Journal of Viral Hepatitis
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.
Abstract and Introduction
Abstract
Rare interstitial lung disease cases have been reported with albinterferon alfa-2b (albIFN) and pegylated interferon alfa-2a (Peg-IFNα-2a) in chronic hepatitis C virus (HCV) patients. Systematic pulmonary function evaluation was conducted in a study of albIFN q4wk vs Peg-IFNα-2a qwk in patients with chronic HCV genotypes 2/3. Three hundred and ninety-one patients were randomly assigned 4:4:4:3 to one of four, open-label, 24-week treatment groups including oral ribavirin 800 mg/d: albIFN 900/1200/1500 μg q4wk or Peg-IFNα-2a 180 μg qwk. Standardized spirometry and diffusing capacity of the lung for carbon monoxide (DLCO) were recorded at baseline, weeks 12 and 24, and 6 months posttreatment, and chest X-rays (CXRs) at baseline and week 24. Baseline spirometry and DLCO were abnormal in 35 (13%) and 98 (26%) patients, respectively. Baseline interstitial CXR findings were rare (4 [1%]). During the study, clinically relevant DLCO declines (≥15%) were observed in 173 patients (48%), and were more frequent with Peg-IFNα-2a and albIFN 1500 μg; 24 weeks posttreatment, 57 patients (18%) still had significantly decreased DLCO, with a pattern for greater rates with albIFN vs Peg-IFNα-2a. One patient developed new interstitial CXR abnormalities, but there were no clinically relevant interstitial lung disease cases. The risk of persistent posttreatment DLCO decrease was not related to smoking, alcohol, HCV genotype, sustained virologic response, or baseline viral load or spirometry. Clinically relevant DLCO declines occurred frequently in chronic HCV patients receiving IFNα/ribavirin therapy and commonly persisted for ≥6 months posttherapy. The underlying mechanism and clinical implications for long-term pulmonary function impairment warrant further research.
Introduction
Therapy with pegylated interferon-alfa (Peg-IFNα) and ribavirin (RBV) has become the standard of care for the treatment of chronic hepatitis C virus (HCV),[1] but it has been associated with a number of adverse events (AEs), including frequent manifestations of dry cough and dyspnoea.[2] Rare, potentially fatal cases of interstitial pneumonitis have been reported with an incidence ranging between 0.3% and 0.03%.[2, 3] Little is known, however, about the chronic effect of IFNα on the lung, and no large-scale prospective study has evaluated the incidence of changes in pulmonary physiology and chest imaging during therapy.
Albinterferon alfa-2b (albIFN) is a fusion polypeptide of recombinant human albumin and recombinant IFNα-2b, with a half-life of ~200 hours and IFNα-like pharmacodynamic properties.[4] Recently, albIFN 900 and 1200 μg injected every 2 weeks in combination with RBV was evaluated in more than 2000 patients and was reported to have similar efficacy to that of Peg-IFNα-2a 180 μg injected once weekly (qwk) for the treatment of chronic HCV.[5, 6] Two cases of progressive interstitial lung disease (ILD; one fatal) occurred with albIFN 1200 μg during the course of those trials. Therefore, systematic investigations of pulmonary function and chest imaging were conducted in the present study that evaluated 3 doses of albIFN administered every 4 weeks (q4wk) compared with Peg-IFNα-2a qwk.[7]
Methods
Patients
A more detailed description of the methods, design and primary results of this trial was published previously.[7] Adult patients with chronic HCV genotype 2 or 3 who had not previously received IFNα therapy were enrolled in the study. Patients with decompensated liver disease or other causes of chronic liver disease, thrombocytopenia (<90 000 platelets/mm3), neutropenia (<1500 neutrophils/mm3), history of moderate–severe psychiatric disease, immunologically mediated disease, uncontrolled thyroid disease, co-infection with hepatitis B virus or HIV, a significant coexisting medical condition, or alcohol or drug dependence were excluded. The hepatologist investigators excluded patients with clinical evidence of preexisting ILD or other clinically severe lung disease.
