosis, patient age, and if compensated cirrhosis was present. For patients not needing to undergo a liver biopsy, researchers found an overall cost savings of $11,000– $41,000 in those who received HCV treatment versus those who did not.38 Additionally, patients who were treated had a better quality of life measured by an increase of quality-adjusted life years (QALY) between 0.5 and 0.75.38 Of note, IFN/RBV was the SOC at the time the data was obtained.38 Even though only 10–20% of patients with HCV develop severe hepatic complications, the high incidence of incarcerated patients may result in a higher financial burden on the State and Federal prison system if more patients become eligible to receive treatment. Treating hepatitis C while patients are incarcerated does have a list of benefits other than potential cost savings. The option of beginning treatment may not be available to some inmates if it were not for being incarcerated. Patients may benefit from having close monitoring and follow-up due to their incarcerated status as well as decreasing the HCV burden and risk for HCV transmission to the community upon release.36 References 1. World Health Organization. Hepatitis C: WHO fact sheet N1 164. 〈http://www.who.int/mediacentre/factsheets/fs164/ en/index.html〉; 2013 Accessed 22.02.14. 2. Center for Disease Control. Hepatitis C FAQs for health professionals. 〈http://www.cdc.gov/hepatitis/HCV/HCVfaq. htm#section1〉; 2012 Accessed 22.02.14. 3. Chak E, Talal AH, Sherman KE, Schiff ER, Saab S. Hepatitis C virus infection in USA: an estimate of true prevalence. Liver Int. 2011;31(8):1090–1101. 4. Moyer VA. Screening for hepatitis C virus infection in adults: US preventive services task force recommendation statement. Ann Intern Med. 2013;159(5):349–357. 5. Weinbaum C, Lyerla R, Margolis HS. Prevention and control of infections with hepatitis viruses in correctional settings. Centers for Disease Control and Prevention. MMWR Recomm Rep. 2003;52(RR-1):1–36. 6. Beck AJ, Maruschak LM. Hepatitis testing and treatment in state prisons. US Department of Justice, Office of Justice Programs, Bureau of Statistics. 〈http://www.bjs.gov/content/pub/pdf/httsp.pdf〉; 2004 Accessed 22.02.14. 7. Ghany MG, Strader DB, Thomas DL, Seeff LB. Diagnosis, management, and treatment of hepatitis C: an update. Hepatology. 2009;49(4):1335–1374. 8. Ghany MG, Nelson DR, Strader DB, Thomas DL, Seeff LB. An update on treatment of genotype 1 chronic hepatitis C virus infection: 2011 practice guideline by the American Association for the study of liver diseases. Hepatology. 2011;54(4):1433–1444. 9. Klevens RM, Hu DJ, Jiles R, Holmberg SD. Evolving epidemiology of hepatitis C virus in the United States. Clin Infect Dis. 2012;55(suppl 1):S3–S9. 10. Smith BD, Morgan RL, Beckett GA, et al. Recommendations for the identification of chronic hepatitis C virus infection among persons born during 1945–1965. MMWR Recomm Rep. 2012;61(RR-4):1–32. 11. Mahajan R, Liu SJ, Klevens RM, Holmberg SD. Indications for testing among reported cases of HCV infection from enhanced hepatitis surveillance sites in the United States, 2004–2010. Am J Public Health. 2013;103(8):1445–1449. 12. Federal Bureau of Prisons. Evaluation and treatment of hepatitis C and cirrhosis. Clinical practice guidelines. 〈http:// www.hepcassoc.org/pdf/2012/mar-federal-guidlines.pdf〉; 2012 Accessed 22.02.14. 13. Centers for Disease Control and Prevention (CDC). Testing for HCV infection: an update of guidance for clinicians and laboratorians. MMWR Morb Mortal Wkly Rep. 2013;62(18):362–365. 14. Smith DB, Bukh J, Kuiken C, et al. Expanded classification of hepatitis C virus into 7 genotypes and 67 subtypes: updated criteria and genotype assignment web resource. Hepatology. 2014;59(1):318–327. 15. American Association for the Study of Liver Diseases and Infectious Diseases Society of America. Recommendations for testing, managing, and treating hepatitis C. Initial treatment of HCV infection in patients starting treatment. 〈http:// www.hcvguidelines.org/full-report/initial-treatment-hcv-infection-patients-starting-treatment〉 Accessed 22.02.14. 16. American Association for the Study of Liver Diseases and Infectious Diseases Society of America. Recommendations for testing, managing, and treating hepatitis C. Retreatment of persons in whom prior therapy has failed. 〈http://www. hcvguidelines.org/full-report/retreatment-persons-whom-prior-therapy-has-failed〉; Accessed 22.02.14. 17. Chen J, Florian J, Carter W, et al. Earlier sustained virologic response end points for regulatory approval and dose selection of hepatitis C therapies. Gastroenterology. 2013;144(7):1450–1455. 18. U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research. Guidance for industry chronic hepatitis C virus infection: developing direct-acting antiviral drugs for treatment. Draft guidance. 〈http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ UCM225333.pdf〉; 2013 Accessed 22.02.14. 19. European Association of the Study of the Liver. EASL clinical practice guidelines: management of hepatitis C virus infection. J Hepatol. 2014;60(2):392–420. 20. Sovaldi [package insert]. Foster City, CA: Gilead Sciences; 2013. 21. Olysio [package insert]. Titusville, NJ: Janssen Therapeutics; 2013. 22. Lawitz E, Mangia A, Wyles D, et al. Sofosbuvir for previously untreated chronic hepatitis C infection. N Engl J Med. 2013;368(20):1878–1887.
