WHEN AND IN WHOM TO INITIATE HCV THERAPY
Successful hepatitis C treatment results in sustained virologic response (SVR), which is tantamount to virologic cure, and as such, is expected to benefit nearly all chronically infected persons. When the US Food and Drug Administration (FDA) approved the first IFN-sparing treatment for HCV infection, many patients who had previously been “warehoused” sought treatment, and the infrastructure (experienced practitioners, budgeted health-care dollars, etc) did not yet exist to treat all patients immediately. Thus, the panel offered guidance for prioritizing treatment first to those with the greatest need. Since that time, there have been opportunities to treat many of the highest-risk patients and to accumulate real-world experience of the tolerability and safety of newer HCV medications. More importantly, from a medical standpoint, data continue to accumulate that demonstrate the many benefits, within the liver and extrahepatic, that accompany HCV eradication. Therefore, the panel continues to recommend treatment for all patients with chronic HCV infection, except those with short life expectancies that cannot be remediated by treating HCV, by transplantation, or by other directed therapy. Accordingly, prioritization tables are now less useful and have been removed from this section.
Despite the strong recommendation for treatment for nearly all HCV-infected patients, pretreatment assessment of a patient’s understanding of treatment goals and provision of education on adherence and follow-up are essential. A well-established therapeutic relationship between practitioner and patient remains crucial for optimal outcomes with new direct-acting antiviral (DAA) therapies. Additionally, in certain settings there remain factors that impact access to medications and the ability to deliver them to patients. In these settings, practitioners may still need to decide which patients should be treated first. The descriptions below of unique populations may help physicians make more informed treatment decisions for these groups (See Unique Patient Populations: Patients with HIV/HCV Coinfection, Unique Patient Populations: Patients with Decompensated Cirrhosis, Unique Patient Populations: Patients who Develop Recurrent HCV Infection Post-Liver Transplantation, and Unique Patient Populations: Patients with Renal Impairment).
Expansions and notes for abbreviations used in this section can be found in Methods Table 3.
A summary of recommendations for When and in Whom to Initiate HCV Therapy is found in the BOX.
Clinical Benefit of Cure
The proximate goal of HCV therapy is SVR (virologic cure), defined as the continued absence of detectable HCV RNA at least 12 weeks after completion of therapy. SVR is a marker for cure of HCV infection and has been shown to be durable, in large prospective studies, in more than 99% of patients followed up for 5 years or more (Swain, 2010); (Manns, 2013). Patients in whom an SVR is achieved have HCV antibodies but no longer have detectable HCV RNA in serum, liver tissue, or mononuclear cells, and achieve substantial improvement in liver histology (Marcellin, 1997); (Coppola, 2013); (Garcia-Bengoechea, 1999). Assessment of viral response, including documentation of SVR, requires use of an FDA-approved quantitative or qualitative nucleic acid test (NAT) with a detection level of 25 IU/mL or lower.
Patients who are cured of their HCV infection experience numerous health benefits, including a decrease in liver inflammation as reflected by improved aminotransferase (ie, alanine aminotransferase [ALT], aspartate aminotransferase [AST]) levels and a reduction in the rate of progression of liver fibrosis (Poynard, 2002b). Of 3010 treatment-naive HCV-infected patients with pretreatment and posttreatment biopsies from 4 randomized trials of 10 different IFN-based regimens (biopsies separated by a mean of 20 months), 39% to 73% of patients who achieved an SVR had improvement in liver fibrosis and necrosis (Poynard, 2002b), and cirrhosis resolved in half of the cases. Portal hypertension, splenomegaly, and other clinical manifestations of advanced liver disease also improved. Among HCV-infected persons, SVR is associated with a more than 70% reduction in the risk of liver cancer (hepatocellular carcinoma [HCC]) and a 90% reduction in the risk of liver-related mortality and liver transplantation (Morgan, 2013); (van der Meer, 2012); (Veldt, 2007).
Cure of HCV infection also reduces symptoms and mortality from severe extrahepatic manifestations, including cryoglobulinemic vasculitis, a condition affecting 10% to 15% of HCV-infected patients (Fabrizi, 2013); (Landau, 2010); (Sise, 2016). HCV-infected persons with non-Hodgkin lymphoma and other lymphoproliferative disorders achieve complete or partial remission in up to 75% of cases following successful therapy for HCV infection (Gisbert, 2005); (Takahashi, 2012); (Svoboda, 2005); (Mazzaro, 2002); (Hermine, 2002). These reductions in disease severity contribute to dramatic reductions in all-cause mortality (van der Meer, 2012); (Backus, 2011). Lastly, patients who achieve SVR have substantially improved qualities of life, which include physical, emotional, and social health (Boscarino, 2015); (Neary, 1999); (Younossi, 2013). Because of the many benefits associated with successful HCV treatment, clinicians should treat HCV-infected patients with antiviral therapy with the goal of achieving an SVR, preferably early in the course of chronic HCV infection before the development of severe liver disease and other complications.