The institutional review boards of the participating centres approved the study protocol, and all patients provided written informed consent.[7]
Study Design
This phase 2b, randomized, multicenter, active-controlled, open-label, dose-ranging study was conducted at 53 centres in 10 countries between October 2008 and May 2009 (ClinicalTrials.gov Identifier: NCT00759200).[7] Patients enrolled in the study were randomly assigned using a centralized interactive voice response system in a ratio of 4:4:4:3 in blocks of 15, to one of four treatment groups, including three albIFN groups (900, 1200 and 1500 μg q4wk; six injections in each group) and the active control Peg-IFNα-2a (Pegasys, Hoffmann–La Roche Ltd, Basel, Switzerland) group (180 μg qwk; 24 injections), with both agents administered subcutaneously. All patients also received oral RBV (Ribasphere, Three Rivers Pharmaceuticals, Warrendale, PA, USA) 800 mg/d in two divided doses. All patients were treated for 24 weeks, with 24-week follow-up.
The primary objective of the study was to assess the safety and tolerability of the albIFN q4wk regimens.[7] The primary efficacy endpoint was sustained virologic response (SVR), defined as undetectable HCV RNA (<20 IU/mL) at 24 weeks after therapy.
Pulmonary Evaluations
Spirometry (forced expiratory volume in 1 s [FEV1], forced vital capacity [FVC] and FEV1/FVC) and diffusing capacity of the lung for carbon monoxide (DLCO) testing were conducted at baseline, treatment weeks 12 and 24 (or end of treatment), and 24 weeks posttreatment. For spirometry and DLCO assessments, patients were referred to a local pulmonary function laboratory that was certified by the central pulmonary function laboratory (Biomedical Systems, Saint Louis, MO, USA) prior to study initiation. Spirometry and DLCO tests were standardized according to American Thoracic Society/European Respiratory Society guidelines,[8,9] and DLCO was corrected for haemoglobin (see details in Supporting Information Data S1). Data were transferred from the local pulmonary function laboratory to the central laboratory, where they were read for quality control purposes and processing prior to being transferred to the study sponsor.
To confirm the abnormalities, spirometry was repeated within 2 weeks for patients with: (i) a ≥ 10% FVC decrease from baseline, if baseline FVC was <80% of the predicted value; (ii) an FVC reduction to <80% of predicted, if baseline FVC was normal (≥80% of predicted); or (iii) a ≥ 10% decrease in FEV1/FVC from baseline. Spirometry and DLCO were repeated within 2 weeks for patients with: (i) a ≥ 15% DLCO decrease from baseline, if baseline DLCO was <80% of the predicted value or (ii) a DLCO reduction to <80% of predicted, if baseline DLCO was normal (≥80% of predicted). These thresholds for reduced absolute values and declines in spirometry and DLCO are considered clinically relevant abnormalities in the context of ILD and therefore were used also to categorize spirometry and DLCO data in the statistical analyses.[10, 11]
Chest X-rays (CXRs; postero-anterior and lateral views) were obtained at baseline and week 24 (or end of treatment). Chest x-rays were read centrally (RadPharm, Princeton, NJ, USA), and abnormal CXRs were reviewed by an independent radiologist (Prof David Lynch, National Jewish Health, Denver, CO, USA). Routine computed tomography of the chest was not included in the study protocol due to ethical concern and several country regulations prohibiting unnecessary X-ray exposure. Clinical AEs were coded according to the Medical Dictionary for Regulatory Activities, with severity graded using the Division of Microbiology and Infectious Diseases toxicity rating scale.[12]
Statistical Methods
Sample size was chosen based on the power to detect treatment-related AEs, rather than statistical power for hypothesis testing.[7] A minimum of 100 patients per albIFN treatment group and 75 in the Peg-IFNα-2a control group were targeted to be randomized and treated in this study to provide >80% power to detect an AE occurring at an actual rate of 2%.
