Wednesday, April 24, 2013

Decline in Pulmonary Function during Chronic Hepatitis C Virus Therapy With Modified Interferon Alfa and Ribavirin

Journal of Viral Hepatitis

Decline in Pulmonary Function during Chronic Hepatitis C Virus Therapy With Modified Interferon Alfa and Ribavirin

G. R. Foster, S. Zeuzem, S. Pianko, S. K. Sarin, T. Piratvisuth, S. Shah, P. Andreone, A. Sood, W.-L. Chuang, C.-M. Lee, J. George, M. Gould, R. Flisiak, I. M. Jacobson, P. Komolmit, S. Thongsawat, T. Tanwandee, J. Rasenack, R. Sola, I. Messina, Y. Yin, S. Cammarata, G. Feutren, K. Brown

J Viral Hepat. 2013;20(4):e115-e123.

Discussion Only

  • Abstract and Introduction
  • Methods
  • Results

  • Long-acting IFN therapy forms the backbone of current treatment for patients with chronic HCV, and many thousands receive these therapies every year. Overt interstitial lung disease (ILD) is a rare, but well-known complication of IFN therapy for chronic HCV.[16, 17] Systematic investigations of pulmonary function during IFN therapy to assess any subclinical changes in pulmonary function and to determine whether these changes predict the risk of ILD on treatment have not, however, been conducted. The occurrence of two cases of ILD with albIFN treatment in a previous trial led to the systematic and standardized evaluation of pulmonary function in the present study.[6]
    To ensure the quality of the pulmonary function tests across the 53 hepatology centres involved in this study, local pulmonary laboratories were certified prior to testing patients and the quality of the individual tests was reviewed prior to validating the results. The absence of standard pulmonary function test values for the populations of several countries in the study created a limitation to the detection of mildly abnormal absolute spirometry values and to the categorization of those values into obstructed, potentially restricted or mixed patterns. Further, the calculation of  diffusing capacity of the lung for carbon monoxide (DLCO) is strongly dependent on haemoglobin level, and a drop in haemoglobin is a common occurrence during RBV therapy. This factor was, however, accounted for by a thorough adjustment of DLCO to the actual haemoglobin level at the time of the test.

    Despite these limitations and the lack of an untreated placebo control, the magnitude and consistency of DLCO changes from baseline in all treatment groups, including the widely used Peg-IFNα-2a, and the reversibility of changes after the end of treatment support an effect of IFNα and RBV treatment. The changes in FVC combined with the stability of the FEV1/FVC ratio—although modest—further support the hypothesis of mild restrictive pulmonary changes and reductions in lung diffusion capacity during treatment. These functional changes were not associated with an increased incidence of respiratory symptoms, such as cough and dyspnoea, and did not appear to be associated with major radiologic lung abnormalities, as only one case of interstitial lung findings was observed by chest X-rays (CXR) at the end of the treatment period. Systematic high-resolution chest computed tomography—a more sensitive method than CXR for detection of interstitial lung changes—was not included in the trial to avoid unnecessary exposure of patients to radiation.

    Spirometry and DLCO measurements declined on treatment weeks 12 and 24 when most patients had undetectable HCV RNA; therefore, the pulmonary changes were unlikely to be related to HCV. In multivariate analyses, baseline HCV RNA level and SVR were not associated with DLCO decline, suggesting that virologic factors did not influence respiratory function. The only baseline factor significantly associated with DLCO decline on treatment was baseline DLCO, although the magnitude of the effect was small. Smoking status did not appear to be a significant factor for DLCO decline on treatment or posttreatment. The risk of persistent DLCO decline was almost three times higher in Asian than in white patients. This high frequency, combined with the large number of patients enrolled in the Asian region, may have contributed to the high rate of DLCO declines observed in this trial.

    Cough and dyspnoea are common AEs in patients receiving Peg-IFNα and RBV therapy. In this study, these AEs occurred early and were frequent in all treatment groups and were rapidly reversible after the end of treatment; declines in DLCO or spirometry measurements did not appear to be associated with these AEs. The absence of an association between cough and decline in pulmonary function is consistent with recent findings that cough during IFNα/RBV therapy may be related to an increased sensitivity of the cough reflex.[18]
    In conclusion, this study revealed the frequent occurrence of DLCO declines of clinically relevant magnitude (≥15% from baseline) during the treatment of chronic HCV with modified IFNα and RBV. These pulmonary changes persisted in some patients for 6 months after the end of treatment, but did not appear to be associated with an increased frequency of respiratory AEs. The potential mechanisms and implications for the risk of developing ILD on HCV treatment, and for long-term pulmonary function after treatment, warrant further research. At present, however, we suggest that patients with HCV who develop severe dyspnoea during IFN therapy should have their respiratory function checked, in particular those who have a preexisting chronic pulmonary disease or CXR abnormalities, and should be referred for pulmonary consultation in case of clinically relevant reductions in pulmonary function tests

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