Benefits of Treatment at Earlier Fibrosis Stages (Metavir Stage Below F2)
Initiating therapy in patients with lower-stage fibrosis augments the benefits of SVR. In a long-term follow-up study, 820 patients with Metavir stage F0 or F1 fibrosis confirmed by biopsy were followed up for up to 20 years (Jezequel, 2015). The 15-year survival rate was statistically significantly better for those who experienced an SVR than for those whose treatment had failed or for those who remained untreated (93%, 82%, and 88%, respectively; P =.003). The study results argue for consideration of earlier initiation of treatment. Several modeling studies also suggest a greater mortality benefit if treatment is initiated at fibrosis stages prior to F3 (Øvrehus, 2015); (Zahnd, 2015); (McCombs, 2015).
Treatment delay may decrease the benefit of SVR. In a report of long-term follow-up in France, 820 patients with biopsy-confirmed Metavir stage F0 or F1 fibrosis were followed up for as long as 20 years (Jezequel, 2015). The authors noted rapid progression of fibrosis in 15% of patients during follow-up, and in patients treated successfully, long-term survival was better. Specifically, at 15 years, survival rate was 92% for those with an SVR versus 82% for treatment failures and 88% for those not treated. In a Danish regional registry study, investigators modeled treatment approaches with the aim of evaluating the benefit to the region in terms of reductions in morbidity and mortality and HCV prevalence (Øvrehus, 2015). Although they note that in their situation of low HCV prevalence (0.4%), with approximately 50% undiagnosed, a policy that restricts treatment to those with Metavir fibrosis stage F3 or higher would decrease mortality from HCC and cirrhosis, the number needed to treat to halve the prevalence of the disease is lower if all eligible patients receive treatment at diagnosis. A modeling study based on the Swiss HIV Cohort Study also demonstrated that waiting to treat HCV infection at Metavir fibrosis stages F3 and F4 resulted in 2- and 5-times higher rates of liver-related mortality, respectively, compared with treating at Metavir stage F2 (Zahnd, 2015).
A US Veterans Administration dataset analysis that used very limited end points of virologic response dating from the IFN-treatment era suggested that early (at a Fibrosis-4 [FIB-4] score of <3.25) initiation of therapy increased the benefit attained with respect to likelihood of treatment success and mortality reduction and ultimately decreased the number of patients needed to treat to preserve 1 life by almost 50% (McCombs, 2015).
Considerations in Specific Populations
Despite the recommendation for treatment of nearly all patients with HCV infection, it remains important for clinicians to understand patient- and disease-related factors that place individuals at risk for HCV-related complications (liver and extrahepatic) as well as for HCV transmission. Although these groups are no longer singled out for high prioritization for treatment, it is nonetheless important that practitioners recognize the unique dimensions of HCV disease and its natural history in these populations. The discussions offered below may assist clinicians in making compelling cases for insurance coverage of treatment when necessary.
Persons With Advanced Liver Disease
For persons with advanced liver disease (Metavir stage F3 or F4), the risk of developing complications of liver disease such as hepatic decompensation (Child Turcotte Pugh [CTP] Class B or C [Methods Table 3]) or HCC is substantial and may occur in a relatively short timeframe. A large prospective study of patients with cirrhosis resulting from HCV infection examined the risk of decompensation, including HCC, ascites, jaundice, bleeding, and encephalopathy, and found that the overall annual incidence rate was 3.9% (Sangiovanni, 2006). The National Institutes of Health (NIH)-sponsored HALT–C study included a group of 220 patients with cirrhosis resulting from HCV infection who were observed for approximately 8 years. A primary outcome of death, hepatic decompensation, HCC, or increase in CTP score of 2 or higher occurred at a rate of 7.5% per year (Everson, 2006); (Di Bisceglie, 2008). Patients with a CTP score of 7 or higher experienced a death rate of 10% per year.
