TRATAMIENTO DE LA HEPATITIS C (Revisión Up To Date) GUIDELINES — Guidelines for the diagnosis and management of HCV infection were released jointly by the American Association for the Study of Liver Diseases (AASLD) and the Infectious Diseases Society of America (IDSA) in 2014 and can be accessed at hcvguidelines.org [2]. The discussion in this topic is generally consistent with those guidelines. Other guidelines include treatment recommendations from the European Association for the Study of the Liver (EASL), which was published in 2014 [3], and United Kingdom consensus guidelines, which were updated in 2014 [4]. World Health Organization (WHO) also released guidelines in 2014 on screening and treatment of HCV, intended primarily for clinicians and policy-makers in low- and middle-income countries [5]. DEFINITIONS — Specific terms have been used to define patient populations based on their exposure and prior response to therapy: ●Treatment-naïve: Patients who have never received any treatment for HCV ●Prior relapsers: Patients who had an undetectable viral load at the end of a prior attempt at treatment (end of treatment response) but who did not achieve a sustained virologic response (negative HCV RNA 24 weeks after completing treatment) ●Partial responders: Patients who achieved a 2 log10 drop in HCV RNA by week 12 of treatment with peginterferon and ribavirin but who did not achieve an end of treatment response ●Null responders: Patients who did not achieve a 1 log10 reduction in HCV RNA by week 4 or a 2 log10 drop in HCV RNA by week 12 of treatment with peginterferon and ribavirin ●Protease inhibitor failures: Patients who did not respond to treatment with boceprevir, telaprevir, or simeprevir in combination with peginterferon and ribavirin Throughout this topic, peginterferon refers specifically to peginterferon-alfa. DECIDING WHOM AND WHEN TO TREAT — With the growing availability of highly effective interferon-free regimens for genotype 1 infection, a curative all-oral treatment is becoming a possibility for the vast-majority of patients. However, the cost of these new agents prevents universal delivery of antiviral therapy. When resources are constrained, prioritizing patients who may benefit most from antiviral treatment is warranted. These issues are discussed in detail elsewhere. SELECTION OF TREATMENT REGIMENS — Regimen selection for patients with genotype 1 infection should take into account the efficacy, duration, and adverse effect profile of the regimen, potential drug interactions, the patient’s history of prior treatment, and the stage of fibrosis. For the individual patient, insurance and financial issues will also likely be an important consideration. This section discusses regimen selection by treatment history in patients for whom the decision to treat has been made (algorithm 1). The various direct-acting antiviral (DAA)-containing regimens (including interferon-free and interferon-containing regimens) available for treatment of genotype 1 infection have not been studied head to head, but in trials are associated with sustained virologic response (SVR) rates in excess of 80 percent among treatment-naïve patients [6-15]. Interferon-free combination regimens have reported SVR rates in excess of 90 percent. In general, we recommend an interferon-free DAA combination regimen, as it avoids the substantial toxicity associated with interferon use. Of note, a DAA should not be used as monotherapy because of the strong likelihood of treatment failure and the potential to develop resistance. Additional details on the administration and efficacy of the various regimens are found elsewhere. Certain DAAs that are not available in the United States and are thus not discussed in this topic may be available in other resource-rich countries, such as daclatasvir in European countries and daclatasvir and asunaprevir in Japan. Clinicians in those locations are advised to check local guidelines on the optimal use of such agents. If an interferon-free combination DAA regimen is not an option for the patient and the patient cannot or does not wish to defer treatment to await one, then a combination regimen of a DAA with peginterferon plus ribavirin can be used. In such cases, the DAAs sofosbuvir and simeprevir, if available, are preferable to telaprevir or boceprevir because of fewer adverse effects and greater ease of administration. In fact, we rarely use telaprevir and boceprevir-based regimens, only in patients for whom imminent treatment is warranted and who do not have access to other DAAs. These are discussed elsewhere. Treatment-naïve patients — For patients who have never undergone antiviral therapy for HCV infection and are initiating antiviral therapy now, several interferon-free options have comparably high expected efficacy and safety. These are ledipasvir-sofosbuvir, ombitasvir-paritaprevir-ritonavir plus dasabuvir with or without ribavirin, and simeprevir plus sofosbuvir. The choice between them depends primarily on the potential for drug interactions and drug toxicity (eg, if the addition of ribavirin is warranted). Additionally, in the United States, the options will be limited by the individuals insurance provider. If cost or insurance coverage is not an issue, we generally favor the regimen