A Phase I Randomized, Controlled, Clinical Trial of Valganciclovir in Idiopathic Pulmonary Fibrosis

Abstract

Rationale: Human herpesviruses Epstein-Barr virus and cytomegalovirus are frequently detectable in the lungs of patients with idiopathic pulmonary fibrosis (IPF) and could contribute to disease pathogenesis.

Objectives: With the goal of inhibiting herpesvirus replication, we tested the safety and tolerability of adding valganciclovir to standard IPF therapy (pirfenidone).

Methods: We performed a single-center, Phase I, double-blind, randomized, placebo-controlled trial comparing valganciclovir 900 mg daily with placebo in patients with IPF with serologic evidence of prior Epstein-Barr virus and/or cytomegalovirus infection who were tolerating full-dose pirfenidone (2,403 mg/d). Subjects were randomized to valganciclovir or placebo 2:1 for 12 weeks of active treatment with off-treatment follow-up for up to 12 months. The primary safety endpoint was the number of subjects discontinuing the study drug before completing 12 weeks of treatment.

Results: Thirty-one subjects with IPF were randomized to valganciclovir (n = 20) or placebo (n = 11). All subjects completed assigned therapy except one subject in the valganciclovir group, who discontinued the study drug after developing a rash. The total number of adverse events was similar between study groups. In a prespecified analysis of secondary physiologic endpoints, we observed a trend toward improved forced vital capacity from randomization to Week 12 in valganciclovir-treated subjects (−10 ml; interquartile range [IQR], −65 to 70 ml) versus placebo-treated subjects (40 ml; IQR, −130 to 60 ml), which persisted through 12 months of follow-up.

Conclusions: Valganciclovir is safe and well tolerated as an add-on therapy to pirfenidone in patients with IPF. Clinical trial registered with ClinicalTrials.gov (NCT02871401)

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive syndrome that results in substantial morbidity and mortality, with an average survival of 3–5 years after diagnosis (1). Despite decades of work, there are only two U.S. Food and Drug Administration (FDA)-approved medications for the treatment of IPF (2, 3), neither of which provides relief of symptoms or halts disease progression. As a result, new therapeutic targets and approaches are urgently needed.

A viral etiology of IPF was first suspected more than half a century ago, but understanding the role of viruses, including herpesviruses, in IPF pathogenesis has been challenging (4–8). Although the majority of adults have been exposed to herpesviruses, these viruses typically remain latent in host cells for the lifetime of the individual. In 2003, our group used a polymerase chain reaction (PCR) strategy for the identification of herpesviruses in lung tissue samples and found that 97% of lungs from patients with IPF contained herpesvirus DNA, including Epstein-Barr virus (EBV) and cytomegalovirus (CMV) (9). Herpesvirus proteins were expressed in alveolar epithelial cells lining areas of fibrosis in IPF lungs but were not detected in alveolar epithelial cells in normal lungs (9). Subsequently, we showed that expression of herpesvirus antigens in IPF lungs colocalizes with markers of endoplasmic reticulum stress (10), which may contribute to alveolar epithelial cell dysfunction and apoptosis. Other studies showed that EBV viral capsid antigen and latent membrane protein 1 were more frequently detected in biopsies from patients with IPF than control subjects, and only biopsies from patients with IPF were positive by both immunohistochemistry and PCR (11). Consistent with these findings, antibody titers to CMV and EBV were reported to be increased in patients with IPF and collagen vascular disease–related interstitial lung disease compared with control subjects (12). More recently, we identified DNA for CMV and EBV in cell-free fluid obtained by bronchoalveolar lavage (BAL) from patients with IPF and control subjects (13). Using PCR to identify DNA for EBV and CMV in concentrated DNA from cell-free BAL, we found that 21/28 subjects with IPF were positive for CMV and 6/28 were positive for EBV DNA (23/28 were positive for at least one of these herpesviruses) (13). Taken together, these data suggest that herpesvirus infection of the alveolar epithelial cells is common in IPF and could contribute to disease pathogenesis.

On the basis of evidence linking herpesviruses to pulmonary fibrosis, we hypothesized that reactivation of latent herpesviruses (EBV and CMV) contributes to the recurrent injury–repair cycle that drives progressive fibrosis in this disease. Valganciclovir is a relatively safe, orally available antiviral drug with good activity against CMV and moderate activity against EBV (14). In this study, we conducted a Phase IB randomized, prospective, placebo-controlled, double-blind clinical trial to evaluate the tolerability of valganciclovir added to FDA-approved therapy (pirfenidone) in patients with IPF. Exploratory analyses evaluate the effect of valganciclovir on clinically meaningful endpoints.