All analyses were performed in the intention-to-treat population with all available data (including spirometry and DLCO retesting), using SAS 9 statistical software (SAS Institute Inc., Cary, NC, USA). All statistical tests were two-sided and performed at the 5% level of significance. No adjustment was made for multiple comparisons. Likelihood ratio test (or Fisher's exact test when >20% of expected contingency table cell counts were <5) was used for categorical variable comparisons, and analysis of variance was used for continuous variable comparisons. A logistic regression model was built to investigate the relation between DLCO decline (≥ vs <15%) and disease characteristic covariates.
Role of the Funding Source
Novartis Pharma AG (Basel) sponsored the study, which was cofunded by Human Genome Sciences (Rockville, MD, USA).[7] Novartis was responsible for collection and statistical analysis of the data and contributed to patient recruitment, trial management and writing and review of the report. A trial steering committee comprising study investigators provided input to the protocol and oversight of the conduct of the study, and an independent data monitoring committee was responsible for ongoing review of safety data during the study. The corresponding author had final responsibility for the decision to submit for publication. The authors had full access to the data, wrote this manuscript and take accountability for the accuracy of the reported analysis.
Results
Patient Disposition, Demographics and Virologic Response
In all, 391 patients were randomly assigned, and 388 received at least one dose of study drug.[7] There were 2 (3%), 5 (5%), 7 (7%) and 7 (7%) patients who did not complete the study in the Peg-IFNα-2a 180-μg qwk and albIFN 900-, 1200-, and 1500-μg q4wk arms, respectively, due to AEs, failure to achieve an early virologic response at week 12, patient request or being lost to follow-up. Patient demographics and disease characteristics were similar across treatment groups. Overall, 278 patients (72%) had HCV genotype 3, and 110 (28%) had genotype 2. Baseline spirometry, DLCO measurements and chest imaging abnormalities were generally similar across groups; exceptions included FEV1 with albIFN 1200 μg, and FVC with albIFN 1200 and 1500 μg, which were lower than with Peg-IFNα-2a ( ). Current smoking was reported by 29% of patients. Of the 343 patients with baseline spirometry, assessments showed values <80% of the predicted value for FEV1 in 11% of patients, for FVC in 6% and for DLCO in 27%. Based on American Thoracic Society spirometry categories,[13,14] 2% of patients showed physiologic obstruction at baseline (all with ongoing asthma or chronic obstructive pulmonary disease at baseline) and 6% were potentially restricted. Of the 387 patients with a baseline CXR, lung abnormalities were found in 5 (1%); 4 had interstitial findings, and 1 had consolidation.
Table 1. Demographic and baseline characteristics
| | All (N = 388) | albIFN | Peg-IFNα-2a180 μg qwk(n = 78) |
| | 900 μg q4wk (n = 102) | 1200 μg q4wk (n = 103) | 1500 μg q4wk (n = 105) |
| Men | 238 (61) | 66 (65) | 65 (63) | 57 (54) | 50 (64) |
| Race |
| Asian | 202 (52) | 53 (52) | 60 (58) | 50 (48) | 39 (50) |
| White | 174 (45) | 46 (45) | 41 (40) | 51 (49) | 36 (46) |
| Black | 4 (1) | 0 | 1 (1) | 2 (2) | 1 (1) |
| Other | 8 (2) | 3 (3) | 1 (1) | 2 (2) | 2 (3) |