Numerous studies have demonstrated that hepatitis C therapy and the achievement of an SVR in this population results in dramatic decreases in hepatic decompensation events, HCC, and liver-related mortality (Morgan, 2013); (van der Meer, 2012); (Backus, 2011); (Dienstag, 2011); (Berenguer, 2009); (Mira, 2013). In the HALT-C study, patients with advanced fibrosis secondary to HCV infection who achieved an SVR, compared with patients with similarly advanced liver fibrosis who did not achieve an SVR, had a decreased need for liver transplantation (hazard ratio [HR], 0.17; 95% confidence interval [CI], 0.06–0.46), decreased development of liver-related morbidity and mortality (HR, 0.15; 95% CI, 0.06–0.38) and decreased HCC (HR, 0.19; 95% CI, 0.04–0.80) (Dienstag, 2011). Importantly, persons with advanced liver disease also require long-term follow-up and HCC surveillance regardless of treatment outcome (see Monitoring Patients who are Starting Hepatitis C Treatment, are on Treatment, or have Completed Therapy).
Given the clinical complexity and the need for close monitoring, patients with advanced liver disease that has already decompensated (CTP Class B or C [Methods Table 3]) should be treated by physicians with experience in treating HCV in conjunction with a liver transplantation center if possible (see Unique Patient Populations: Patients with Decompensated Cirrhosis).
Persons Who Have Undergone Liver Transplantation
In HCV-infected individuals, HCV infection of the liver allograft occurs universally in those with viremia at the time of transplantation. Histologic features of hepatitis develop in about 75% of recipients in the first 6 months following liver transplantation (Neumann, 2004). By the fifth postoperative year, up to 30% of untreated patients have progressed to cirrhosis (Neumann, 2004); (Charlton, 1998). A small proportion of patients (4%-7%) develop an accelerated course of liver injury (cholestatic hepatitis C, associated with very high levels of viremia) with subsequent rapid allograft failure. Recurrence of HCV infection posttransplantation is associated with decreased graft survival for recipients with HCV infection compared to recipients who undergo liver transplantation for other indications (Forman, 2002).
Effective HCV therapy pretransplantation resulting in an SVR (virologic cure) prevents HCV recurrence posttransplantation (Everson, 2003). In addition, complete HCV viral suppression prior to transplantation prevents recurrent HCV infection of the graft in the majority of cases (Forns, 2004); (Everson, 2005). Preliminary data from a study of patients with complications of cirrhosis secondary to HCV infection, who were wait-listed for liver transplantation, that included patients with MELD scores up to 14 and CTP scores up to 8 found that treatment with sofosbuvir and weight-based ribavirin for up to 48 weeks was well tolerated and was associated with an overall posttransplant SVR rate of 70% (Curry, 2015). Posttransplant SVR was nearly universal among patients who had undetectable HCV RNA for 28 days or longer prior to transplantation.
Treatment of established HCV infection posttransplantation also yields substantial improvements in patient and in graft survival (Berenguer, 2008); (Picciotto, 2007). The availability of effective IFN-free HCV treatments has addressed the major hurdles to treating HCV recurrence posttransplantation: poor tolerability and efficacy. In a multicenter, open-label study that evaluated the ability of sofosbuvir plus ribavirin to induce virologic suppression in 40 patients post–liver transplant with compensated recurrence of HCV infection, daily sofosbuvir and ribavirin for 24 weeks achieved an SVR at 12 weeks (SVR12) in 70% (Charlton, 2015). No deaths, graft losses, or episodes of rejection occurred. Six patients had serious adverse events, all of which were considered unrelated to study treatment. There were no drug interactions reported between sofosbuvir and any of the concomitant immunosuppressive agents. In contrast, treatment with sofosbuvir plus ribavirin with or without PEG-IFN in 64 patients with severe, decompensated cirrhosis resulting from recurrence of HCV infection following liver transplantation was associated with an overall SVR12 rate of 59% and a mortality rate of 13% (Forns, 2015). On an intent-to-treat basis, treatment was associated with clinical improvement in 57% and stable disease in 22% of patients. Given the clinical complexity including drug interactions and the need for close monitoring, patients with liver transplant should be treated by physicians with experience in treating this population (see Unique Patient Populations: Patients who Develop Recurrent HCV Infection Post-Liver Transplantation).
Persons at Greater Risk for Rapidly Progressive Fibrosis and Cirrhosis
Fibrosis progression is variable across different patient populations as well as within the same individual over time. Many of the components that determine fibrosis progression and development of cirrhosis in an individual are unknown. However, certain factors, such as coinfection with HIV or hepatitis B virus (HBV) and prevalent coexistent liver diseases (eg, nonalcoholic steatohepatitis [NASH]), are well-recognized contributors to accelerated fibrosis progression.
