November 26, 2013

Gastroenterology
Volume 145, Issue 6 , Pages 1488-1490, December 2013

Paul Y. Kwo, Margaret S. Sozio

published online 28 October 2013.

Philip S. Schoenfeld, Section Editor, John Y. Kao, Section Editor

Chou R, Hartung D, Rahman B, et al. Comparative effectiveness of antiviral treatment for hepatitis C virus infection in adults: a systematic review. Ann Intern Med 2013;158:114–123.

Hepatitis C affects approximately 3.2 million Americans and is a major cause of complications related to chronic liver disease, such as cirrhosis and hepatocellular cancer (Gastroenterology 2002;123:2082–2099). It is also the leading indication for liver transplantation in the United States (Gastroenterology 2010;138:513–521). Treatment for hepatitis C has evolved from interferon in the early 1990s, to dual therapy with pegylated interferon and ribavirin in the early 2000s, to triple therapy with the addition of direct-acting antiviral agents for genotype 1 in 2011 (Hepatology 2009;49:1335–1374).

A number of studies have examined the effectiveness of therapies for hepatitis C and a recent meta-analysis has now examined advantages and disadvantages of interferon-based therapy for hepatitis C (Ann Intern Med 2013;158:114–123). Specifically, a meta-analysis of antiviral therapy for hepatitis C in treatment-naïve patients with genotypes 1, 2, 3, or 4 was performed to determine if patient characteristics or type of antiviral therapy affected sustained virologic response (SVR) rate. In addition, the harmful effects of therapy as well as clinical outcomes were examined.

The authors noted a slightly higher likelihood of SVR in 7 studies across genotypes 1–4 with pegylated interferon alfa-2a therapy compared with pegylated interferon alfa-2b with an absolute difference of 8 percentage points and a pooled relative risk (RR) of 0.87 (95% confidence interval [CI], 0.80–0.95). When the SVR rates were examined from 6 trials, lowering the dose of pegylated interferon alfa-2b from the standard dose of 1.5 μg/kg resulted in slightly lower SVR rates in genotype 2/3 patients with pooled RR of 0.90 (95% CI, 0.81–0.99). Comparison of weight-based dosing of ribavirin with fixed dosing in patients with genotypes 2 and 3 found no effect on SVR across 3 trials, although one showed lower SVR rates with reduced doses of ribavirin in patients with advanced fibrosis. Moreover, the SVR rates in genotypes 2 and 3 did not improve by extending treatment from 24 to 48 weeks in 2 trials. Higher SVR rates were noted in genotype 2/3 patients when treatment duration was 24 weeks versus truncating therapy at 12–16 weeks (pooled RR, 1.2; 95% CI, 1–1.3). However, the SVR rate was not affected by 12- to 16-week treatment durations in those patients with rapid virologic response.

Boceprevir, 1 of 2 currently approved protease inhibitors, in conjunction with pegylated interferon alfa-2b and ribavirin, was shown to have higher SVR rates than dual therapy. A 4-week lead-in with dual therapy followed by 44 weeks of triple therapy with boceprevir had an absolute increase in SVR of 31 percentage points (95% CI, 23–39) compared with dual therapy. Changing the regimen to eliminate the lead in period or shortening the length of treatment did not improve SVR. Six trials looked at the use of the protease inhibitor telaprevir in treating hepatitis C. Telaprevir was used with either pegylated interferon alfa-2a or -2b and ribavirin for the first 8–12 weeks, followed by dual therapy for the duration of treatment. Forty-eight weeks of telaprevir-based triple therapy increased the SVR rate by 22 percentage points (95% CI, 13–31). Three trials with telaprevir found response-guided therapy, defined as undetected HCV viral load at weeks 4 and 12 for a total treatment of 24 weeks, was more effective than dual therapy. One trial with boceprevir showed similar efficacy between response-guided therapy (defined as undetected HCV viral load at weeks 8 and 24) for a total of 28 weeks of treatment and fixed duration therapy for 48 weeks. Regardless of treatment regimen, SVR rates were lower in advanced fibrosis, higher viral loads, older patients, and black patients across boceprevir and telaprevir studies by approximately 10% compared with those without these features of poor response. Retrospective analyses of boceprevir and telaprevir registration trials have demonstrated that the presence of the favorable interleukin (IL)-28B CC genotype is associated with a higher likelihood of SVR and a 24- to 28-week treatment duration, although these datasets are incomplete (J Hepatol 2011;54:S542–S543; J Hepatol 2011;54:S6–S6).

No difference in rates of withdrawal from therapy was found between pegylated interferon alfa-2a and-2b. Boceprevir-based triple therapy was associated with higher rates of neutropenia compared with dual therapy (33% vs 18%), anemia (25% vs 12%), and dysgeusia (35% vs 13%), whereas telaprevir-based triple therapy was found to be associated with higher risk of anemia (52% vs 39%) and rash (49% vs 35%). However, there were no differences in rates of withdrawal with bocepravir-based therapies compared with dual therapy. Three studies of telaprevir for 24 weeks showed no difference in withdrawal rates compared with dual therapy, whereas only 1 trial of telaprevir-based treatment for 24–48 weeks found higher rates of withdrawal compared with dual therapy (RR, 3.8; 95% CI, 2.6–5.7).