Methods

Study Design and Eligibility Criteria

We conducted a single-center (Interstitial Lung Disease Clinic at Vanderbilt University Medical Center), prospective, randomized, placebo-controlled, double-blind pilot study of valganciclovir in patients with IPF (NCT02871401). This study was approved by the Institutional Review Board at Vanderbilt University Medical Center (#160693). Eligible patients had 1) a definite or probable IPF diagnosis by American Thoracic Society criteria (15) and were on stable-dose treatment with the antifibrotic drug pirfenidone for >1 month; 2) evidence of past EBV or CMV infection as determined by serologic testing for anti-EBV and anti-CMV IgG antibodies; 3) forced vital capacity (FVC) >40% predicted, diffusing capacity of the lung for carbon monoxide (Dl_CO) >30% predicted, and forced expiratory volume in 1 second (FEV₁)/FVC >0.7 by pulmonary function testing (PFT); 4) resting oxygen saturation >89%; and 5) age between 21 and 80 years. Exclusion criteria included active tobacco use, emphysema >40% as determined by investigator review of chest computed tomography, diagnosis of collagen vascular disease, use of immunosuppressant drug treatment, or underlying liver, kidney, or hematological disease. A complete list of inclusion and exclusion criteria is shown in the online supplement. A small subset of subjects participated in an exploratory bronchoscopy substudy, the results of which will be reported separately. Subjects were randomized (2:1) to pirfenidone plus valganciclovir 900 mg or pirfenidone plus matching placebo, dosed daily for 12 weeks. The Vanderbilt Investigational Drug Pharmacy performed randomization upon receipt of a prescription from the investigator.

Valganciclovir Dosing and Side Effect Monitoring

The dose of valganciclovir used in this study (900 mg/d dosed orally) is within the FDA-approved dosing range for other indications and is comparable to doses used for chronic suppressive therapy after treatment for an active CMV infection in solid organ transplant recipients. The major side effect of valganciclovir is bone marrow suppression, causing anemia, leukopenia, or thrombocytopenia. Side effects were monitored by laboratory testing (complete blood count with differential and complete metabolic profile), subject diaries, and direct questioning. Dose adjustments of valganciclovir are required in the setting of renal impairment, and dose modifications for renal insufficiency were planned according to recommended guidelines on the basis of estimated creatinine clearance using the Cockroft-Gault equation. The study drug was dispensed by the Vanderbilt Investigational Drug Pharmacy to the patient by mail or given to the patient by study staff, together with instructions regarding dosing and drug storage. Valganciclovir was provided by Roche Genentech.

Procedures

After informed consent, subjects completed a screening visit including medical history and physical examination, vital signs with resting room-air pulse oximetry, laboratory studies (complete metabolic profile [CMP], complete blood count with differential [CBC], EBV, and CMV serologies), complete PFT (spirometry, lung volumes, and Dl_CO), a review of current medications, and a review of IPF diagnostic information (medical history, high-resolution computed tomography, and surgical biopsy as indicated). The subjects meeting eligibility criteria completed additional enrollment procedures, including a 6-minute walk test (6MWT), CMP and CBC (if enrollment occurred >30 d after the screening visit), education about self-monitoring and diary recording, and investigator prescription of study drug. The subjects meeting eligibility criteria at the screening visit were allowed to complete the enrollment procedures at the same visit.

Active-treatment follow-up visits occurred at Weeks 4, 8, and 12, with posttreatment visits at 6, 9, and 12 months after enrollment (coinciding with routine clinical care visits). Each active-treatment visit included medical history, a physical examination, an adverse event review, a review of current medications, CMP, and CBC. The 12-week end-of-treatment visit also included PFTs, 6MWT, resting room-air pulse oximetry, and the collection and reconciliation of study drug. A follow-up study visit was conducted by telephone at Week 16. Posttreatment visits included medical history, physical examination, vital signs with resting room-air pulse oximetry, PFT, and 6MWT.

PFTs were captured for all subjects using CareFusion Sensormedics pulmonary function testing equipment (CareFusion) according to current American Thoracic Society/European Respiratory Society guidelines, including spirometry (FEV₁ and FVC) by National Health and Nutrition Examination Survey, total lung capacity by body box plethysmography and Dl_CO by percentage predicted according to Crapo. Resting oxygen saturation measurements were performed after the removal of supplemental oxygen for 5 minutes. Exercise capacity was determined on the basis of the 6MWT, which was performed using current guidelines (16) on room air.