HIV coinfection. HIV coinfection accelerates fibrosis progression among HCV-infected persons, (Benhamou, 1999); (Macias, 2009); (Konerman, 2014) although control of HIV replication and restoration of CD4+ cell counts may mitigate this to some extent (Benhamou, 2001); (Bräu, 2006). However, antiretroviral therapy is not a substitute for HCV treatment. In the largest paired-biopsy study, 282 HIV/HCV-coinfected patients with 435 paired biopsies were prospectively evaluated; (Konerman, 2014) one-third of patients showed fibrosis progression of at least one Metavir stage at a median of 2.5 years. Importantly, 45% of patients with no fibrosis on initial biopsy had progression. Finally, a more rapid progression to death following decompensation combined with a lack of widespread access to liver transplantation and poor outcomes following transplantation highlight the need for treatment in this population regardless of current fibrosis stage (see Unique Patient Populations: Patients with HIV/HCV Coinfection) (Pineda, 2005); (Merchante, 2006); (Terrault, 2012).
HBV coinfection and other coexistent liver diseases. The prevalence of HBV/HCV coinfection is estimated at 1.4% in the United States and 5% to 10% globally (Tyson, 2013); (Chu, 2008). Persons with HBV/HCV coinfection and detectable viremia of both viruses are at increased risk for disease progression, decompensated liver disease, and the development of HCC.
HBV/HCV coinfected individuals are susceptible to a process called viral interference wherein one virus may interfere with the replication of the other virus. Thus, when treating one or both viruses with antiviral drugs, periodic retesting of HBV DNA and HCV RNA levels during and after therapy is prudent, particularly if only one of the viruses is being treated at a time. Treatment of HCV infection in such cases utilizes the same genotype-specific regimens as are recommended for HCV monoinfection (see Initial Treatment of HCV Infection). HBV infections in such cases should be treated as recommended for HBV monoinfection (Lok, 2009).
Persons with other chronic liver diseases who have coincident chronic HCV infection should be considered for hepatitis C therapy, given the potential for rapid progression of liver disease. An IFN-free regimen is generally preferred for immune-mediated liver diseases such as autoimmune hepatitis, because of the potential for IFN-related exacerbation.
Persons With Extrahepatic Manifestations of Chronic HCV Infection
Severe renal impairment. Chronic hepatitis C is associated with a syndrome of cryoglobulinemia and an immune complex and lymphoproliferative disorder that produces arthralgias, fatigue, palpable purpura, renal disease (eg, membranoproliferative glomerulonephritis), neurologic disease (eg, peripheral neuropathy, central nervous system vasculitis), and reduced complement levels (Agnello, 1992). Because patients with chronic hepatitis C frequently have laboratory evidence of cryoglobulins (more than 50% in some series), antiviral treatment is imperative for those with the syndrome of cryoglobulinemia and symptoms or objective evidence of end-organ manifestations. IFN-based regimens can produce clinical remission; however, the adverse effects of IFN may mimic manifestations of cryoglobulinemia (Saadoun, 2014). Although clinical data are not yet available, the use of IFN-free DAA regimens is an attractive option for these patients. Organ-threatening disease (eg, severe neuropathy, renal failure, digital ischemia), in addition to antiviral HCV therapy, should be treated more acutely with immunosuppressive agents or plasmapheresis to clear immune complexes.
Glomerular disease results from deposition of HCV-related immune complexes in the glomeruli (Johnson, 1993). Successful treatment of HCV using IFN-based regimens can reverse proteinuria and nephrotic syndrome but usually does not fully ameliorate azotemia (Johnson, 1994). No clinical trial data are yet available on IFN-free regimens, but the high rates of SVR (virologic cure) with antiviral therapy support their use in management of hepatitis C–related renal disease and cryoglobulinemia.
Nonhepatic Manifestations of Chronic HCV Infection
The relationship between chronic hepatitis C and diabetes (most notably type 2 diabetes and insulin resistance) is complex and incompletely understood. The prevalence and incidence of diabetes is increased in the context of hepatitis C (White, 2008). In the United States, type 2 diabetes occurs more frequently in HCV-infected patients, with a more than 3-fold greater risk in persons older than 40 years (Mehta, 2000). The positive correlation between quantity of plasma HCV RNA and established markers of insulin resistance confirms this relationship (Yoneda, 2007). Insulin resistance and type 2 diabetes are independent predictors of a more rapid progression of liver fibrosis and an impaired response to IFN-based therapy (Petta, 2008). Patients with type 2 diabetes and insulin resistance are also at increased risk for HCC (Hung, 2010).
