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

Disclosures

J Viral Hepat. 2013;20(4):e115-e123. 

In This Article

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 ( Table 1 ). 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.

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 (Table 2). 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.

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 (Table 3). 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.

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.

Comments

3090D553-9492-4563-8681-AD288FA52ACE

processing....