| Mean age, year (SD) | 42.4 (11.8) | 42.2 (12.4) | 43.2 (12.0) | 41.3 (11.3) | 43.3 (11.4) |
| Age ≥45 years | 177 (46) | 43 (42) | 46 (45) | 46 (44) | 42 (54) |
| Pulmonary history |
| Current smoker | 113 (29) | 29 (28) | 33 (32) | 32 (31) | 19 (24) |
| Ongoing respiratory disorders at baseline | 46 (12) | 9 (9) | 11 (11) | 14 (13) | 12 (15) |
| Mean FEV1, % predicted (SD) | 99.8 (15.9) | 100.8 (15.6) | 97.7 (15.7)‖ | 98.4 (15.4) | 102.7 (17.1) |
| FEV1 <80% of predicted | 36 (11) | 9 (10) | 11 (12) | 11 (12) | 5 (7) |
| FVC, % predicted (SD) | 103.7 (16.2) | 105.7 (16.0) | 101.9 (17.2)¶ | 101.1 (14.1)# | 106.9 (17.3) |
| FVC <80% of predicted | 20 (6) | 3 (3) | 7 (8) | 8 (9) | 2 (3) |
| Mean FEV1/FVC ratio (SD) | 79.6 (7.6) | 78.7 (6.4) | 79.9 (8.4) | 80.6 (7.1) | 78.7 (8.2) |
| Normal* | 315 (92) | 87 (96) | 79 (90) | 84 (89) | 65 (93) |
| Obstructed† | 8 (2) | 1 (1) | 2 (2) | 2 (2) | 3 (4) |
| Potentially restricted‡ | 20 (6) | 3 (3) | 7 (8) | 8 (9) | 2 (3) |
| Obstructed and potentially restricted§ | 0 | 0 | 0 | 0 | 0 |
| Baseline DLCO (% predicted, corrected for haemoglobin), n | 363 | 98 | 95 | 97 | 73 |
| Mean DLCO (SD) | 90.0 (15.6) | 90.8 (14.6) | 89.1 (17.1) | 89.3 (14.3) | 90.8 (16.9) |
| DLCO <80% of predicted | 98 (27) | 21 (21) | 30 (32) | 26 (27) | 21 (29) |
| Baseline CXR, n | 387 | 101 | 103 | 105 | 78 |
| Any lung abnormality | 5 (1) | 0 | 3 (3) | 0 | 2 (3) |
Data are number (%) unless noted. albIFN, albinterferon alfa-2b; CXR, chest X-ray; DLCO, diffusing capacity of the lung for carbon monoxide; FEV1, forced expiratory volume in 1 s; FVC, forced vital capacity; Peg-IFNα-2a, pegylated interferon alfa-2a. *Normal defined as FEV1/FVC ratio ≥80% and FVC ≥80% of predicted value. †Obstructed defined as FEV1/FVC ratio <80% and FVC ≥80% of predicted. ‡Potentially restricted defined as FEV1/FVC ratio ≥80% and FVC <80% of predicted. §Obstructed and potentially restricted defined as FEV1/FVC ratio <80% and FVC <80% of predicted. ‖P = 0.048 vs Peg-IFNα-2a 180 μg qwk. ¶P = 0.051 vs Peg-IFNα-2a 180 μg qwk. #P = 0.02 vs Peg-IFNα-2a 180 μg qwk.
At the end of treatment, rates of undetectable HCV RNA were in the range of 89% to 96% across treatment groups.[7] At the end of posttreatment follow-up, SVR rates were 85%, 76%, 76% and 78% with Peg-IFNα-2a 180 μg qwk and albIFN 900, 1200 and 1500 μg q4wk, respectively (all P = NS).
Respiratory Adverse Events and Chest X-rays
Respiratory AEs were reported by 42% of patients. Four cases of pneumonia and one of restrictive pulmonary disease (dyspnoea and reduced DLCO) were reported as serious AEs in the albIFN groups, with no serious respiratory AEs reported in the Peg-IFNα-2a group (). The case of serious restrictive pulmonary disease occurred in the albIFN 1500-μg q4wk group and was characterized by dyspnoea that was reported at month 1 and worsened by month 3, requiring hospitalization. At baseline, this patient was asymptomatic with normal spirometry and DLCO, but with interstitial findings on CXR. By month 3, DLCO had declined by 66%, with FVC suggestive of restrictive lung disease, and interstitial findings on CXR and chest computed tomography, but in the absence of lung biopsy, there was no confirmed diagnosis of ILD. Dyspnoea resolved after treatment discontinuation and pulmonary function tests improved. No definitive case of ILD was reported by the principal investigators on site.