Successful antiviral treatment has been associated with improved markers of insulin resistance and greatly reduced incidence of new onset of type 2 diabetes and insulin resistance in HCV-infected patients (Arase, 2009). Most recently, antiviral therapy for HCV infection has been shown to improve clinical outcomes related to diabetes. In a large prospective cohort from Taiwan, the incidence rates of end-stage renal disease, ischemic stroke, and acute coronary syndrome were greatly reduced in HCV-infected patients with diabetes who received antiviral therapy compared with untreated, matched controls (Hsu, 2014). Therefore, antiviral therapy may prevent progression to diabetes in patients with prediabetes who have hepatitis C and may reduce renal and cardiovascular complications in patients with established diabetes who have hepatitis C.
In patients with chronic hepatitis C, fatigue is the most frequently reported symptom and has a major effect on quality of life and activity level evidenced by numerous measures of impaired quality of life (Foster, 1998). The presence and severity of fatigue appears to correlate poorly with disease activity, although it may be more common and severe in HCV-infected individuals with cirrhosis (Poynard, 2002a). Despite difficulties in separating fatigue symptoms associated with hepatitis C from those associated with other concurrent conditions (eg, anemia, depression), numerous studies have reported a reduction in fatigue after cure of HCV infection (Bonkovsky, 2007). In the Virahep-C study, 401 patients with HCV infection were evaluated for fatigue prior to and after treatment, using validated scales to assess the presence and severity of fatigue (Sarkar, 2012). At baseline, 52% of patients reported having fatigue, which was more frequent and severe in patients with cirrhosis than in those without cirrhosis. Achieving an SVR was associated with a substantial decrease in frequency and severity of fatigue. A recent analysis of 413 patients from the NEUTRINO and FUSION trials who were treated with a sofosbuvir-containing regimen and who achieved an SVR12 demonstrated improvement in patient fatigue (present in 12%) from the pretreatment level (Younossi, 2014). After achieving an SVR12, participants had marked improvements in fatigue over their pretreatment scores measured by 3 separate validated questionnaires. Additional studies support and extend these findings beyond fatigue, with improvements in overall health-related quality of life and work productivity observed following successful HCV therapy (Gerber, 2016); (Younossi, 2015b); (Younossi, 2015c); (Younossi, 2015d).
The reported prevalence of HCV infection in patients with porphyria cutanea tarda approximates 50% and occurs disproportionately in those with cirrhosis (Gisbert, 2003). The treatment of choice for active porphyria cutanea tarda is iron reduction by phlebotomy and maintenance of a mildly iron-reduced state without anemia. However, although improvement of porphyria cutanea tarda during HCV treatment with IFN has frequently been described (Takikawa, 1995), there are currently insufficient data to determine whether treating HCV infection with DAAs and achievement of SVR improve porphyria cutanea tarda.
Lichen planus is characterized by pruritic papules involving mucous membranes, hair, and nails. Antibodies to HCV are present in 10% to 40% of patients with lichen planus, but a causal link with chronic infection is not established. Resolution of lichen planus has been reported with IFN-based regimens, but there have also been reports of exacerbation of lichen planus with these treatments. Although it is unknown whether DAAs will have more success against lichen planus, treatment with IFN-free regimens would appear to be a more advisable approach to addressing this disorder (Gumber, 1995).
Benefit of Treatment to Reduce Transmission
Persons who have successfully achieved an SVR (virologic cure) no longer transmit the virus to others. As such, successful treatment of HCV infection benefits public health. Several health models have shown that even modest increases in successful treatment of HCV infection among persons who inject drugs can decrease prevalence and incidence (Martin, 2013a); (Durier, 2012); (Martin, 2013b); (Hellard, 2012). Models developed to estimate the impact of HCV testing and treatment on the burden of hepatitis C at a country level reveal that large decreases in HCV prevalence and incidence are possible as more persons are successfully treated (Wedemeyer, 2014). There are also benefits to eradicating HCV infection between couples and among families, and thus eliminating the perception that an individual might be contagious. In addition, mother-to-child transmission of HCV does not occur if the woman is not viremic, providing an additional benefit of curing a woman before she becomes pregnant (Thomas, 1998). However, the safety and efficacy of treating women who are already pregnant to prevent transmission to the fetus have not yet been established, and thus treatment is not recommended for pregnant women.