Outcomes

The primary endpoint was the safety and tolerability of valganciclovir, measured by the proportion of subjects discontinuing the study drug before completing 12 weeks of treatment. Further assessment of safety was determined by an ongoing review of CBC, CMP, physical examination, functional status assessments, and adverse event reporting. Treatment-emergent adverse events (TEAEs) were defined as a sign or symptom that emerged during treatment or within the 4 weeks after the last dose of the study drug that were absent pretreatment or that worsened relative to the pretreatment state. Any adverse event deemed related to the study drug was also considered a TEAE, regardless of elapsed time since the last study drug dose. Adverse events were graded using the National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0 during the study evaluation and listed individually. Prespecified key secondary safety endpoints include the frequency of individual adverse events.

Prespecified key secondary physiologic endpoints included absolute change in FVC (in ml) and change in FVC as percentage of predicted between screening/enrollment and the 12-week end-of-treatment visit and between screening/enrollment and the 12-month visit. A prespecified exploratory subgroup analysis evaluated the key physiologic endpoint, with subjects stratified by CMV serostatus.

Statistical Analysis

Enrollment of 30 subjects randomized 2:1 provides 70% power to detect a 25% higher proportion of subjects withdrawing in the valganciclovir-treated subjects (25%) compared with placebo-treated subjects (0%), with a one-sided type I error of 0.1. Patient characteristics were summarized as the mean and standard deviation for continuous variables or as the number and percentage for categorical variables. The safety and physiologic endpoints were analyzed on an intention-to-treat basis among enrolled subjects who were prescribed the study drug (the point of randomization). The frequency of adverse events, including the primary safety endpoint of the proportion of subjects completing 12 weeks of treatment, were compared by Fischer’s exact test.

Absolute change in FVC in milliliters and in the percentage of predicted from enrollment was compared between treatment groups at Week 12 and Month 12 using a nonparametric Mann-Whitney U test. A linear mixed model for repeated measures was used, with change in FVC from enrollment to Week 12, Month 6, Month 9, and Month 12 as a dependent variable and with enrollment FVC, time (modeled continuously), treatment group, and treatment by time interaction as explanatory variables, to test for a between–treatment-group difference in change in FVC from randomization to 12 months. The median change in FVC, relative to enrollment, was plotted for Week 12 through Month 12, with subjects stratified by treatment group and CMV serostatus. Missing data were not imputed in any analysis. All analyses were performed using R 3.6.1 (http://www.r-project.org), STATA 11.0 (StataCorp), or GraphPad Prism version 8.3 (GraphPad).

Results

Patient Characteristics

Between January 1, 2018, and January 31, 2019, 40 patients were screened, and 31 met eligibility criteria and were randomized, with 20 randomized to valganciclovir and 11 to placebo (Figure 1). Only one screened subject was excluded on the basis of negative serologies for both CMV and EBV. Baseline characteristics were similar in both treatment groups (Table 1) and comparable with other recent IPF clinical trial populations (2, 3, 17, 18). The majority of subjects in both groups were male, with a mean age of 68.2 (8.0) years in the placebo group and 66.9 (7.2) years in the valganciclovir group. A larger proportion of subjects in the valganciclovir group were CMV seropositive (90% [18/20] vs. 55% [6/11]). The baseline FVC was 69.4 ± 7.7% predicted in the placebo group and 69.4 ± 19.0% predicted in the valganciclovir group.

Figure 1.

Summary of study screening and enrollment. CMV = cytomegalovirus; Dl_CO = diffusing capacity of the lung of carbon monoxide; EBV = Epstein-Barr virus; eGFR = estimated glomerular filtration rate.

Table 1.

