Effect of fibrosis on adverse events in patients with hepatitis C treated with telaprevir

Alimentary Pharmacology & Therapeutics

Early View (Online Version of Record published before inclusion in an issue)

Effect of fibrosis on adverse events in patients with hepatitis C treated with telaprevir

K. Bichoupan1,*, J. M. Schwartz2, V. Martel-Laferriere1, E. R. Giannattasio2, K. Marfo2, J. A. Odin1, L. U. Liu1, T. D. Schiano1, P. Perumalswami1, M. Bansal1, P. J. Gaglio2, H. Kalia2, D. T. Dieterich1, A. D. Branch1, J. F. Reinus2

Effect of fibrosis on adverse events in patients with hepatitis C treated with telaprevir

A study published ahead of print the Alimentary Pharmacology & Therapeutics investigates adverse events of telaprevir-based therapy in patients with and without advanced fibrosis or cirrhosis.

Summary Source

A study published ahead of print the Alimentary Pharmacology & Therapeutics investigates adverse events of telaprevir-based therapy in patients with and without advanced fibrosis or cirrhosis.
Data about adverse events are needed to optimise telaprevir-based therapy in a broad spectrum of patients.

Dr Bichoupan and colleagues from New York, USA investigated adverse events of telaprevir-based therapy in patients with and without advanced fibrosis or cirrhosis in a real-world setting.
Data on 174 hepatitis C-infected patients initiating telaprevir-based therapy at Mount Sinai and Montefiore medical centres were collected.

Biopsy data and FIB-4 scores identified patients with advanced fibrosis
The research team built multivariable fully adjusted models to assess the effect of advanced fibrosis on specific adverse events and discontinuation of treatment due to an adverse event.

The team reported that patients with and without advanced fibrosis were similar in BMI, ribavirin exposure, gender, prior treatment history, hemoglobin and creatinine, but differed in race.

Overall, 47% of patients completed treatment and 40% of patients achieved SVR.

Treated patients with and without advanced fibrosis or cirrhosis had similar rates of adverse events.

The team noted that advanced fibrosis was independently associated with ano-rectal discomfort.

The researchers found that 3 patients decompensated and had advanced fibrosis.

The discontinuation of all treatment medications due to an adverse event was significantly associated with older age, female gender, and lower platelets.

Dr Bichoupan's team concludes, "Adverse events were common, but were not significantly related to the presence of advanced fibrosis or cirrhosis."

"More critical monitoring in older and female patients with low platelets throughout treatment may reduce adverse event-related discontinuations

Aliment Pharmacol Ther 2013: 38(11-12): 1373–1384
26 November 2013

Alimentary Pharmacology & Therapeutics

Discussion Only

Full Text Available Here

Article first published online: 24 NOV 2013 DOI: 10.1111/apt.12560

We analysed the occurrence rates of adverse events and treatment discontinuation during TVR in patients with genotype-1 HCV infection, with special attention to individuals with advanced fibrosis or cirrhosis. In addition, we identified factors associated with treatment discontinuation due to adverse events and other factors that were associated with specific adverse events.

Most importantly, we found the presence of advanced fibrosis or cirrhosis to have no effect on the safety of TVR. Through a multivariable fully adjusted model, fibrosis stage had no effect on drug discontinuation due to adverse events. Older age, lower haemoglobin and lower BMI were all significantly associated with severe anaemia. Higher levels of haemoglobin also were associated with fatigue, hypokalemia and ano-rectal discomfort. This could be explained by the fact that patients with higher haemoglobin levels were likely to remain on treatment longer and were thus exposed to more drug. We were surprised by the association between previous treatment history and skin burning, but are aware that our sample size is small. Our most important finding regarding adverse events was the strong associations between black race and naïve or prior-relapse patients with hospital admissions.

Our results reflect the fact that experience in daily clinical practice (effectiveness) may be different from that in registration trials (efficacy).[13] The high rate of treatment discontinuation due to adverse events in members of our cohort was not surprising as randomised controlled trials recruit lower risk patients that are intensely monitored. In the ADVANCE[5] and REALIZE[6] trials, 73% and 62% of telaprevir-treated patients completed therapy, respectively. Our treatment completion rate of 47% highlights the effect that clinical-trial monitoring and patient selection may have on efficacy. In addition, adverse events caused 22% of our patients, but only 10–13% of trial participants, to discontinue therapy. In our study, prior treatment was not associated with discontinuation due to an adverse event. Other studies, notably CUPIC (cite here), have provided additional data regarding results of TVR in well-compensated cirrhotics.

Differences in the patient populations studied may help explain why our real-world treatment results differ from those of the registration trials. Our study included older patients, more patients with advanced fibrosis or cirrhosis, more black and Hispanic patients, and larger patients (BMI and weight) than did the registration trials. In addition, our inclusion and exclusion criteria were more flexible than those found in randomised controlled trials. As a result, our patients may have been less adherent and sicker than those in clinical trials.