Examination of the literature found no studies that compared long-term outcomes between treatment regimens, although no difference was found in 6-month mortality among the available regimens that were compared. Nineteen cohort studies looked at associations between SVR, regardless of the treatment regimen used, and long-term outcomes and found lower all-cause mortality with SVR. One study that controlled for confounders showed lower all-cause mortality in patients who achieved SVR stratified by genotypes: Genotype 1 had a hazard ratio (HR) of 0.71 (95% CI, 0.60–0.86), genotype 2 had a HR of 0.62 (95% CI, 0.44–0.87), and genotype 3 had a HR of 0.51 (95% CI, 0.35–0.75), versus those who did not achieve SVR.

Comment

Hepatitis C, particularly genotype 1, has traditionally been difficult to treat with pegylated interferon and ribavirin owing to suboptimal SVR rates and associated side effects. However, with improved understanding of viral kinetics and identification of polymorphisms including IL-28B, clinicians may now identify patients who are at greater likelihood of achieving SVR with interferon-based therapies, with overall SVR rates for hepatitis C genotypes 1–3 of approximately 70% using protease-based triple therapy for genotype 1 and dual therapy for genotypes 2 and 3 (Nature 2009;461:399–401). Moreover, additional classes of direct-acting antivirals are in development in combination with pegylated interferon/ribavirin, as well as without pegylated interferon and ribavirin with SVR rates in some trials are >90% and treatment durations ranging from 8 to 24 weeks (N Engl J Med 2012;366:216–224).

In their meta-analysis, Chou et al analyze available data from pegylated interferon-based trials from the past 6 years to provide an overview for the practitioner treating hepatitis C with interferon based therapies. As with any meta-analysis, there are limitations in the quality and heterogeneity of the studies, making it more difficult at times to draw conclusions. In addition, further data have become available that make comparing across studies difficult including the IL-28B genotype status in genotype 1 populations, and the recognition that genotype 3 remains more problematic to treat compared with genotype 2 (Aliment Pharmacol Ther 2008;28:397–404). However, the analysis by Chou et al confirms many of today's standard practices and clarifies much of the available data.

Chou et al found that pegylated interferon alfa-2b had slightly lower rates of SVR in genotypes 1–4 than pegylated interferon alfa-2a; however, the absolute difference was low (8 percentage points) and the 95% CI approached 1 (0.80–0.95). Similar findings were noted in a Cochrane database review, where the absolute difference was 6 percentage points with a RR of 1.11 (95% CI, 1.04–1.19), again across all genotypes (Hepatology 2010;51:1176–1184). However, the largest available trial with 3070 genotype-1–infected patients showed no difference in SVR between pegylated interferon alfa-2a and -2b (N Engl J Med 2009;361:580–593). To date, major society guidelines have not recommended one interferon over another; therefore, clinicians may choose either interferon to treat their HCV- infected patients (Hepatology 2011;54:1433–1444).

Chou et al's study suggested that weight-based dosing of ribavirin does not improve SVR in genotypes 2 or 3. However, given that genotype 3 is more difficult to treat than genotype 2, even in the direct acting antiviral era, additional studies should address whether weight-based dosing of ribavirin may lead to better SVR rates in combination with interferon or a direct-acting antiviral than flat-dose ribavirin in genotype 3 (N Engl J Med 2013;368:1867–1877). Of note, the 2 pegylated interferons differ with regard to ribavirin dose for genotypes 2/3 with pegylated interferon alfa 2a being combined with 800 mg of ribavirin and pegylated interferon alfa 2b being combined with 800–1400 mg of ribavirin.

It was demonstrated that 24 weeks of dual therapy for genotype 2 or 3 is as efficacious as 48 weeks, confirming current recommendations. In addition, 12–16 weeks of therapy for genotypes 2 or 3 in patients with rapid viral response provided similar rates of SVR as compared with treatment for 24 weeks, although a study of almost 1500 subjects, which showed that 24 weeks of treatment with fixed dose ribavirin was superior to 16 weeks in patients with rapid viral response, was not included in that analysis (N Engl J Med 2007;357:124–134). Additionally, relapse rates are higher in groups treated for 12–16 weeks (6%–30% compared with 3%–13% with 24 weeks of treatment), and this should be taken into account when deciding duration of treatment in this population. In our practice treating genotypes 2 and 3, we consider the overall likelihood of patient response to treatment in conjunction with whether they have achieved rapid virologic response to decide whether or not to consider shortening therapy. In the era of pegylated interferon and ribavirin, we are willing to truncate therapy in genotype 2 patients who achieve rapid viral response and do not have cirrhosis and we use weight-based ribavirin regardless of pegylated interferon type. For genotype 3, we encourage all patients to complete 24 weeks of therapy with weight-based ribavirin regardless of type of interferon.