Baseline characteristics of study subjects

	Placebo	Valganciclovir
	n = 11	n = 20
Sex
Male	9 (81.8)	16 (80)
Female	2 (18.2)	4 (20)
Age	68.2 (8.0)	66.9 (7.7)
BMI	30.4 (4.9)	30.6 (4.6)
Years since IPF diagnosis	3.9 (3.1)	2.4 (1.5)
Serology
EBV only	6 (54.6)	2 (10)
CMV only	1 (9.1)	0
EBV + CMV	4 (36.4)	18 (90)
Certainty of IPF diagnosis
Definite	8 (72.7)	19 (95)
Probable	3 (27.3)	1 (5)
O2 saturation at rest	94.9 (2.7)	94.8 (2.1)
Pulmonary function tests
FVC% predicted	69.4 (7.7)	69.4 (19.0)
FEV1% predicted	79.7 (10.8)	76.9 (20.5)
TLC% predicted	62.1 (7.2)	62.19 (17.7)
DlCO% predicted	41.0 (8.9)	47.3 (10.2)
Laboratory studies
WBC	8.7 (2.3)	8.1 (1.8)
Hemoglobin	13.8 (1.8)	15.0 (1.0)
Platelets	244 (55)	216 (52)
Creatinine	0.96 (0.19)	0.97 (0.20)

Definition of abbreviations: BMI = body mass index; CMV = cytomegalovirus; Dl_CO = diffusing capacity of the lung of carbon monoxide; EBV = Epstein-Barr virus; FEV₁ = forced expiratory volume in 1 second; FVC = forced vital capacity; IPF = idiopathic pulmonary fibrosis; TLC = total lung capacity; WBC = white blood cell.

Data are presented as mean (standard deviation) or n (%).

Safety and Tolerability

During the active-treatment and monitoring phase (randomization to Week 16), serious adverse events were reported in three study subjects (one in the placebo group and two in the valganciclovir group). In the valganciclovir group, one subject developed a rash that required the discontinuation of the study medication; a second subject was hospitalized for pneumonia. One subject assigned to placebo died of prostate cancer after completing 12 weeks of the study medication but before Week 16 monitoring. There were no dose adjustments or other interruptions of the study drug in either treatment group (besides the subject with rash described above). The rate of discontinuation of the study drug because of adverse events did not differ between the two groups (5% [1/20] vs. 0% [0/11]; one-sided P = 1.0). A total of 46 TEAEs occurred among study subjects, including 13 in the placebo group and 33 in the valganciclovir group (Table 2). At the end-of-treatment visit, the mean white blood cell change in the valganciclovir treatment group was significantly lower than in the placebo group (−1.26 ± 1.45 10³/ml vs. 1.09 ± 1.70 × 10³/ml; P = 0.005) (see Table E1 in the online supplement); however, no subjects required dose adjustment or therapy interruption because of cytopenias. Otherwise, no differences in laboratory values were identified at the 12-week end-of-treatment visit. Overall, valganciclovir treatment was well tolerated over the 12 weeks of treatment.

Table 2.

Summary of AEs during active treatment (randomization to Week 16)