The Society for Healthcare Epidemiology of America (SHEA) advises that health-care workers who have substantial HCV viral replication (>104 genome equivalents/mL) be restricted from performing procedures that are prone to exposure (Henderson, 2010) and that all health-care workers with confirmed chronic HCV infection should be treated. For reasons already stated above, the achievement of an SVR in such individuals will not only eliminate the risk of HCV transmission to patients but also decrease circumstantial loss of experienced clinicians. Given concerns about underreporting of infection and transmission (Henderson, 2010), the availability of effective, all-oral regimens should lead to greater willingness on the part of exposure-prone clinicians to be tested and treated.
Successful treatment of HCV-infected persons at greatest risk for transmission represents a formidable tool to help stop HCV transmission in those who continue to engage in high-risk behaviors. To guide implementation of hepatitis C treatment as a prevention strategy, studies are needed to define the best candidates for treatment to stop transmission, the additional interventions needed to maximize the benefits of HCV treatment (eg, preventing reinfection), and the cost-effectiveness of the strategies when used in target populations.
Persons who inject drugs. Injection drug use (IDU) is the most common risk factor for HCV infection in the United States and Europe, with an HCV seroprevalence of 10% to 70%; (Amon, 2008); (Nelson, 2011) IDU also accounts for the majority of new HCV infections (approximately 70%) and is the key driving force in the perpetuation of the epidemic. Given these facts and the absence of an effective vaccine against HCV, testing and linkage to care combined with treatment of HCV infection with potent IFN-free regimens has the potential to dramatically decrease HCV incidence and prevalence (Martin, 2013b). However, treatment-based strategies to prevent HCV transmission have yet to be studied, including how to integrate hepatitis C treatment with other risk-reduction strategies (eg, opiate substitution therapy, needle and syringe exchange programs) (Martin, 2013a).
In studies of IFN-containing treatments in persons who inject drugs, adherence and efficacy rates are comparable to those of patients who do not use injection drugs. A recent meta-analysis of treatment with PEG-IFN with or without ribavirin in active or recent injection drug users showed SVR rates of 37% and 67% for HCV genotype 1 or 4 and 2 or 3, respectively (Aspinall, 2013). As shorter, better-tolerated, and more efficacious IFN-free therapies are introduced, these SVR rates are expected to improve. Importantly, the rate of reinfection in this population is lower (2.4/100 person-years of observation) than that of incident infection in the general population of injection drug users (6.1-27.2/100 person-years), although reinfection increases with active or ongoing IDU (6.44/100 person-years) and available data on follow-up duration are limited (Aspinall, 2013); (Grady, 2013).
Ideally, treatment of HCV-infected persons who inject drugs should be delivered in a multidisciplinary care setting with services to reduce the risk of reinfection and for management of the common social and psychiatric comorbidities in this population. Regardless of the treatment setting, recent and active IDU should not be seen as an absolute contraindication to HCV therapy. There is strong evidence from various settings in which persons who inject drugs have demonstrated adherence to treatment and low rates of reinfection, countering arguments that have been commonly used to limit access to this patient population (Aspinall, 2013); (Hellard, 2014); (Grebely, 2011). Indeed, combining HCV treatment with needle exchange and opioid agonist therapy programs in this population with a high prevalence of HCV infection has shown great value in decreasing the burden of HCV disease. Elegant modeling studies illustrate the high return on the modest investment of addressing this often-ignored segment of the HCV-infected population (Martin, 2013b). These conclusions were drawn before the introduction of the latest DAA regimens. Conversely, there are no data to support the utility of pretreatment screening for illicit drug or alcohol use in identifying a population more likely to successfully complete HCV therapy. These requirements should be abandoned, because they create barriers to treatment, add unnecessary cost and effort, and potentially exclude populations that are likely to obtain substantial benefit from therapy. Scale up of HCV treatment in persons who inject drugs is necessary to positively impact the HCV epidemic in the United States and globally.
HIV-infected men who have sex with men (MSM) who engage in high-risk sexual practices. Over the past decade, a dramatic increase in incident HCV infections among HIV-infected MSM who did not report IDU as a risk factor has been demonstrated in several US cities (van de Laar, 2010). Recognition and treatment of HCV infection (including acute infection) in this population may represent an important step in preventing subsequent infections. As with persons who inject drugs, HIV/HCV-coinfected MSM who engage in ongoing high-risk sexual practices should be treated for their HCV infection in conjunction with continued education on risk-reduction strategies. In particular, safer-sex strategies should be emphasized given the high rates of reinfection after SVR, which may approach 30% over 2 years, in HIV-infected MSM with acute HCV infection (Lambers, 2011).