Table 2. Incidence of respiratory adverse events and infections
| | All (N = 388) | albIFN | Peg-IFNα-2a 180 μg qwk (n = 78) |
| 900 μg q4wk (n = 102) | 1200 μg q4wk (n = 103) | 1500 μg q4wk (n = 105) |
| Respiratory AE | 164 (42) | 4 (46) | 3 (37) | 46 (44) | 3 (42) |
| Serious respiratory AE | 2 (1) | 1 (1) | 0 | 1 (1) | 0 |
| Respiratory AE leading to discontinuation of IFN or RBV | 3 (1) | 1 (1) | 0 | 1 (1) | 1 (1) |
| Common respiratory AE (n ≥ 5) |
| Cough | 93 (24) | 24 (24) | 22 (21) | 31 (30) | 16 (21) |
| Dyspnoea | 44 (11) | 14 (14) | 8 (8) | 15 (14) | 7 (9) |
| Dyspnoea exertional | 27 (7) | 6 (6) | 9 (9) | 4 (4) | 8 (10) |
| Productive cough | 22 (6) | 4 (4) | 8 (8) | 7 (7) | 3 (4) |
| Oropharyngeal pain | 20 (5) | 5 (5) | 7 (7) | 3 (3) | 5 (6) |
| Epistaxis | 11 (3) | 3 (3) | 4 (4) | 2 (2) | 2 (3) |
| Obstructive airways | 5 (1) | 3 (3) | 0 | 2 (2) | 0 |
| Throat irritation | 5 (1) | 0 | 1 (1) | 2 (2) | 2 (3) |
| Serious LRTI | 4 (1) | 3 (3) | 1 (1) | 0 | 0 |
| LRTI leading to discontinuation of IFN or RBV | 1 (0) | 0 | 0 | 0 | 1 (1) |
| LRTI | 10 (3) | 5 (5) | 2 (2) | 2 (2) | 1 (1) |
| Pneumonia | 4 (1) | 3 (3) | 1 (1) | 0 | 0 |
| Bronchitis | 2 (1) | 0 | 0 | 1 (1) | 1 (1) |
| Other (unspecified) | 4 (1) | 2 (2) | 1 (1) | 1 (1) | 0 |
Data are number (%). No statistically significant difference in any group. AE, adverse event; albIFN, albinterferon alfa-2b; IFN, interferon; LRTI, lower respiratory tract infection; Peg-IFNα-2a, peginterferon alfa-2a; RBV, ribavirin.
Respiratory AEs led to treatment discontinuation in 3 patients, 2 receiving albIFN (pneumonia in the 900-μg q4wk group and restrictive lung disease with exertional dyspnoea in the 1500-μg q4wk group) and 1 with exertional dyspnoea in the Peg-IFNα-2a 180-μg qwk group; these AEs reversed after the end of treatment. The most frequently noted respiratory AEs were cough (24%) and dyspnoea (11%), and there was no significant difference among treatment groups. Cough and dyspnoea, which were reported as early as 2 weeks after the start of treatment with their prevalence peaking at weeks 10–12, were reversible in most patients by 12 weeks after treatment.
Changes in Pulmonary Function on Treatment
Over the entire study duration, changes were seen in both spirometry and DLCO. The mean maximum reduction (SD) in FEV1 was 7.3% (12.1%), FVC fell by 5.9% (8.0%), and FEV1/FVC decreased by 2.6% (4.6%). Maximum declines were observed at treatment week 12 (Fig. 1). Absolute declines ≥10% from baseline occurred in 89 patients (26%) for FEV1, 78 (23%) for FVC and 10 (3%) for FEV1/FVC. The presence of symmetric declines in FEV1 and FVC combined with a normal FEV1/FVC is suggestive of mild pulmonary restriction.
