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"Treatment is recommended for all patients with chronic
HCV infection" - HCV Guidelines Updated Oct 22 2015
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http://hcvguidelines.org/full-report/when-and-whom-initiate-hcv-therapy
, except those with short life expectancies that cannot be remediated by treating HCV, by transplantation, or by other directed therapy. Patients with short life expectancies owing to liver disease should be managed in consultation with an expert.
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, 2015) Deferral practices based on fibrosis stage alone are inadequate and shortsighted.
Experts at the American Association for the Study for Liver Diseases (AASLD) and the Infectious Diseases Society of America (IDSA) have updated
HCVguidelines.org, a website developed to provide up-to-date guidance on the treatment of hepatitis C virus (HCV). Based on expanded "real-world" experience with the tolerability and efficacy of newer HCV medications, the section on "When and in Whom to Initiate HCV Therapy" no longer includes tables that offer recommendations on how to prioritize patients for treatment.
You can learn more about the update here:
http://www.idsociety.org/HCV_Therapy_Update/
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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 sections on HIV/HCV coinfection, cirrhosis, liver transplantation, and 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.
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. (0vrehus, 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. (0vrehus, 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)
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 RBV 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 replacement 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)
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) 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. (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.
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.
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); (Brau, 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. (Pineda, 2005); (Merchante, 2006); (Terrault, 2012)
Press Release-
Hepatitis C Guidance Underscores the Importance of Treating HCV Infection: Panel Recommends Direct-Acting Drugs for Nearly All Patients with Chronic Hepatitis C
Experts at the American Association for the Study for Liver Diseases (AASLD) and the Infectious Diseases Society of America (IDSA) have updated HCVguidelines.org, a website developed in collaboration with the International Antiviral Society-USA (IAS-USA) to provide up-to-date guidance on the treatment of hepatitis C virus (HCV). Based on expanded "real-world" experience with the tolerability and efficacy of newer HCV medications, the section on "When and in Whom to Initiate HCV Therapy" no longer includes tables that offer recommendations on how to prioritize patients for treatment.
"When the direct-acting medications were first introduced, all our knowledge about how these drugs worked came from clinical trials. We needed to gain more experience with their safety before we encouraged all infected persons to initiate therapy. We now have that experience," said panel co-chair David Thomas, MD.
According to the guidance, successful hepatitis C treatment results in sustained virologic response-or virologic cure-and thus would benefit nearly all of those chronically infected with HCV. Previously, the panel of experts who write the guidance had prioritized treatment with the direct-acting anti-virals for those with the greatest need, particularly those with severe liver disease.
Since the panel's initial recommendation, there have been opportunities to treat many of the highest-risk patients and to learn more about the new medications. "There are also expanding data on the benefits of HCV treatment for patients with all stages of disease, including mild liver disease," added panel co-chair Raymond Chung, MD.
Because of the cost of the new drugs, or regional availability of appropriate health care providers, a practitioner may still need to decide which patients should be treated first. Additionally, those with short life expectancies unrelated to HCV infection are not recommended for treatment with these newer therapies, according to the guidance. "However, the goal is to treat all patients as promptly as feasible to improve health and to reduce HCV transmission" said panel co-chair Henry Masur, MD.
"A good relationship between doctor and patient is crucial to achieving the best outcomes with direct-acting therapies. The physician needs to make an assessment of a patient's understanding of the treatment goals and provide education on the importance of adherence to the therapy and follow-up care," added panel co-chair Gary Davis, MD.
Visit www.HCVguidelines.org for updates to this and other sections of the guidance.
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