Total AEs	Total AEs			Serious AEs
	Total	Placebo	Val	Total	Placebo	Val
	46	13	33	3	1	2
At least 1 AE	18 (58.1)	4 (36.4)	14 (70)	3 (9.7)	1 (9.1)	2 (10)
Cough	4 (12.9)	1 (9.1)	3 (15)	0 (0)	0 (0)	0 (0)
Leukocytosis	4 (12.9)	3 (27.3)	1 (5)	0 (0)	0 (0)	0 (0)
Diarrhea	2 (6.5)	0 (0)	2 (10)	0 (0)	0 (0)	0 (0)
Elevated liver enzymes	2 (6.5)	0 (0)	2 (10)	0 (0)	0 (0)	0 (0)
Pneumonia	2 (6.5)	0 (0)	2 (10)	1 (3.2)	0 (0)	1 (5)
Worsened dyspnea	2 (6.5)	2 (18.2)	0 (0)	0 (0)	0 (0)	0 (0)
Acute pain of right shoulder	1 (3.2)	0 (0)	1 (5)	0 (0)	0 (0)	0 (0)
Acute respiratory failure	1 (3.2)	0 (0)	1 (5)	0 (0)	0 (0)	0 (0)
Acute sinusitis	1 (3.2)	0 (0)	1 (5)	0 (0)	0 (0)	0 (0)
Bilateral arm swelling	1 (3.2)	0 (0)	1 (5)	0 (0)	0 (0)	0 (0)
Bilateral lower leg edema	1 (3.2)	0 (0)	1 (5)	0 (0)	0 (0)	0 (0)
Carbuncle on face	1 (3.2)	0 (0)	1 (5)	0 (0)	0 (0)	0 (0)
Depression	1 (3.2)	1 (9.1)	0 (0)	0 (0)	0 (0)	0 (0)
Dyspepsia	1 (3.2)	1 (9.1)	0 (0)	0 (0)	0 (0)	0 (0)
Hoarseness	1 (3.2)	0 (0)	1 (5)	0 (0)	0 (0)	0 (0)
Hypertension	1 (3.2)	0 (0)	1 (5)	0 (0)	0 (0)	0 (0)
Hypoxic during flight	1 (3.2)	0 (0)	1 (5)	0 (0)	0 (0)	0 (0)
Jaw pain	1 (3.2)	0 (0)	1 (5)	0 (0)	0 (0)	0 (0)
Lymphopenia	1 (3.2)	1 (9.1)	0 (0)	0 (0)	0 (0)	0 (0)
Nausea	1 (3.2)	0 (0)	1 (5)	0 (0)	0 (0)	0 (0)
Nephrolithiasis	1 (3.2)	0 (0)	1 (5)	0 (0)	0 (0)	0 (0)
Pain in back	1 (3.2)	1 (9.1)	0 (0)	0 (0)	0 (0)	0 (0)
Paroxysmal atrial fibrillation	1 (3.2)	0 (0)	1 (5)	0 (0)	0 (0)	0 (0)
Prostate cancer recurrence	1 (3.2)	1 (9.1)	0 (0)	0 (0)	1 (9.1)*	0 (0)
Rash	1 (3.2)	0 (0)	1 (5)	0 (0)	0 (0)	1 (5)†
Respiratory tract infection	1 (3.2)	0 (0)	1 (5)	0 (0)	0 (0)	0 (0)
Sore throat	1 (3.2)	0 (0)	1 (5)	0 (0)	0 (0)	0 (0)
Throat tightening	1 (3.2)	1 (9.1)	0 (0)	0 (0)	0 (0)	0 (0)
Thrombocytopenia	1 (3.2)	0 (0)	1 (5)	0 (0)	0 (0)	0 (0)
Tooth pain	1 (3.2)	0 (0)	1 (5)	0 (0)	0 (0)	0 (0)
Upper respiratory infection	1 (3.2)	0 (0)	1 (5)	0 (0)	0 (0)	0 (0)
Vertigo	1 (3.2)	0 (0)	1 (5)	0 (0)	0 (0)	0 (0)
Weakness	1 (3.2)	0 (0)	1 (5)	0 (0)	0 (0)	0 (0)
Weight loss	1 (3.2)	0 (0)	1 (5)	0 (0)	0 (0)	0 (0)
Worsening anemia	1 (3.2)	1 (9.1)	0	0 (0)	0 (0)	0 (0)
Worsening in hypertension	1 (3.2)	0 (0)	1 (5)	0 (0)	0 (0)	0 (0)

Definition of abbreviations: AE = adverse event; Val = valganciclovir.

^*Death due to AE.

^†Study drug discontinued because of AE.

Treatment Effects on Secondary Physiologic Endpoints

From baseline to Week 12, the median absolute change in FVC was −40 (interquartile range [IQR], 60 to −130) ml in the placebo group and −10 (IQR, 70 to −65) ml in the valganciclovir group (Figure 2A). Absolute change in FVC% predicted was −2% (IQR, −4% to 2%) in the placebo group and 0% (IQR, −1% to 2%) in the valganciclovir group (Figure 2B). At the end of the follow-up period (12 mo after study enrollment), the median change in FVC% predicted was −1% (IQR, −4% to 1%) in the valganciclovir group and −5% (IQR, −10% to 1%) in the placebo group (P = 0.161 for treatment-group × time interaction in the mixed-effect model) (Figure 3). No significant differences were observed for other physiologic endpoints (Table E2). In the prespecified subgroup analysis stratifying by CMV serostatus, subgroups were too small to draw substantive conclusions as to the differential effect of treatment based on CMV serostatus; point estimates suggested similar treatment response regardless of CMV serostatus (Figures E1A and E1B).

Figure 2.

Absolute change in (A) forced vital capacity (FVC) in milliliters and (B) FVC% predicted from randomization to Week 12 (on treatment period) in subjects treated with placebo or Val. Each dot represents an individual subject. Val = valganciclovir.

Figure 3.

Absolute change in forced vital capacity (FVC) (% predicted) between baseline and follow-up visits, through 12-month follow-up. Data are presented as median (dot/square) and interquartile range (whiskers). The P value represents time × treatment interaction using a linear mixed-effect model adjusted for baseline FVC% predicted.