of ledipasvir-sofosbuvir for its favorable adverse effect profile, its minimal drug interactions, and its extreme ease of administration (a single pill once daily) (algorithm 1). ●Ledipasvir-sofosbuvir — For treatment-naïve patients, the duration of this regimen depends on the viral load and the presence of cirrhosis. For patients with a viral load 6 million international units/mL or with cirrhosis, ledipasvir-sofosbuvir is given for 12 weeks. In patients with and without cirrhosis, these regimens result in SVR rates greater than 94 percent [13,16,17]. (See Ledipasvir-sofosbuvir below.) ●Ombitasvir-paritaprevir-ritonavir plus dasabuvir — For treatment-naïve patients, the duration of this regimen and the addition of weight-based ribavirin (1000 mg for those ≤75 kg and 1200 mg for those >75 kg) depend on the infecting subtype and the presence of cirrhosis. For patients with subtype 1a infection, the regimen is given with ribavirin for 12 weeks in patients without cirrhosis and for 24 weeks in patients with cirrhosis. For patients with subtype 1b infection, the regimen is given without ribavirin for 12 weeks in patients without cirrhosis and with ribavirin for 12 weeks in patients with cirrhosis. These regimens result in SVR rates greater than 95 percent [18-20]. SVR rates are especially high for subtype 1b (99 to 100 percent). (See Ombitasvir-paritaprevir-ritonavir and dasabuvir below.) ●Simeprevir plus sofosbuvir — This regimen is given for 12 weeks in patients without cirrhosis and for 24 weeks in patients with cirrhosis. There is no clear efficacy benefit to balance the additional cost or potential side effects of adding ribavirin to the regimen, although it is reasonable to use weight-based ribavirin in select populations. The regimen of simeprevir plus sofosbuvir also has an expected SVR rate that exceeds 90 percent, although it has been formally studied in fewer patients [12]. (See Simeprevir plus sofosbuvir below.) We do not use the regimen of sofosbuvir and ribavirin for 24 weeks in genotype 1 infected patients because of the longer treatment duration and lower expected SVR rates compared with other regimens. Treatment-experienced patients Prior peginterferon and ribavirin failure — For patients who have failed prior treatment with peginterferon and ribavirin and are initiating antiviral therapy now, several interferon-free regimens have comparably high expected efficacy and safety. The options are the same as for treatment-naïve patients and are ledipasvir-sofosbuvir, ombitasvir-paritaprevir-ritonavir plus dasabuvir with or without ribavirin, and simeprevir plus sofosbuvir. The choice between them depends primarily on the potential for drug interactions and drug toxicity (eg, if the addition of ribavirin is warranted). Additionally, in the United States, the options will be limited by the individuals insurance provider. If cost or insurance coverage is not an issue, we generally favor the regimen of ledipasvir-sofosbuvir for its favorable adverse effect profile, its minimal drug interactions, and its extreme ease of administration (a single pill once daily) (algorithm 1). ●Ledipasvir-sofosbuvir — Among treatment-experienced patients, the duration of ledipasvir-sofosbuvir depends on the presence of cirrhosis. For those without cirrhosis, the regimen is given for 12 weeks. This results in an approximately 95 percent SVR rate, which was not substantially improved by increasing the duration to 24 weeks [15]. In contrast, for those with cirrhosis, the regimen is given for 24 weeks. This results in an approximately 100 percent SVR rate, compared with 86 percent with only 12 weeks [15]. Alternatively, ledipasvir-sofosbuvir plus weight-based ribavirin (1000 mg for those ≤75 kg and 1200 mg for those >75 kg) given for 12 weeks has comparable efficacy to ledipasvir-sofosbuvir for 24 weeks in patients with cirrhosis. (See Ledipasvir-sofosbuvir below.) ●Ombitasvir-paritaprevir-ritonavir plus dasabuvir — The duration of this regimen and the addition of weight-based ribavirin depend on the infecting subtype and the presence of cirrhosis. For patients with subtype 1a infection, the regimen is given with ribavirin for 12 weeks in patients without cirrhosis and for 24 weeks in patients with cirrhosis. For patients with subtype 1b infection, the regimen is given without ribavirin for 12 weeks in patients without cirrhosis and with ribavirin for 12 weeks in patients with cirrhosis. These regimens result in SVR rates greater than 94 percent [19,21,22]. (See Ombitasvir-paritaprevir-ritonavir and dasabuvir below.) ●Simeprevir plus sofosbuvir — This regimen is given for 12 weeks in treatment-experienced patients without cirrhosis and for 24 weeks in those with cirrhosis. In patients with prior null response, this regimen resulted SVR rates in excess of 90 percent, even in the setting of advanced fibrosis [12]. Patients with prior partial response are expected to have comparable response rates. There is no clear efficacy benefit to balance the additional cost or potential side effects of adding ribavirin to the regimen, although it is reasonable to use weight-based ribavirin in select populations. (See Simeprevir plus sofosbuvir below.) We do not use the regimen of sofosbuvir and ribavirin for 24 weeks in genotype 1 infected