Figure 1.
Left panels, mean absolute changes from baseline in percent of predicted values; right panels, percent of patients with absolute decline in percent of predicted values. albIFN, albinterferon alfa-2b; DLCO, diffusing capacity of the lung for carbon monoxide; FEV 1, forced expiratory volume in 1 s; FVC, forced vital capacity; Peg-IFNα-2a, peginterferon alfa- 2a. *P < 0.05 for comparison between albIFN and Peg-IFNα-2a treatment arms The maximum DLCO decline (mean change [SD] from baseline of the percent predicted absolute value, corrected for haemoglobin) was 15.4% (11.2%) and was similar across all treatment groups; as with the changes in spirometry, the maximum decline was observed at treatment week 12 (Fig. 1). In all, 173 patients (49%) had a DLCO decline ≥15%—a value considered clinically relevant—and 32 (9%) had a decline ≥30%. At baseline, 27% of patients had a reduced DLCO (absolute DLCO <80% of predicted), while on treatment, 249 patients (65%) had a reduced DLCO and 13 (3%) had a severe DLCO reduction (≤50% of predicted), with no statistically significant difference between treatment groups. Of 13 patients with DLCO <50% of predicted, 1 had a serious pulmonary AE of restrictive lung disease (as described previously).
In general, no significant differences were found across treatment groups for changes in DLCO or spirometry, with the exceptions of a greater mean decline (SD) in FEV1 with albIFN 1200 μg q4wk than with Peg-IFNα-2a 180 μg qwk at treatment week 24 (−4.3 [8.8] vs −0.8 [8.5]; P = 0.01), and fewer patients with a DLCO decline ≥15% with albIFN 900 and 1200 μg than with Peg-IFNα-2a at week 12 (21 [26%] and 19 [25%] vs 25 [42%]; P = 0.04 and 0.03, respectively; Fig. 1).
No significant association was found between DLCO decline ≥15% vs <15% and the incidence of any respiratory AEs (77/172 [45%] vs81/184 [44%]), cough (42/172 [24%] vs 47/184 [26%]) or dyspnoea (17/172 [10%] vs 26/184 [14%]).
Pulmonary Function in Posttreatment Period
Pulmonary function changes were largely reversible by 24 weeks posttreatment, but clinically relevant declines from baseline persisted in 57/315 patients (18%) for DLCO (≥15% decline), 39/302 (13%) for FVC (≥10% decline) and 40/302 (13%) for FEV1 (≥10% decline; Fig. 1). These persistent abnormalities were statistically significant for FVC with albIFN 1200 μg q4wk vs Peg-IFNα-2a 180 μg qwk (13/77 [17%] vs4/66 [6%]; P = 0.046) and were numerically more frequent for DLCO with albIFN 900 and 1200 μg vs Peg-IFNα-2a (17/81 [21%] and 17/80 [21%] vs 9/69 [13%], respectively).
Predictive Factors of DLCO Declines on Treatment
Multivariate analysis of baseline and treatment factors showed a greater risk of DLCO decline ≥15% at treatment week 12 to be associated with higher baseline DLCO (% predicted, corrected for haemoglobin) and treatment with albIFN 900 and 1200 μg q4wk compared with Peg-IFNα-2a 180 μg qwk (). At 24 weeks posttreatment, a greater risk of persistent DLCO decline ≥15% from baseline was associated with female gender and Asian region (but not body mass index), higher baseline DLCO and lesser DLCO decline at treatment week 12. Smoking was not a risk factor for DLCO decline on treatment or posttreatment. Likewise, neither baseline HCV RNA ≥800 000 IU/mL nor SVR was associated with decline in DLCO.
