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Correspondence |

Direct-Acting Antiviral Medications for Hepatitis C Virus Infection and Pulmonary Arterial Hypertension FREE TO VIEW

Laurent Savale, MD, PhD; Marie-Camille Chaumais, PharmD, PhD; David Montani, MD, PhD; Xavier Jaïs, MD; Christophe Hezode, MD, PhD; Teresa-Maria Antonini, MD; Audrey Coilly, MD; Jean-Charles Duclos-Vallée, MD, PhD; Didier Samuel, MD, PhD; Gerald Simonneau, MD; Marc Humbert, MD, PhD; Olivier Sitbon, MD, PhD
Author and Funding Information

FINANCIAL/NONFINANCIAL DISCLOSURES: The authors have reported to CHEST the following: The French pulmonary hypertension pharmacovigilance network, VIGIAPATH, is supported by the Agence Nationale de Sécurité du Médicament et des Produits de Santé (ANSM). L. S., X. J., O. S., D. M., G. S., and M. H. have relationships with drug companies including Actelion, Gilead, Bayer, GSK, Novartis, and Pfizer. In addition to being investigators in trials involving these companies, other relationships include consultancy services and memberships of scientific advisory boards. T-M. A. has been a clinical investigator and/or speaker for Abbvie, Bristol-Myers Squibb, Gilead Sciences, Janssen Pharmaceuticals, Merck Sharp & Dohme, and Roche. J-C. D-V. has been a clinical investigator, speaker and/or consultant for Astellas, Bristol-Myers Squibb, Gilead Sciences, Janssen Pharmaceuticals, Abbvie, Novartis, and Roche. A. C. has been a speaker and/or consultant for Abbvie, Astellas, BMS, Gilead, Janssen, MSD, and Novartis. D. S. has been a consultant for Astellas, Novartis, Gilead Sciences, Abbvie, MSD, LFB, and Biotest. C. H. has been speaker and/or adviser for Abbvie, BMS, Gilead, Janssen, and MSD. M.-C. C. has a relationship with Gilead Sciences for consultancy services.

aUniversité Paris-Sud, Faculté de Médecine, le Kremlin Bicêtre, France

bAssistance Publique-Hôpitaux de Paris (AP-HP), Service de Pneumologie, Département Hospitalo-Universitaire (DHU) Thorax Innovation, Hôpital Bicêtre, le Kremlin Bicêtre, France

cINSERM UMR_S 999, Hôpital Marie Lannelongue, le Plessis Robinson, France

dUniversité Paris-Sud, Faculté de Pharmacie, Chatenay Malabry, France

eAP-HP, Service de Pharmacie, DHU Thorax Innovation, Hôpital Antoine Béclère, Clamart, France

fAP-HP, Centre Hépatobiliaire, DHU Hepatinov, Hôpital Paul Brousse, Villejuif, France

gINSERM, Unité 1193, Villejuif F-94800, France

hAP-HP, Service d'hépatologie, Hôpital Henri Mondor, Créteil, France

CORRESPONDENCE TO: Laurent Savale, MD, PhD, Service de Pneumologie, Hôpital Bicêtre, Assistance Publique Hôpitaux de Paris, 78, rue du Général Leclerc, 94270 Le Kremlin Bicêtre, France


Copyright 2016, American College of Chest Physicians. All Rights Reserved.


Chest. 2016;150(1):256-258. doi:10.1016/j.chest.2016.04.031
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Published online

We read with interest the article by Renard et al in CHEST (March 2016) reporting newly diagnosed or worsening pulmonary arterial hypertension (PAH) in 3 patients treated with sofosbuvir for hepatitis C virus (HCV) infection. As discussed by the authors, the causal link between direct-acting antiviral (DAA) medications for HCV and PAH is difficult to confirm at this stage because all 3 patients had concomitant PAH risk factors (portal hypertension and/or HIV infection). To supplement these observations, we have collected all cases of PAH monitored in the French referral center for severe pulmonary hypertension with a history of DAA therapy. Patients who received concomitant interferon therapy were excluded. A total of 16 patients were identified.

Among them, 13 had a known history of PAH associated with portal hypertension (PoH) and/or HIV infection treated before initiation of DAA therapy. After a median follow-up of 7 months after initiation of DAA exposure, we did not observe any case of clinical, functional, or echocardiographic worsening of preexisting PAH. Invasive hemodynamic assessment by means of right heart catheterization performed before and after treatment in 9 of them did not show significant increase in pulmonary vascular resistance (PVR) (4.4 ± 1.1 Wood units [WU] before DAA therapy vs 5.1 ± 2.7 Wood units, 7.2 months [interquartile range 25-75: 4.8-10.4]) after initiation of DAA therapy, P = .17). However, 3 of them had an increase in PVR exceeding 20% vs baseline.