patients because of the lower expected SVR rates compared with other regimens. Prior protease inhibitor failures — For patients who have failed prior treatment with a protease inhibitor-containing regimen (ie, simeprevir, telaprevir, or boceprevir plus peginterferon and ribavirin) and are initiating antiviral therapy now, we favor ledipasvir-sofosbuvir (algorithm 1). In such patients, ledipasvir-sofosbuvir is given for 12 weeks to those without cirrhosis and 24 weeks to those with cirrhosis. For patients with cirrhosis who are expected to tolerate ribavirin (ie, no anemia or renal impairment), an equally effective regimen is ledipasvir-sofosbuvir plus weight based ribavirin for 12 weeks. These regimens result in SVR rates from 96 to 100 percent [15,23]. They are discussed in greater detail elsewhere. If a patient has failed one protease inhibitor, treatment with another protease inhibitor (eg, paritaprevir or simeprevir) is not recommended due to likely resistance development and thus subsequent treatment failure. Thus, the regimens of ombitasvir-paritaprevir-ritonavir plus dasabuvir or simeprevir plus sofosbuvir are not options for these patients. Sofosbuvir and ribavirin has not been studied in such patients, but presumably would achieve a similarly suboptimal response rate as seen in treatment-naïve individuals. Prior sofosbuvir-based regimen failure — Patients who relapsed following treatment with certain sofosbuvir-containing regimens may be successfully retreated with a ledipasvir-sofosbuvir regimen, based on results of small studies [24,25]. For patients who have failed prior sofosbuvir plus ribavirin with or without peginterferon and cannot wait for additional data (ie, in patients with advanced liver disease who are deemed to warrant imminent treatment), we attempt retreatment with ledipasvir-sofosbuvir plus ribavirin for 24 weeks [2]. (See Ledipasvir-sofosbuvir below.) Although there are no data yet on using ledipasvir-sofosbuvir in patients who have failed simeprevir plus sofosbuvir, it plausibly would have similar efficacy in this population. An alternative is to wait for additional data or for other novel interferon-free regimens that could potentially have activity in this setting. ADDITIONAL TREATMENT CONSIDERATIONS Patients with cirrhosis Compensated — Because of the risk of progression to more severe liver disease, we treat patients with advanced fibrosis or compensated cirrhosis promptly if highly effective interferon-free direct-acting antiviral (DAA) regimens are available. Although interferon-free regimens appear effective and safe for such patients, treatment should generally be undertaken in consultation with an expert in managing patients with cirrhosis. The regimen selection depends on the prior treatment history, as discussed above. In locations where interferon-free regimens are not available, however, the decision to treat with an interferon-based regimen depends on the balance between the risk of deferring therapy and the risk of serious adverse effects of such a regimen, which can be substantial in this population. Treatment with an interferon-containing regimen should be undertaken in consultation with an expert in managing patients with cirrhosis. Some studies have suggested an excess of serious adverse events, including decompensating events and death, among patients with cirrhosis when peginterferon and ribavirin were given with first-generation HCV protease inhibitors [26,27]. In the CUPIC study, which included 455 patients with HCV genotype 1 and compensated cirrhosis, 45 percent of those treated with telaprevir and 33 percent of those treated with boceprevir experienced serious adverse events, including death [26]. Predictors of serious adverse events included platelet count ≤100,000/microL and albumin 40 mL/min to receive ledipasvir-sofosbuvir plus ribavirin for 12 or 24 weeks [28]. SVR rates were high (87 to 89 percent), and although serious adverse events were common (10 to 42 percent, depending on the level of decompensation and duration of the regimen), few were deemed related to the treatment. Of note, because of increased levels of simeprevir in the setting of Child B and C cirrhosis, the agent is not recommended in patients with hepatic impairment. Recurrence after liver transplantation — Recurrence of HCV occurs in more than 95 percent of patients after liver transplantation. Management of HCV recurrence post-transplant is discussed elsewhere. Patients with renal impairment — The selection of a HCV antiviral regimen for patients with renal disease depends upon the extent of renal impairment in addition to the genotype, extent of underlying liver disease, and history of past antiviral treatment. Levels of sofosbuvir and its metabolite are substantially higher in patients with severe renal impairment (estimated glomerular filtration rate [eGFR] 75 kg. ●For patients receiving peginterferon alfa-2b, the ribavirin dose is 800 mg for patients weighing 85 to 105 kg, and 1400 mg for >105 kg. MONITORING DURING INTERFERON-FREE REGIMENS — Clinical assessment during treatment with an interferon-free regimen focuses on adherence to the regimen and emergence of adverse effects. Monitoring viral levels during treatment with interferon-free regimens has minimal prognostic value, as