The issue of the ageing HCV population is one that clinicians must increasingly address. In our patients, older age was significantly associated with treatment discontinuation of all drugs due to an adverse event. The mean patient ages in REALIZE[6] and ADVANCE[5] were 51 (Range: 23–69) and 49 years (Range: 19–69) respectively. The mean age of our patients was 56 years and the median age 58 years with a range of 26–74. We treated 17 patients (10%) over age 65 years; data on patients over age 65 years were lacking in the registration trials.[10] Recently, Hu et al.[14] reported poorer SVR rates and greater treatment withdrawal rates during 24 weeks of dual therapy in geriatric as compared with younger patients. Older patients in their study also were more likely to relapse. The effect of age on safety and SVR was investigated in two other studies, but no significant association was found, possibly because of small sample sizes.[15, 16] Our finding suggests that the influence of age on the effectiveness of future treatments be investigated.

Anaemia is the most difficult adverse event to control during triple therapy with a protease inhibitor-containing regimen. In our patients, severe anaemia was associated with older age, lower baseline haemoglobin and lower BMI. These same predictive factors also have been found by Butt et al. in HCV-HIV co-infected patients being treated with long-term pegylated interferon alfa-2a and ribavirin.[17] As pegylated interferon causes suppression of hematopoiesis and ribavirin causes haemolysis,[18-20] lower BMI may lead to greater ribavirin exposure resulting in more anaemia. Interestingly, we saw a strong relationship between EPO use and the completion of therapy, suggesting that improved prediction and management of anaemia may enhance treatment completion rates. Note must be made of the fact that ribavirin dose reductions could not be obtained for all patients in our study limiting the assessment of the effect of growth factors on response.

Telaprevir treatment is only indicated in patients with compensated (Child-Pugh class A) cirrhosis.[4] The overall number of patients with bridging fibrosis or cirrhosis in ADVANCE was only 21% of the entire cohort.[5] Our study provides more information about the effect of fibrosis stage on treatment-related side effects. With the exception of ano-rectal discomfort, we found no significant difference in the side-effect profile of TVR in patients with or without advanced liver fibrosis. We suspect that the difference in rates of ano-rectal discomfort was due to immune compromise in patients with advanced fibrosis.[21, 22] Our study provides more information about the effect of fibrosis stage on treatment-related side effects.

Our study also provides additional information on the relationship between race and treatment safety. Only 7% of patients in ADVANCE were black and only 10% were Hispanic. In the REALIZE study, 4% of patients were black and 9% were Hispanic in the nonlead-in telaprevir group. Twenty-two per cent of patients in our cohort were black and 32% were Hispanic. We did not find race to be predictive of treatment discontinuation due to an adverse event. This can be explained partially by the small effect of race and ethnicity on pharmacokinetic properties of ribavirin and pegylated interferon reported by Brennan et al.[23] Other work has shown that black patients treated with dual therapy have lower SVR rates than other individuals.[24-26]

Our study was limited by relatively small sample size, the use of medical records as a source of information and lack of biopsy data for all patients, which may have caused some patients in our cohort to be misclassified as having either F0–F2 or F3–F4 fibrosis. Collected data were based on standard clinical treatment. For this reason, ITPA genotype and IL28b data were lacking, preventing us from building meaningful SVR models. In addition, during the implementation of any new treatment regimen, there may be a learning curve with respect to patient selection and side-effect management. Our study was conducted in an academic medical setting where patients may be different from those in other private practice settings as well as in clinical trials. The house staff and physician extenders assessed adverse events at every visit and in phone conversations. Finally, it must be understood that we only observed associations between observed factors in our study group and outcomes. We do not construe these factors to be the sole cause of these adverse events and discontinuations.

Recently, Hezode et al. published a study examining the safety and efficacy of 16 weeks of telaprevir and boceprevir in well-compensated cirrhotics. In the CUPIC study by week 16, 23% discontinued all treatment medications and 15% discontinued due to adverse events.[27] In an updated analysis from the International Liver Congress Meeting in Amsterdam 2013, 47% of patients discontinued prematurely and 21% discontinued due to severe adverse events.[28] Our results support the results in the CUPIC trial. Our results are remarkably similar in that 52% discontinued treatment early and 22% discontinued due to adverse events. In addition, results from our multivariable analysis echo similar conclusions by Hezode et al. In both studies, low platelets were associated with discontinuation due to an adverse event, and older age and lower baseline haemoglobin were associated with anaemia.

In summary, our data show that there were few differences in the side-effect profile of triple therapy between patients with advanced fibrosis or cirrhosis and those without. Despite the lack of difference found between patients with and without advanced fibrosis or cirrhosis, the rate of adverse events was still high. Providers must be vigilant in monitoring for safety in all patients treated with telaprevir. Our findings may help practitioners increase the safety of HCV treatment by increasing awareness of potential risk factors for development of adverse events. Our study group represents the composition of the HCV-infected population as it may appear in the future.[29] Older and female patients with low platelet counts may experience more severe side effects of triple therapy, suggesting that closer monitoring of these patients may be prudent. We also observed four decompensation events in three patients with advanced fibrosis. Until new and safer drugs for treatment of genotype-1 hepatitis C become available for clinical use, more information about the effects of race and fibrosis stage on the tolerability and outcome of therapy is needed.

http://onlinelibrary.wiley.com/doi/10.1111/apt.12560/full