Infection in Patients With Chronic Hepatitis C
Infection in Patients With Chronic Hepatitis C
The results of this study further confirm that there is no association between the onset of bacterial infection and neutropenia in patients with compensated CHC undergoing antiviral-PegIFNa-based therapy. In addition, our data clearly indicate that cirrhosis is the main factor that predisposes to the development of infection.
The strong correlation between neutropenia and infection is well documented especially in patients with haematological malignancies or neutropenia due to chemotherapy. However, in patients with CHC who develop neutropenia under treatment with pegIFNa and ribavirin but have no other predisposing factor for bacterial infections, it is still debatable whether they are at higher risk of infections. On the other hand, the summary of pegIFNa characteristics recommends that low baseline white blood or neutrophil counts should be considered as contraindication for treatment initiation and that pegIFNa dosing should be reduced or discontinued in patients who develop different grades of neutropenia during therapy mainly due to the fear of bacterial infections. These recommendations have been followed in almost all clinical trials. However, factors playing an important role in the risk of infection in patients with cancer, such as alterations in the function of many organs or mucosal damage, are absent in cases with CHC. As CHC is a curable disease with the majority of patients achieving viral eradication, it is mandatory to try to apply treatment in as many patients as they can tolerate it.
In our study, we analysed data from a sizable real life cohort of patients with 318 treatment courses. Worth mentioning is the fact that we did not obtain data from patients treated within clinical studies, while we included in the analysis patients with comorbitities such as diabetes that may increase the risk of infection. We found no association between rates of infection and NNC (<1000 or <750 cells/μL) even after the adjustment for known or possible confounders. Five of eight patients with severe infection had neutrophils <750 cells/μL and none <500 cells/μL. Our results are in accordance with the data reported by Soza et al., Antonini et al. and Cooper et al., but not with the results of Puoti et al. suggesting an independent association between infections and neutropenia. Comparisons of the data from the above studies are difficult due to different patient population, different definitions and dose or schedule of the treatment.
We did not observe any death in our cohort, which is in agreement with all previous reports and with a large survey of 11 241 patients treated with IFNa in which only one death was reported in a cirrhotic patient due to sepsis.
Another important finding of our study is the significant association between severity of liver damage and infections. It is well established that patients with decompensated liver disease are at particular risk of bacterial infections during treatment with PegIFNa and ribavirin. We found that the only variable independently associated with the risk of infection was the presence of cirrhosis at baseline. Patients with cirrhosis had fivefold higher risk of infection during treatment compared to patients without cirrhosis independently of NNC and baseline WBC. These results are in contrast with the results of Cooper et al. and Antonini et al.; both of these small studies failed to show that cirrhosis is associated with higher risk of infection. It is however noteworthy that Roomer et al. in a similar cohort of 321 patients with hepatitis C found a trend towards a higher risk of infections in patients with cirrhosis. The retrospective design and the differences in the populations among studies might be possible explanations of the discordance.
As the risk of infection during anti viral therapy does not correlate with the NNC or WBC, an alternative hypothesis should be sought. PegIFNa has been shown to affect the function of neutrophils by increasing the oxidative surge and chemotaxis, while advanced liver disease can affect the host immune system with impaired function of reticuloendothilial system and complement. More data are needed to answer the questions regarding the effects of IFNa on the function of neutrophils in patients with different stages of CHC.
An interesting observation was that all infections developed between 3 and 6 months of treatment, with a median time of 17 weeks. This is in accordance with other reports and underlines the need for closer follow-up particularly in patients with advanced fibrosis during the first months of treatment.
It might be argued that neutropenia during treatment with pegIFNa is more common and intense in patients with cirrhosis. In addition, patients with cirrhosis have lower number of WBC or neutrophils before treatment initiation. In our study, 6.3% of patients had baseline WBC <4000/μL with 75% of them having cirrhosis. Although the mean reduction in WBC during therapy was significantly higher in noncirrhotics than cirrhotics, the number of patients who developed neutropenia was not significantly different between these two groups. In multivariate analysis, we found that baseline WBC count was the only independent factor associated with the risk of neutropenia during treatment. In particular, the risks of NNC <1000 or <750 cells/μL during treatment were 26-fold and 54-fold higher in patients with baseline WBC <5000 than ≥5000 cells/μL. This finding supports previous results from a small study by Renou et al.