Discussion

This study represents the first randomized controlled trial of antiherpesvirus therapy as an add-on to standard therapy for IPF. Valganciclovir was well tolerated in this patient population, with only 1/20 subjects stopping valganciclovir without completing the planned 12 weeks of therapy. Laboratory evaluation demonstrated a clinically insignificant difference in the white blood cell count in valganciclovir treatment group subjects compared with the placebo after 12 weeks of treatment. This Phase IB trial was, by design, underpowered to detect a treatment benefit on the clinically meaningful outcome of change in FVC, and the point estimates were not concerning for treatment-related harm by this measure. Together, these data, coupled with data from a prior short open-label study of intravenous ganciclovir in patients with IPF (19), support a future study powered to evaluate the efficacy of herpesvirus treatment in IPF.

Pirfenidone was approved for the treatment of IPF in 2014, and recognized side effects include nausea and/or diarrhea (3). Nausea and diarrhea are also potential side effects of valganciclovir. Despite this potential interaction, only 2/20 valganciclovir-randomized subjects reported gastrointestinal side effects, and none were severe enough to require dose modification, interruption, or therapy discontinuation. Leukopenia is another potential side effect of concern among patients with IPF, particularly with the recognition that a subset of patients with IPF have short peripheral blood telomeres (20–22) and could be at increased risk for bone marrow suppression. We observed a statistically significant reduction in leukocyte count among valganciclovir-treated subjects from randomization to Week 12, although no subjects developed leukopenia, and no subjects required dose reduction or treatment interruption. Mildly elevated liver enzymes were observed in two valganciclovir-treated subjects. A larger proportion of valganciclovir-treated subjects reported at least one adverse event (14/20 vs. 4/11), although this difference was not statistically significant. Overall, the addition of valganciclovir to pirfenidone was well tolerated, and side effects were generally mild. The tolerability profile supports the feasibility of a large study powered for clinically meaningful endpoints.

Valganciclovir is approved for the treatment of CMV, although available data suggest there is also clinically significant activity against EBV (23). In this small study, there was an imbalance in EBV-only versus CMV-seropositive subjects between the two groups. It is possible that this imbalance enriched the valganciclovir group for those most likely to benefit from treatment, although point estimates from prespecified serostatus-stratified analyses (Figure E1) do not suggest a large serostatus-by-treatment interaction.

The mechanism through which herpesviruses may contribute to the pathogenesis of IPF remains uncertain, although available data suggest several possibilities. Herpesviruses that infect humans via the respiratory tract, including EBV and CMV, remain latent in lung epithelial cells and may undergo low-level reactivation that is typically controlled by antiviral T lymphocytes (24). In IPF, late herpesvirus antigen expression is detected in hyperplastic alveolar epithelial cells in areas of fibrosis and colocalizes with markers of endoplasmic reticulum stress (10). These findings suggest that immune surveillance mechanisms in IPF may be inadequate to completely control herpesvirus replication and increased expression of viral proteins, inducing an endoplasmic reticulum stress response. In addition, the presence of herpesvirus DNA in BAL from patients with familial IPF and presymptomatic family members (13) suggests that some degree of lytic replication occurs in IPF, possibly contributing to epithelial injury. Alternatively, latent or intermittent viral reactivation may lead to ongoing cytokine and interferon production (25), which may synergize to drive ongoing epithelial injury (26). In either circumstance, antiherpesviral treatments such as valganciclovir could affect the progression of fibrosis by limiting viral replication in the distal lung, as has been demonstrated in mouse models (27).

Strengths and Limitations

There are several other important limitations of this study, including the small sample size, relatively short duration of treatment, performance of the study at a single center, and restriction to patients already tolerating full-dose pirfenidone. As a result, this study cannot ascertain tolerability in patients receiving nintedanib or patients who could not tolerate either agent. Although no pharmacokinetic or pharmacodynamic interaction is expected with either antifibrotic agent, stratification based on background treatment will be important for assessing both tolerability and efficacy in future studies. In addition, a more comprehensive analysis of all human herpesviruses (HHVs), including HHV-6, HHV-7, and HHV-8, could be beneficial in understanding the full scope of herpesvirus contributions to IPF pathogenesis.

In conclusion, no limiting safety or tolerability signals were identified in patients with IPF by the addition of valganciclovir to pirfenidone treatment. Preliminary efficacy data support feasibility to perform a larger study with adequate power to address efficacy endpoints.