Incarcerated persons. Among incarcerated individuals, the rate of HCV seroprevalence ranges from 30% to 60% (Post, 2013) and the rate of acute infection is approximately 1% (Larney, 2013). Screening for HCV infection is relatively uncommon in state prison systems. Treatment uptake has been limited in part because of the toxic effects and long treatment duration of older IFN-based therapies as well as concerns about cost (Spaulding, 2006). In particular, truncation of HCV treatment owing to release from prison has been cited as a major limitation to widespread, effective HCV treatment in correctional facilities (Post, 2013); (Chew, 2009). Shorter (12- to 24-week) HCV therapies reduce duration of stay-related barriers to HCV treatment in prisons. Likewise, the improved safety of newer, all-oral regimens diminishes concerns of toxic effects. Coordinated treatment efforts within prison systems would likely rapidly decrease the prevalence of HCV infection in this at-risk population, although research is needed in this area.
Persons on hemodialysis. The prevalence rate of HCV infection is markedly elevated in persons on hemodialysis and ranged from 2.6% to 22.9% in a large multinational study (Fissell, 2004). Studies in the United States found a similarly elevated prevalence rate of 7.8% to 8.9% (Centers for Disease Control and Prevention, 2001); (Finelli, 2005). Importantly, the seroprevalence of HCV was found to increase with time on dialysis, suggesting that nosocomial transmission, among other risk factors, plays a role in HCV acquisition in these patients (Fissell, 2004). Improved education and strict adherence to universal precautions can drastically reduce nosocomial HCV transmission risks for persons on hemodialysis, (Jadoul, 1998) but clearance of HCV viremia through treatment-induced SVR eliminates the potential for transmission.
HCV-infected persons on hemodialysis have a decreased quality of life and increased mortality compared with uninfected persons on hemodialysis (Fabrizi, 2002); (Fabrizi, 2007); (Fabrizi, 2009). HCV infection in this population also has a deleterious impact on kidney transplantation outcomes with decreased patient and graft survival (Fabrizi, 2014). The increased risk for nosocomial transmission and the substantial clinical impact of HCV infection in those on hemodialysis are compelling arguments for HCV therapy as effective antiviral regimens that can be used in persons with advanced renal failure become available (see Unique Patient Populations: Patients with Renal Impairment).
Populations Unlikely to Benefit From HCV Treatment
Patients with a limited life expectancy that cannot be remediated by treating HCV, by transplantation, or by other directed therapy do not require treatment. Patients with short life expectancies owing to liver disease should be managed in consultation with an expert. Chronic hepatitis C is associated with a wide range of comorbid conditions (Butt, 2011); (Louie, 2012). Little evidence exists to support initiation of HCV treatment in patients with limited life expectancy (less than 12 months) owing to non–liver-related comorbid conditions. For these patients, the benefits of HCV treatment are unlikely to be realized and palliative care strategies should take precedence (Holmes, 2006); (Maddison, 2011).
An accurate assessment of fibrosis remains vital, as degree of hepatic fibrosis is one of the most robust prognostic factors used to predict HCV disease progression and clinical outcomes (Everhart, 2010). Individuals with severe fibrosis require surveillance monitoring for liver cancer, esophageal varices, and hepatic function (Garcia-Tsao, 2007); (Bruix, 2011). In some instances, the recommended duration of treatment is also longer.
Although liver biopsy is the diagnostic standard, sampling error and observer variability limit test performance, particularly when inadequate sampling occurs. Up to one-third of bilobar biopsies had a difference of at least 1 stage between the lobes (Bedossa, 2003). In addition, the test is invasive and minor complications are common, limiting patient and practitioner acceptance. Serious complications such as bleeding, although rare, are well recognized.
Noninvasive tests to stage the degree of fibrosis in patients with chronic HCV infection include models incorporating indirect serum biomarkers (routine tests), direct serum biomarkers (components of the extracellular matrix produced by activated hepatic stellate cells), and vibration-controlled transient liver elastography. No single method is recognized to have high accuracy alone and each test must be interpreted carefully. A recent publication of the Agency for Healthcare Research and Quality found evidence in support of a number of blood tests; however, at best, they are only moderately useful for identifying clinically significant fibrosis or cirrhosis (Selph, 2014).