Table 3. Multivariate logistic regression of DLCO decline (≥ vs <15%) at week 12 on treatment and at week 24 posttreatment, and impact of demographic and disease characteristics
| Parameter | Parameter estimate | SE | Odds ratio (95% CI) | P-value |
| Week 12 DLCO decline on treatment (≥ vs <15%) |
| Intercept | −6.3703 | 1.0329 | | <0.001 |
| Treatment: albIFN 1500 μg q4wk | 0.0044 | 0.3803 | 1.00 (0.48, 2.12) | 0.99 |
| Treatment: albIFN 1200 μg q4wk | −0.8172 | 0.4112 | 0.44 (0.20, 0.99) | 0.046 |
| Treatment: albIFN 900 μg q4wk | −0.9264 | 0.4031 | 0.40 (0.18, 0.87) | 0.02 |
| Baseline DLCO % predicted corrected for haemoglobin | 0.0668 | 0.0108 | 1.07 (1.05, 1.09) | <0.001 |
| Week 24 posttreatment DLCO decline (≥ vs <15%)* |
| Intercept | −8.232 | 1.5332 | | <0.001 |
| Gender (male vs female) | −1.1605 | 0.4126 | 0.31 (0.14, 0.70) | 0.005 |
| Region (Asian vs non-Asian) | 1.0451 | 0.4108 | 2.84 (1.27, 6.36) | 0.01 |
| DLCO decline % predicted corrected for haemoglobin at week 12 | −0.0859 | 0.0201 | 0.92 (0.88, 0.95) | <0.001 |
| Baseline DLCO % predicted corrected for haemoglobin | 0.0578 | 0.0161 | 1.06 (1.03, 1.09) | <0.001 |
The covariates tested included treatment group (albinterferon alfa-2b [albIFN] 900, 1200, and 1500 μg q2wk vs pegylated interferon alfa-2a 180 μg qwk); age (≥ vs <45 years); gender (male vs female); genotype (2 vs 3); weight (≥ vs <75 kg); body mass index (≥ vs <25 kg/m2); smoking status (current vs not current); alcohol use (history vs no history); baseline alanine aminotransaminase (> vs ≤1.5x upper limit of normal); baseline γ-glutamyl transpeptidase (> vs ≤ upper limit of normal); region (Asian vs non-Asian); baseline hepatitis C virus RNA (≥ vs <800,000 IU/mL); hepatitis C virus disease duration (years); pulmonary history (history vs no history); and baseline forced expiratory volume in 1 s (FEV1), baseline forced vital capacity (FVC %), baseline FEV1/FVC and baseline diffusing capacity of the lung for carbon monoxide (DLCO). *Additional variables included were sustained virologic response (yes vs no); FEV1, FVC % and FEV1/FVC at week 12; and DLCO decline at week 12.
Genetic variation of the interleukin 28B single nucleotide polymorphisms rs12979860 has been shown to be associated with virologic response to IFN in patients with chronic HCV.[15] In this study, the interleukin 28B genotype was measured in a subgroup of 117 patients and was not found to be associated with DLCO decline.
Discussion
Long-acting IFN therapy forms the backbone of current treatment for patients with chronic HCV, and many thousands receive these therapies every year. Overt 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 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 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.
