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Numerous factors associated with response to interferon-based therapy have been identified (Table 40) (Table 41). Although data are limited, because of the importance of the interferon response in patients receiving interferon-containing therapy, most of the same factors likely affect response to DAAs to some degree. Viral factors are limited to viral genotype, HCV RNA titer, and possibly mutations in certain regions of the viral genome. Viral subtype is relevant because differing rates of resistance to protease inhibitors have been noted in patients with genotypes 1a and 1b. In addition, several host factors are associated with response, some of which are fixed, while others may be modifiable.
Table 40. Factors Associated With Reduced Response to Interferon-Based Therapy
Table 41. Factors Associated With Reduced Response to Direct-Acting Antivirals
The underlying reasons behind the significant influence of viral genotype on treatment response are unknown. Different viral genotypes may truly be more and less sensitive to the effects of interferons (and/or ribavirin), or they may influence the host response to infection (eg, gene expression profile), which in turn affects the response to therapy. Responses to interferon-based therapy are greatest with genotype 2, followed by genotype 3, genotype 4, and then genotype 1. Genotypes 5 and 6 are likely similar to genotype 3 or possibly genotype 4, but data on these subtypes are limited. High viral titer is associated with nonresponse and seems to be more relevant with the harder-to-treat genotypes and with genotype 3 infection.
Genotype 1a has a lower barrier to resistance to protease inhibitors, and therefore emergence of resistance is more frequent with this viral subtype than with genotype 1b. The presence of the Q80K substitution in patients with genotype 1a HCV lowered the response rate for simeprevir plus peginterferon/ribavirin and, in the presence of cirrhosis, for simeprevir plus sofosbuvir in phase III trials.[47,152]
The presence of NS5A RAVs at baseline is associated with reduced SVR rates to elbasvir/grazoprevir in patients with genotype 1a HCV infection.[124,126] As a result, the FDA approved elbasvir/grazoprevir regimen for treatment-naive or peginterferon/ribavirin-experienced patients with genotype 1a HCV infection who have baseline NS5A RAVs, specifically NS5A polymorphisms at amino acid positions 28, 30, 31, or 93, is 16 weeks with the inclusion of ribavirin. This is in contrast to the 12-week treatment duration without ribavirin that is indicated for the same population in the absence of baseline NS5A RAVs.
Polymorphisms associated with reduced susceptibility to DAAs have also been reported in NS5B of HCV genotypes 1a and 1b infection from DAA-naive patients.
Response to interferon-free DAA therapy varies by genotype. Some DAA regimens provide pangenotypic activity, although treatment response rates may still differ by genotype and across subpopulations. The baseline level of HCV RNA may also be predictive. Higher baseline levels are associated with an increased risk of relapse with some but not all DAA regimens. Specifically, in the ION-3 study, a higher relapse rate was observed in patients with a baseline HCV RNA > 6 million IU/mL who received only 8 weeks of ledipasvir/sofosbuvir compared with those who received 12 weeks of therapy. It is based on this observation that the FDA has recommended 12 weeks of therapy with ledipasvir/sofosbuvir for treatment-naive patients without cirrhosis but have added that for those with baseline HCV RNA levels < 6 million IU/mL, 8 weeks of therapy can be considered. However, it is notable that this was not a prespecified analysis, and it is challenging to use in clinical practice because of the variability in the HCV RNA assays. Using a defined absolute threshold for HCV RNA may be difficult because repeated testing may give results above or below this threshold, even on the same sample of blood due to the innate variability in quantitative polymerase chain reaction assays. These challenges may discourage the use of HCV RNA levels to define treatment duration in the future. Nonetheless, several large observational studies have demonstrated high SVR rates in qualified patients receiving the 8-week ledipasvir/sofosbuvir in real-world settings.[37,38]
More advanced fibrosis and particularly the presence of cirrhosis is a strong negative predictor of treatment outcome in patients with HCV infection. The reason why cirrhosis is associated with interferon nonresponse is unknown but is likely to be multifactorial. Data from a long-term follow-up study indicated that SVR is associated with reduced long-term, all-cause mortality in patients with chronic HCV infection and advanced fibrosis. The presence of cirrhosis can also reduce responsiveness to DAA therapy, although this is often managed by extending treatment duration.
Genomewide association studies have identified single nucleotide polymorphisms near the IL28B gene that are strongly associated with both spontaneous and interferon-treatment-induced viral clearance.[154-156] The IL28B genotype greatly influences response to interferon-based therapy and so is most relevant in the less interferon-responsive viral genotypes (ie, genotypes 1 and 4). The mechanisms underlying the association between the IL28B genotype and response are unknown.