Despite the relatively large sample size and the clear inclusion and exclusion criteria, our study has some limitations. Specific statistical care should have been taken as not all of the submitted subjects were independent of each other. Nevertheless, the small percentage of these cases in relation to the total sample, and the fact that in patients who were administered more than one treatment course the infection occurrence was no more than one per subject, makes this limitation rather insignificant. To reinforce our results, we ran the analysis including only the first treatment course of each subject without significant differentiation in our results.
In conclusion, our findings support that there is no association between on-therapy neutropenia and development of infection in CHC patients with well-compensated liver disease who are treated with a pegIFNa-based regimen. Our results reinforce the reports from few previous retrospective studies and provide supporting evidence to re-examine the dose-reduction policy or the use of growth factors in cases with neutropenia. Most importantly, our results indicate that cirrhosis is the main factor associated with a higher risk of infection during antiviral treatment. These findings remain of clinical significance in the era of the triple combination with the first-generation HCV protease inhibitors which have been recently used for the treatment of patients with genotype 1. From the existing experience, the new triple regimes seem to have important limitations and to increase toxicity. Noteworthy, in the French early access programme of boceprevir-or telaprevir-based triple therapy including only patients with cirrhosis, severe infections were reported in 24 (4.8%) of 497 patients, while there were six deaths (2.8%) mostly due to sepsis (five of six). Therefore, physicians should keep high index of suspicion for infections especially in patients with cirrhosis who receive regimens including pegIFNa, independently of WBC and neutrophil counts. Careful assessment of liver damage before therapy and close monitoring during therapy are essential, particularly for candidates of triple therapy, to minimize the detrimental consequences of infections.
Discussion
The results of this study further confirm that there is no association between the onset of bacterial infection and neutropenia in patients with compensated CHC undergoing antiviral-PegIFNa-based therapy. In addition, our data clearly indicate that cirrhosis is the main factor that predisposes to the development of infection.
The strong correlation between neutropenia and infection is well documented especially in patients with haematological malignancies or neutropenia due to chemotherapy. However, in patients with CHC who develop neutropenia under treatment with pegIFNa and ribavirin but have no other predisposing factor for bacterial infections, it is still debatable whether they are at higher risk of infections. On the other hand, the summary of pegIFNa characteristics recommends that low baseline white blood or neutrophil counts should be considered as contraindication for treatment initiation and that pegIFNa dosing should be reduced or discontinued in patients who develop different grades of neutropenia during therapy mainly due to the fear of bacterial infections. These recommendations have been followed in almost all clinical trials. However, factors playing an important role in the risk of infection in patients with cancer, such as alterations in the function of many organs or mucosal damage, are absent in cases with CHC. As CHC is a curable disease with the majority of patients achieving viral eradication, it is mandatory to try to apply treatment in as many patients as they can tolerate it.
In our study, we analysed data from a sizable real life cohort of patients with 318 treatment courses. Worth mentioning is the fact that we did not obtain data from patients treated within clinical studies, while we included in the analysis patients with comorbitities such as diabetes that may increase the risk of infection. We found no association between rates of infection and NNC (<1000 or <750 cells/μL) even after the adjustment for known or possible confounders. Five of eight patients with severe infection had neutrophils <750 cells/μL and none <500 cells/μL. Our results are in accordance with the data reported by Soza et al., Antonini et al. and Cooper et al., but not with the results of Puoti et al. suggesting an independent association between infections and neutropenia. Comparisons of the data from the above studies are difficult due to different patient population, different definitions and dose or schedule of the treatment.