Vibration-controlled transient liver elastography is a noninvasive way to measure liver stiffness and correlates well with measurement of substantial fibrosis or cirrhosis in patients with chronic HCV infection. The measurement range does overlap between stages (Ziol, 2005); (Afdhal, 2015); (Castera, 2005).
The most efficient approach to fibrosis assessment is to combine direct biomarkers and vibration-controlled transient liver elastography (Boursier, 2012); (European Association for the Study of the Liver and Asociacion Latinoamericana para el Estudio del Higado, 2015). A biopsy should be considered for any patient who has discordant results between the 2 modalities that would affect clinical decision making. For example, one shows cirrhosis and the other does not. The need for liver biopsy with this approach is markedly reduced.
Alternatively, if direct biomarkers or vibration-controlled transient liver elastography are not available, the AST-to-platelet ratio index (APRI) or FIB-4 index score can help, (Sebastiani, 2009); (Castera, 2010); (Chou, 2013) although neither test is sensitive enough to rule out substantial fibrosis (Chou, 2013). Biopsy should be considered in those in whom more accurate fibrosis staging would impact treatment decisions. Individuals with clinically evident cirrhosis do not require additional staging (biopsy or noninvasive assessment).
When therapy is deferred, it is especially important to monitor liver disease in these patients. In line with evidence-driven recommendations for treatment of nearly all HCV-infected patients, several factors must be taken into consideration if treatment deferral is entertained or mandated by lack of medication access. As noted, strong and accumulating evidence argue against deferral because of decreased all-cause morbidity and mortality, prevention of onward transmission, and quality-of-life improvements for patients treated regardless of baseline fibrosis. Additionally, treatment of HCV infection may improve or prevent extraheptatic complications, including diabetes mellitus, cardiovascular disease, renal disease, and B-cell non-Hodgkin lymphoma, (Conjeevaram, 2011); (Hsu, 2015); (Torres, 2015) which are not tied to fibrosis stage (Allison, 2015); (Petta, 2016). Deferral practices based on fibrosis stage alone are inadequate and shortsighted.
Fibrosis progression varies markedly between individuals based on host, environmental, and viral factors (Table 1) (Feld, 2006). Fibrosis may not progress linearly. Some individuals (often those aged >50 years) may progress slowly for many years followed by an acceleration of fibrosis progression. Others may never develop substantial liver fibrosis despite longstanding infection. The presence of existing fibrosis is a strong risk factor for future fibrosis progression. Fibrosis results from chronic hepatic necroinflammation, and thus a higher activity grade on liver biopsy and higher serum transaminase values are associated with more rapid fibrosis progression (Ghany, 2003). However, even patients with normal ALT levels may develop substantial liver fibrosis over time (Pradat, 2002); (Nutt, 2000). The limitations of transient elastography and liver biopsy in ascertaining the progression of fibrosis must be recognized.
Host factors associated with more rapid fibrosis progression include male sex, longer duration of infection, and older age at the time of infection (Poynard, 2001). Many patients have concomitant nonalcoholic fatty liver disease, and the presence of hepatic steatosis with or without steatohepatitis on liver biopsy, elevated body mass index, insulin resistance, and iron overload are associated with fibrosis progression (Konerman, 2014); (Everhart, 2009). Chronic alcohol use is an important risk factor because alcohol consumption has been associated with more rapid fibrosis progression (Feld, 2006). A safe amount of alcohol consumption has not been established. Cigarette smoking may also lead to more rapid fibrosis progression. For more counseling recommendations, please see Testing and Linkage to Care.
Immunosuppression leads to more rapid fibrosis progression, particularly HIV/HCV coinfection and solid organ transplantation (Macias, 2009); (Konerman, 2014); (Berenguer, 2013). Therefore, immunocompromised patients should be treated even if they have mild liver fibrosis at presentation.
Level of HCV RNA does not correlate with stage of disease (degree of inflammation or fibrosis). Available data suggest that fibrosis progression occurs most rapidly in patients with HCV genotype 3 infection (Kanwal, 2014); (Bochud, 2009). Aside from coinfection with HBV or HIV, no other viral factors are consistently associated with disease progression.
Although an ideal interval for assessment has not been established, annual evaluation is appropriate to discuss modifiable risk factors and to update testing for hepatic function and markers for disease progression. For all individuals with advanced fibrosis, liver cancer screening dictates a minimum of evaluation every 6 months.
When and in Whom to Initiate HCV Therapy Table 1. Factors Associated With Accelerated Fibrosis Progression
HCV genotype 3
Changes made July 6, 2016.