References
-
Ghany MG, Strader DB, Thomas DL, Seeff LB, for the American Association for the Study of Liver Diseases. Diagnosis, management, and treatment of hepatitis C: an update. Hepatology 2009; 49: 1335–1374
-
Slavenburg S, Heijdra YF, Drenth JP. Pneumonitis as a consequence of (peg)interferon-ribavirin combination therapy for hepatitis C: a review of the literature. Dig Dis Sci 2010; 55: 579–585
-
Arase Y, Suzuki F, Suzuki Y et al. Hepatitis C virus enhances incidence of idiopathic pulmonary fibrosis. World J Gastroenterol 2008; 14: 5880–5886
-
Subramanian GM, Fiscella M, Lamousé- Smith A, Zeuzem S, McHutchison JG, G. R. Foster et al. Albinterferon a-2b: a genetic fusion protein for the treatment of chronic hepatitis C. Nat Biotechnol 2007; 25: 1411–1419
-
Nelson DR, Benhamou Y, Chuang WL, et al; for ACHIEVE-2/3 Study Team. Albinterferon alfa-2b was not inferior to pegylated interferon-α in a randomized trial of patients with chronic hepatitis C virus genotype 2 or 3. Gastroenterology 2010; 139: 1267–1276
-
Zeuzem S, Sulkowski MS, Lawitz EJ et al; for ACHIEVE-1 Study Team. Albinterferon alfa-2b was not inferior to pegylated interferon-a in a randomized trial of patients with chronic hepatitis C virus genotype 1. Gastroenterology 2010; 139: 1257–1266
-
Pianko S, Zeuzem S, Chuang WL et al. Randomized trial of albinterferon- alfa-2b every four weeks for genotype 2/3 chronic hepatitis C. J Viral Hepat 2012; 19: 623–634
-
MacIntyre N, Crapo RO, Viegi G et al. Standardisation of the singlebreath determination of carbon monoxide uptake in the lung. Eur Respir J 2005; 26: 720–735
-
Miller R, Hankinson J, Brusasco V et al. Standardization of spirometry. Eur Respir J 2005; 26: 319–338
-
Noble PW, Albera C, Bradford WZ et al; CAPACITY Study Group. Pirfenidone in patients with idiopathic pulmonary fibrosis (CAPACITY): two randomised trials. Lancet 2011; 377: 1760–1769
-
Raghu G, Collard HR, Egan JJ et al; ATS/ERS/JRS/ALAT Committee on Idiopathic Pulmonary Fibrosis. An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management. Am J Respir Crit Care Med 2011; 183: 788–824
-
Division of Microbiology and Infectious Diseases Adult Toxicity Tables. Available at: www.niaid.nih.gov/LabsAndResources/resources/DMIDClinRsrch/pages/toxtables.aspx. (accessed 2 February 2011)
-
Hankinson JL, Odencrantz JR, Fedan KB. Spirometric reference values from a sample of the general U.S. population. Am J Respir Crit Care Med 1999; 159: 179–187
-
Pellegrino R, Viegi G, Brusasco V et al. Interpretative strategies for lung function tests. Eur Respir J 2005; 26: 948–968
-
Ge D, Fellay J, Thompson AJ et al. Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance. Nature 2009; 461: 399–401
-
Moorman J, Saad M, Kosseifi S, Krishnaswamy G. Hepatitis C virus and the lung: implications for therapy. Chest 2005; 128: 2882– 2892
-
Spagnolo P, Zeuzem S, Richeldi L, du Bois RM. The complex interrelationships between chronic lung and liver disease: a review. J Viral Hepat 2010; 17: 381–390
-
Dicpinigaitis PV, Weiner FR. Chronic cough associated with interferon/ribavirin therapy for hepatitis C. J Clinical Pharm Ther 2011; 36: 416–418.
Acknowledgements
Lead investigators: Australia: Crawford D, Desmond P, George J, Pianko S, Sasadeusz J, Weltman M; Canada: Anderson F, Fournier C, Gould M, Swain M, Wong F, Yoshida E; Germany: Berg T, Buggisch P, Gerken G, Goeser T, Rasenack J, Zeuzem S (principal investigator);India: Habeeb A, Kapoor D, Kar P, Prabhakar B, Sarin S, Shah S, Sood A; Italy: Andreone P, Brunetto M, Craxi A, Mondelli M, Rizzetto M;Poland: Flisiak R, Jablkowski M; Spain: Andrade R, Barcena R, Buti M, Castellano D, Diago M, Perez R, Romero M, Sola R; Taiwan: Chang T, Chuang W, Kao J, Lee C; Thailand: Komolmit P, Piratvisuth T, Sukeepaisarnjaroen W, Tanwandee T, Thongsawat S; United Kingdom: Brown A, Cramp M, Foster GR, Mills P; United States: Jacobson I, Bain V.
J Viral Hepat. 2013;20(4):e115-e123. © 2013 Blackwell Publishing
Source