We did not observe any death in our cohort, which is in agreement with all previous reports and with a large survey of 11 241 patients treated with IFNa in which only one death was reported in a cirrhotic patient due to sepsis.
Another important finding of our study is the significant association between severity of liver damage and infections. It is well established that patients with decompensated liver disease are at particular risk of bacterial infections during treatment with PegIFNa and ribavirin. We found that the only variable independently associated with the risk of infection was the presence of cirrhosis at baseline. Patients with cirrhosis had fivefold higher risk of infection during treatment compared to patients without cirrhosis independently of NNC and baseline WBC. These results are in contrast with the results of Cooper et al. and Antonini et al.; both of these small studies failed to show that cirrhosis is associated with higher risk of infection. It is however noteworthy that Roomer et al. in a similar cohort of 321 patients with hepatitis C found a trend towards a higher risk of infections in patients with cirrhosis. The retrospective design and the differences in the populations among studies might be possible explanations of the discordance.
As the risk of infection during anti viral therapy does not correlate with the NNC or WBC, an alternative hypothesis should be sought. PegIFNa has been shown to affect the function of neutrophils by increasing the oxidative surge and chemotaxis, while advanced liver disease can affect the host immune system with impaired function of reticuloendothilial system and complement. More data are needed to answer the questions regarding the effects of IFNa on the function of neutrophils in patients with different stages of CHC.
An interesting observation was that all infections developed between 3 and 6 months of treatment, with a median time of 17 weeks. This is in accordance with other reports and underlines the need for closer follow-up particularly in patients with advanced fibrosis during the first months of treatment.
It might be argued that neutropenia during treatment with pegIFNa is more common and intense in patients with cirrhosis. In addition, patients with cirrhosis have lower number of WBC or neutrophils before treatment initiation. In our study, 6.3% of patients had baseline WBC <4000/μL with 75% of them having cirrhosis. Although the mean reduction in WBC during therapy was significantly higher in noncirrhotics than cirrhotics, the number of patients who developed neutropenia was not significantly different between these two groups. In multivariate analysis, we found that baseline WBC count was the only independent factor associated with the risk of neutropenia during treatment. In particular, the risks of NNC <1000 or <750 cells/μL during treatment were 26-fold and 54-fold higher in patients with baseline WBC <5000 than ≥5000 cells/μL. This finding supports previous results from a small study by Renou et al.
Despite the relatively large sample size and the clear inclusion and exclusion criteria, our study has some limitations. Specific statistical care should have been taken as not all of the submitted subjects were independent of each other. Nevertheless, the small percentage of these cases in relation to the total sample, and the fact that in patients who were administered more than one treatment course the infection occurrence was no more than one per subject, makes this limitation rather insignificant. To reinforce our results, we ran the analysis including only the first treatment course of each subject without significant differentiation in our results.
In conclusion, our findings support that there is no association between on-therapy neutropenia and development of infection in CHC patients with well-compensated liver disease who are treated with a pegIFNa-based regimen. Our results reinforce the reports from few previous retrospective studies and provide supporting evidence to re-examine the dose-reduction policy or the use of growth factors in cases with neutropenia. Most importantly, our results indicate that cirrhosis is the main factor associated with a higher risk of infection during antiviral treatment. These findings remain of clinical significance in the era of the triple combination with the first-generation HCV protease inhibitors which have been recently used for the treatment of patients with genotype 1. From the existing experience, the new triple regimes seem to have important limitations and to increase toxicity. Noteworthy, in the French early access programme of boceprevir-or telaprevir-based triple therapy including only patients with cirrhosis, severe infections were reported in 24 (4.8%) of 497 patients, while there were six deaths (2.8%) mostly due to sepsis (five of six). Therefore, physicians should keep high index of suspicion for infections especially in patients with cirrhosis who receive regimens including pegIFNa, independently of WBC and neutrophil counts. Careful assessment of liver damage before therapy and close monitoring during therapy are essential, particularly for candidates of triple therapy, to minimize the detrimental consequences of infections.
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