In clinical studies the addition of telaprevir to peginterferon/ribavirin increased SVR rates across all IL28B genotypes, with the largest increases observed among patients with the CT or TT genotype. Another analysis found that patients with the CC genotype treated with boceprevir had SVR rates that were only marginally higher than that seen in the peginterferon/ribavirin control group. Among patients with the CT or TT genotype, SVR rates were substantially higher with boceprevir-based therapy vs peginterferon/ribavirin alone. The major difference between the results seen with the 2 protease inhibitors for patients with the IL28B CC genotype is in the different response rates in the control groups. It is likely that both protease inhibitors modestly improve SVR rates in patients with the IL28B CC genotype but that the major benefit occurs in those with non-CC genotypes. It is notable that in both studies, most patients with the CC genotype were able to shorten therapy, which is itself a significant benefit, even if SVR rates remain similar to those with peginterferon/ribavirin alone. In treatment-experienced patients who receive protease inhibitors, the IL28B genotype seems to be of minimal importance. Data from clinical trials clearly demonstrate that although IL28B genotype is undoubtedly a factor in the initial response to peginterferon-based therapy, there are factors beyond the IL28B genotype that affect response. Previous response to peginterferon-based therapy takes into account the IL28B genotype and other factors. Therefore, as a reflection of interferon responsiveness, previous response remains the strongest predictor of response to DAA therapy in patients also receiving interferon. At present, therefore, IL28B genotyping is of little value for treatment-experienced patients. Response during the lead-in phase also provides information about overall interferon responsiveness, and in this context, the IL28B genotype becomes less important once the lead-in response is known.
Hepatic gene expression profiling has identified patterns that are strongly associated with treatment response in patients receiving peginterferon/ribavirin. Nonresponders to therapy show up-regulation of interferon-stimulated genes (ISGs) before receiving interferon-based treatment. These ISGs appear to be near-maximally induced; therefore, only minimal further gene induction, or none at all, is seen with interferon treatment.[160,161] The causes of ISG preactivation are unknown but may relate to IL28B genotype. Gene expression profiling may prove useful when considering DAA therapy; however, it is not available for clinical use at the present time.
Interferon-gamma-inducible protein 10 (IP-10, CXCL10) is a chemokine produced by many cell types, including hepatocytes, that drives lymphocytes and other inflammatory cells to sites of active inflammation. Multiple studies have shown that higher IP-10 serum levels are associated with treatment nonresponse in patients receiving interferon-based therapy.[163-165] IP-10 is an interferon-inducible cytokine and may therefore be a serum marker of ISG preactivation in the liver, although the mechanisms relating IP-10 level to treatment response are unclear. IP-10 levels are not sufficient to predict treatment outcome alone; however, IP-10 levels add to the predictive nature of the IL28B genotype. Patients with an unfavorable IL28B genotype and an IP-10 level > 600 pg/mL have a low chance of achieving SVR with peginterferon/ribavirin (24%), compared with those having a low IP-10 level (< 600 pg/mL) and a favorable CC IL28B genotype (89%). Combining IP-10 level with other predictors of response may help identify which patients should be treated, but to date there are few clinical guidelines on how to make best use of IP-10 results. Whether IP-10 levels relate to treatment outcome with DAAs is not known.
Body Mass Index/Insulin Resistance
Increased body mass index, particularly if associated with hepatic steatosis and insulin resistance, is a strong negative predictor of treatment response to peginterferon/ribavirin-based therapy. Increased doses of interferon and ribavirin may partially overcome the effects of increased body weight, but responses in obese and diabetic patients are poor. Encouraging overweight patients to lose weight, ideally at least 10% of their body weight, through diet and exercise may significantly improve treatment outcomes, although this can be difficult to achieve in practice.
Insulin resistance, even in the absence of diabetes or obesity, is strongly associated with treatment outcome with peginterferon/ribavirin therapy; indeed, the effect of significant insulin resistance on treatment outcome is similar to that of viral genotype. Unfortunately, initial trials of insulin-sensitizing agents such as metformin and pioglitazone have not shown significant improvements in HCV treatment outcome in patients receiving peginterferon/ribavirin.[170,171] Weight loss can improve insulin sensitivity and therefore should be encouraged in overweight patients before starting therapy.
Notably, data from a 2012 exploratory analysis of 147 patients treated with telaprevir-containing triple therapy demonstrated that baseline insulin resistance did not influence virologic response rate at any time point. The addition of the protease inhibitor may overcome the negative effect of insulin resistance on SVR.
Coffee, Vitamin D, and S-Adenosyl Methionine
Increased coffee consumption has been associated with reduced progression of preexisting liver diseases and lower risk of hepatocellular carcinoma. Data from the HALT-C trial showed that patients who consumed more than 3 cups of coffee daily during peginterferon/ribavirin therapy had improved early viral kinetics and higher rates of SVR. Although this finding was derived from a study of more than 800 patients, confirmation from other cohorts would be valuable.
Small trials have reported that low vitamin D levels are associated with nonresponse to interferon-based therapy. In vitro data suggest that vitamin D improves interferon signaling and may have direct antiviral effects. A small, randomized study of vitamin D supplementation conducted in 72 patients with genotype 1 HCV infection showed improved virologic responses to peginterferon/ribavirin therapy. Confirmatory data on the role of vitamin D in HCV treatment responses are awaited.
S-adenosylmethionine has been shown to improve interferon signaling, and a study in previous nonresponders to interferon-based therapy showed that supplementation with S-adenosylmethionine improved early viral kinetics with a modest improvement in rates of SVR.