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23. Jacobson I, Ghalib RM, Rodriguez-Torres M, et al. SVR results of a once-daily regimen of simeprevir (TMC435) plus sofosbuvir (GS-7977) with or without ribavirin in cirrhotic and non-cirrhotic HCV genotype 1 treatment-naïve and prior null responder patients: the COSMOS study. Hepatology. 2013;58:1379A. 24. Jacobson I, Dore GJ, Foster GR, et al. Simeprevir (TMC435) with peginterferon/ribavirin for chronic HCV genotype-1 infection in treatment-naïve patients: results from QUEST-1, a phase III trial. J Hepatol. 2013;58:1425A. 25. Manns M, Marcellin P, Fred Poordad FP, et al. Simeprevir (TMC435) with peginterferon/ribavirin for treatment of chronic HCV genotype-1 infection in treatment-naïve patients: results from QUEST-2, a phase III trial. J Hepatol. 2013;58:1413A. 26. Lenz O, Verbinnen T, Lin TI, et al. In vitro resistance profile of the hepatitis C virus NS3/4A protease inhibitor TMC435. Antimicrob Agents Chemother. 2010;54(5):1878–1887. 27. Jacobson IM, Gordon SC, Kowdley KV, et al. Sofosbuvir for hepatitis C genotype 2 or 3 in patients without treatment options. N Engl J Med. 2013;368(20):1867–1877. 28. Zeuzem S, Dusheiko GM, Salupere R. Sofosbuvir and ribavirin for 12 or 24 weeks for patients with HCV genotype 2 or 3: the VALENCE trial. Hepatology. 2013;58:1085A. 29. Moreno C, Hezode C, Marcellin P, et al. Simeprevir with peginterferon/ribavirin in treatment-naive or -experienced patients with chronic HCV genotype 4 infection: a phase III study. 14th European AIDS Conference;2013 [Abstract PS9/6]. 30. Pegasys [package insert]. San Francisco, CA: Genentech USA, Inc; 2013. 31. Copegus [package insert]. San Francisco, CA: Genentech USA, Inc; 2013. 32. Incivek [package insert]. Cambridge, MA: Vertex; 2013. 33. Victrelis [package insert]. Whitehouse Station, NJ; 2014. 34. Rice JP, Burnett D, Tsotsis H, et al. Comparison of hepatitis C virus treatment between incarcerated and community patients. Hepatology. 2012;56(4):1252–1260. 35. Allen SA, Spaulding AC, Osei AM, Taylor LE, Cabral AM, Rich JD. Treatment of chronic hepatitis C in a state correctional facility. Ann Intern Med. 2003;138(3):187–190. 36. Chew KW, Allen SA, Taylor LE, Rich JD, Feller E. Treatment outcomes with pegylated interferon and ribavirin for male prisoners with chronic hepatitis C. J Clin Gastroenterol. 2009;43(7):686–691. 37. Iacomi F, Iannicelli G, Franceschini A, et al. HCV infected prisoners: should they be still considered a difficult to treat population? BMC Infect Dis. 2013;13:1–7. 38. Tan JA, Joseph TA, Saab S. Treating hepatitis C in the prison population is cost‐saving. Hepatology. 2008;48(5): 1387–1395.