In contrast, PAH was diagnosed after DAA therapy initiation in 3 patients who were asymptomatic before exposure. PoH was definitively ruled out in the first patient, who had a liver fibrosis stage F3, after performing a liver ultrasound, a gastroscopy, and a measurement of transhepatic pressure gradient. However, the 2 other patients had cirrhosis with evident PoH. The clinical, functional, and hemodynamic evolution of these 3 patients after cessation of DAA therapy and specific management of PAH is reported in Table 1. Interestingly, PAH was reversible in the patient without PoH with persistent normalization of pulmonary pressure 9 months after DAA withdrawal and without PAH-targeted therapies. In addition, PAH was dramatically improved with PAH-targeted therapy but not totally reversible in the other 2 patients. Indeed, we observed a dramatic and unusual reduction of PVR by 75% in the second patient and a near-normalization of PVR (<3 WU) in the third patient.

Table Graphic Jump Location
Table 1 Cases of PAH Diagnosed After DAA Therapy
a Sustained virological response was obtained with DAA therapy for patients 1 and 3.
b Patient 2 received 2 other lines of DAA 3 years earlier (asunaprevir + daclatasvir + interferon + ribavirin during 24 weeks) and 1 year earlier (sofosbuvir + simeprevir during 12 weeks).

CO = cardiac output; DAA = direct-acting antiviral; PAH = pulmonary arterial hypertension; PoH = portal hypertension; PVR = pulmonary vascular resistance; mPAP = mean pulmonary arterial pressure; WU = Wood units.

It remains a great challenge to definitively confirm the causal role of a medication in the occurrence of PAH, mainly in patients with HCV infection because of frequent concomitant PAH risk factors such as PoH, HIV infection, and/or exposure to other drugs and toxins.,, In our study, the observation of a reversible case after DAA therapy in a patient without cofounding risk factor gives an additional signal for a potential involvement of DAA therapy in the development of PAH. At this stage, health care providers and drug regulatory agencies must be aware of a potential involvement of DAAs in pulmonary vascular side effects. To provide further clinical evidence to support a causal link, a systematic report of future suspected cases would be essential.

References

Renard S. .Borentain P. .Salaun E. .et al Severe pulmonary arterial hypertension in patients treated for hepatitis C with sofosbuvir. Chest. 2016;149:e69-e73 [PubMed]journal. [CrossRef] [PubMed]
 
Galie N. .Humbert M. .Vachiery J.L. .et al 2015 ESC/ERS guidelines for the diagnosis and treatment of pulmonary hypertension: The Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT). Eur Respir J. 2015;46:903-975 [PubMed]journal. [CrossRef] [PubMed]
 
Savale L. .Sattler C. .Gunther S. .et al Pulmonary arterial hypertension in patients treated with interferon. Eur Respir J. 2014;44:1627-1634 [PubMed]journal. [CrossRef] [PubMed]
 
Savale L. .Chaumais M.C. .Sitbon O. .Humbert M. . Pulmonary arterial hypertension in patients treated with interferon. Eur Respir J. 2015;46:1851-1853 [PubMed]journal. [CrossRef] [PubMed]
 

Figures

Tables

Table Graphic Jump Location
Table 1 Cases of PAH Diagnosed After DAA Therapy
a Sustained virological response was obtained with DAA therapy for patients 1 and 3.
b Patient 2 received 2 other lines of DAA 3 years earlier (asunaprevir + daclatasvir + interferon + ribavirin during 24 weeks) and 1 year earlier (sofosbuvir + simeprevir during 12 weeks).

CO = cardiac output; DAA = direct-acting antiviral; PAH = pulmonary arterial hypertension; PoH = portal hypertension; PVR = pulmonary vascular resistance; mPAP = mean pulmonary arterial pressure; WU = Wood units.

References

Renard S. .Borentain P. .Salaun E. .et al Severe pulmonary arterial hypertension in patients treated for hepatitis C with sofosbuvir. Chest. 2016;149:e69-e73 [PubMed]journal. [CrossRef] [PubMed]
 
Galie N. .Humbert M. .Vachiery J.L. .et al 2015 ESC/ERS guidelines for the diagnosis and treatment of pulmonary hypertension: The Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT). Eur Respir J. 2015;46:903-975 [PubMed]journal. [CrossRef] [PubMed]
 
Savale L. .Sattler C. .Gunther S. .et al Pulmonary arterial hypertension in patients treated with interferon. Eur Respir J. 2014;44:1627-1634 [PubMed]journal. [CrossRef] [PubMed]
 
Savale L. .Chaumais M.C. .Sitbon O. .Humbert M. . Pulmonary arterial hypertension in patients treated with interferon. Eur Respir J. 2015;46:1851-1853 [PubMed]journal. [CrossRef] [PubMed]
 
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