almost all patients without cirrhosis in the large clinical trials of interferon-free regimens achieve an undetectable HCV viral level by four weeks of treatment. Thus, the main reason to check viral levels during therapy is to assess adherence to the regimen. Given the expense of the medicines and the potential risk of viral resistance with inappropriate use, we check HCV RNA quantitative testing at weeks 4 and 12 (end of treatment) in clinical practice. The joint guidelines from the AASLD and IDSA recommend rechecking HCV RNA quantitative testing at week 6 if the week 4 level is detectable and discontinuing therapy if the level has increased by >1 log [2]. Although there are no direct clinical data to support this practice, we agree that this is an appropriate approach. Although a week 12 (or end of treatment) viral level is undetectable in the vast majority of treated patients and many providers choose not to check this, documentation of a detectable level at this time point may reflect incomplete adherence to the regimen and can help distinguish between viral breakthrough and relapse. To monitor for potential drug toxicity, we check basic laboratory tests (eg, complete blood count, basic chemistry panel, and liver enzyme and bilirubin levels) at weeks 1 to 2, 4, 8, and 12, with more frequent monitoring for concerning results or trends. If an increase in the alanine aminotransferase exceeds 10-fold the baseline level or is accompanied by symptoms or hyperbilirubinemia, treatment discontinuation is recommended [2]. FOLLOW-UP AFTER TREATMENT — Virologic response to treatment should be assessed by checking the viral load at 12 to 24 weeks following the cessation of therapy. SVR is defined by an undetectable viral level at this time point. An undetectable level at week 12 after treatment is generally maintained through week 24. However, a small proportion of patients (approximately two percent) experience virologic relapse between weeks 12 and 24 [81]. Thus, some practitioners also check the viral load at 24 weeks if SVR was determined at 12 weeks. Patients who achieve a sustained virologic response (SVR) who do not have bridging fibrosis or cirrhosis do not require any specific follow-up for their HCV, though some will check an HCV viral load one year after the completion of treatment to confirm that the patient has achieved an SVR. Patients who fail to achieve an SVR should be followed for signs of progression of their liver disease. Patients with bridging fibrosis and cirrhosis, regardless of whether they attain an SVR, warrant ongoing monitoring because they continue to be at risk of hepatocellular carcinoma or other complications of advanced liver disease, which require ongoing surveillance. MAINTENANCE THERAPY IN NONRESPONDERS — Long term maintenance therapy with peginterferon does not halt liver disease progression [82], and maintenance therapy is not recommended for nonresponders. SUMMARY AND RECOMMENDATIONS ●The goal of treatment is to eradicate hepatitis C virus (HCV) RNA, which is predicted by the achievement of a sustained virologic response (SVR), defined by the absence of HCV RNA by polymerase chain reaction six months after stopping treatment. An SVR is associated with a 99 percent chance of being HCV RNA negative during long-term follow-up and can therefore be considered cure of the HCV infection. ●With the growing availability of highly effective interferon-free regimens for genotype 1 infection, a curative all-oral treatment is becoming a possibility for the vast-majority of patients. However, the cost of these new agents prevents universal delivery of antiviral therapy. When resources are constrained, prioritizing patients who benefit most from antiviral treatment is warranted. These issues are discussed in detail elsewhere. (See Patient evaluation and selection for antiviral therapy for chronic hepatitis C virus infection, section on Deciding whom and when to treat.) ●For patients with chronic genotype 1 HCV infection who are initiating antiviral therapy, we recommend an interferon-free regimen instead of an interferon-containing regimen (Grade 1A). Most interferon-free regimens are highly effective for all patient populations and are well tolerated, without the well-known toxicity associated with interferon. For treatment-naïve patients and those who have failed treatment with peginterferon and ribavirin, ledipasvir-sofosbuvir, ombitasvir-paritaprevir-ritonavir plus dasabuvir with or without ribavirin, and simeprevir plus sofosbuvir have comparably high expected efficacy and safety. The choice between them depends primarily on the potential for drug interactions and drug toxicity. Additionally, in the United States, the options will be limited by the individuals insurance provider. If cost or insurance coverage is not an issue, we suggest ledipasvir-sofosbuvir(Grade 2B). ●Ledipasvir-sofosbuvir regimens achieve SVR rates of approximately 95 percent or higher with only mild to moderate side effects, most commonly fatigue or headache. Duration of ledipasvir-sofosbuvir depends on treatment history and the presence of cirrhosis (algorithm 1). Among treatment-naïve patients, treatment duration can be 8 weeks for those without cirrhosis and a viral level
Posted on: Tue, 27 Jan 2015 04:23:00 +0000