Both telaprevir and boceprevir were found to be more efficacious at treating hepatitis C than dual therapy. However, triple therapy with telaprevir resulted in a higher rate of anemia and rash compared with dual therapy, with no change in withdrawal rates in patients treated for 24 weeks. Triple therapy with boceprevir also had no increased rates of withdrawal compared with dual therapy, although boceprevir regimens were associated with higher rates of neutropenia, anemia, dysgeusia, and thrombocytopenia. More recently, studies have suggested that real-world experiences with triple therapy in a less selective population may result in higher rates of withdrawal from therapy. One preliminary study of veterans with hepatitis C treated with either boceprevir or telaprevir found approximately 10% higher rates of withdrawal overall, although side effects were similar. Futility rates in the veteran population treated with telaprevir were double that seen in clinical trials (Clin Gastroenterol Hepatol 2013;11:1021–1027). Moreover, a recent report has suggested that those with platelet counts <100,000/mL and an albumin <3.5 g/dL are at increased risk for significant side effects with triple therapy (J Hepatol 2013;59:434–441). The meta-analysis paper did not comment on the efficacy of pegylated interferon alfa-2a compared with interferon alfa-2b in triple therapy. One trial has been reported with pegylated interferon alfa-2a and boceprevir with a similar SVR rate noted in nonresponders to that found with pegylated interferon-alfa-2b–based therapy with bocepravir (Clin Gastroenterol Hepatol 2013;11:81–87.e84; N Engl J Med 2011;364:1207–1217). One trial with telaprevir utilized both pegylated interferons and found no difference in SVR rates (Gastroenterology 2011;140:459–468 e451).

Chou et al's study did not evaluate therapy in treatment experienced patients, but this remains an important area of investigation. SVR rates in patients with genotype 1 who were previously treated with dual therapy increased to 55%–66% with boceprevir compared with 21% with pegylated interferon and ribavirin (N Engl J Med 2011;364:1207–1217). Telaprevir also had improved response rates in previously treated patients, with SVR rates ranging from 29% to 88% SVR in null responders and relapsers, respectively, compared with 5%–24% SVR in patients treated with dual therapy (N Engl J Med 2011;364:2417–2428) Thus, in the treatment of nonresponders, relapsers to a previous course of interferon-based therapy will have a high opportunity for SVR with telaprevir- or bocepravir-based therapy. Null responders require new approaches and some centers have used a 4-week pegylated interferon lead-in as a tool to gauge interferon responsiveness in difficult to treat populations with those who have greater than a log10 continuing with addition of either boceprevir or telaprevir and those with less than a log10 reduction stopping therapy altogether. The polymorphism IL-28B plays little role in nonresponders with accurate viral kinetics and is not required. In those without viral kinetics who have been treated, a lead-in can be used to determine interferon responsiveness. No direct-acting antiviral therapy that has been approved by the US Food and Drug Administration is available for treatment of genotypes 2 or 3al, though sofosbuvir, a nucleotide polymerase inhibitor, is expected to be approved with ribavirin. A recent study looking at 16 weeks of sofosbuvir and ribavirin in treatment-experienced patients with genotypes 2 or 3 found response rates of 73% compared with response rates of 25% in historical controls (N Engl J Med 2013;368:1867–1877).

Although no studies comparing long-term outcomes of different treatment regimens are available in the literature, Chou et al reviewed 19 cohort studies evaluating long-term outcomes associated with SVR. Although the quality of the studies ranged from poor to fair, all studies found a lower risk of all-cause mortality in patients who achieved SVR, regardless of fibrosis level, with HRs ranging from 0.07 to 0.71 depending on the study and genotype. This supports the findings in long-term histologic follow-up studies, where interferon therapy has been associated with reduced rates of fibrosis (Gastroenterology 2002;122:1303–1313). These longer-term clinical outcomes are important and will constitute an important endpoint for hepatitis C therapeutic trials. This compliments ongoing efforts to improve therapies for hepatitis C and the recent recommendations of population-based screening for hepatitis C by the US Centers for Disease Control and Prevention to identify those who will benefit from therapy (MMWR Recomm Rep 2012;61:1–32).

Preliminary studies suggest that newer, interferon-free therapies will be more efficacious, better tolerated with markedly improved safety profiles, and associated with shorter treatment duration, although many parts of the world will continue to use interferon as part of hepatitis C therapy for years to come. With better outcomes available to more hepatitis C–infected individuals, the meta-analysis by Chou et al provides further evidence that successful therapy for hepatitis C improves clinical outcomes, supports the importance of diagnosing and treating hepatitis C in the general population, and, in addition, confirmed many of the findings in current practice guidelines. Although response rates are better with triple therapy, “difficult-to-treat” groups remain difficult to treat—confirming the continued need for better therapies that are better tolerated, especially in those with cirrhosis. The meta-analysis confirms our current practice in the treatment of hepatitis C in the United States, although this is about to undergo a dramatic change. However, many countries that still utilize interferon-based therapy will benefit from this analysis and all of those who treat hepatitis C can tell their patients that SVR is indeed associated with better outcomes that will only improve as we move forward to reduce the worldwide burden of chronic hepatitis C.

PII: S0016-5085(13)01503-5

doi:10.1053/j.gastro.2013.10.029

© 2013 AGA Institute. Published by Elsevier Inc. All rights reserved.

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