Association of Ledipasvir-Sofosbuvir Treatment With Uveitis in Patients Treated for Hepatitis C

Key Points

Questions

Are there potential ocular adverse effects associated with ledipasvir-sofosbuvir (Harvoni), a treatment for hepatitis C?

Findings

In this case series, 6 patients treated with ledipasvir-sofosbuvir presented with signs of posterior uveitis. All patients had been treated with ledipasvir-sofobuvir in the past 2 years and had a negative systemic workup for uveitis.

Meanings

These cases suggest the possibility of an association between ledispavir-sofosbuvir for hepatitis C and a mild posterior uveitis different from interferon retinopathy.

This case series reports findings of posterior-predominant uveitis in 6 patients who were treated with ledipasvir-sofosbuvir for hepatitis C.

Abstract

Importance

Ledipasvir-sofosbuvir has become the current standard of care for hepatitis C since its release in 2014. Therefore, potential adverse effects are important to identify.

Objective

To report findings of uveitis after treatment with ledipasvir-sofosbuvir for hepatitis C.

Design, Setting, and Participants

This case series includes patients treated in an urban academic setting with ledipasvir-sofosbuvir for hepatitis C from June 2015 to June 2017 who are known to have developed signs and symptoms of posterior uveitis.

Exposures

All patients had been treated with ledipasvir-sofosbuvir for hepatitis C for a total of 12 weeks. All patients but 1 had finished treatment prior to presentation.

Main Outcomes and Measures

Signs of posterior uveitis on ophthalmic testing.

Results

Data were collected from 6 patients (median age, 64.5 [range, 54-72] years). Five patients were male; 4 were white, and 2 were African American. The mean (SD) time between beginning of treatment and presentation was 8.8 (5.5) months. Both eyes were affected in 3 of the 6 patients (total, 9 eyes). The median presenting visual acuity in affected eyes was 20/40 (range, 20/20-20/70). All patients had a negative systemic uveitis workup. Five patients presented with blurred vision, and 1 had a paracentral scotoma. The main ocular findings were peripheral vasculitis (in 8 of 9 eyes), papillitis (in 7 of 9 eyes), and cystoid macular edema (in 6 of 9 eyes). The median follow-up was 8 (range, 4-13) months. The median final visual acuity was 20/40 (range, 20/20-20/200).

Conclusions and Relevance

In these patients, it appears that treatment with ledipasvir-sofosbuvir for hepatitis C was associated with a mild posterior uveitis different than interferon retinopathy. Given the large number of patients treated with ledipasvir-sofosbuvir, these findings cannot be considered causative, and an association cannot be quantified at this time.

Introduction

Since 2014, combination therapy containing sofosbuvir has been the standard of care for the treatment of chronic hepatitis C (HCV) infection.¹ One of the most common combinations is ledipasvir-sofosbuvir (Harvoni [Gilead Sciences]), which has a cure rate of up to 99% for chronic genotype 1 HCV infection.² These newer-generation antiviral medications have substantially changed the prognosis of patients infected with HCV.

While interferon treatment has been known to cause retinal vasculopathy,³ hepatitis C infection itself has not been associated with uveitis or retinopathy. Sofosbuvir has previously been associated with impairment of tear function and squamous metaplastic changes to the ocular surface.⁴ Additionally, to our knowledge, there has been 1 reported case⁵ of acute anterior nongranulomatous uveitis and cotton wool spots after initiation of ribavirin and sofosbuvir. We report a series of 6 patients who presented with new, predominantly posterior uveitis after initiation of or completed treatment with ledipasvir-sofosbuvir.

Methods

All patients in this study consented to the presentation of deidentified information pertaining to their pathology. All participants were treated in accordance with the Declaration of Helsinki. Institutional review board exemption was granted by Wayne State University.

For all patients, the initiation date and duration of treatment with ledipasvir-sofosbuvir were noted. Initial examination included a full, dilated ophthalmic examination as well as ancillary testing, including fluorescein angiography and optical coherence tomography. Follow-up was dictated by the pathology and severity of loss of visual acuity. In general, most patients were seen within 1 month of initial presentation. Repeated ancillary testing was obtained at follow-up visits when clinically appropriate.

Results

Data were collected from 6 patients. The median age was 64.5 (range, 54-72) years. Five of 6 patients were male. Four patients were white, and 2 were African American. The median presenting visual acuity in the 9 affected eyes was 20/40 (range, 20/20-20/70). Three patients (50%) had bilateral involvement on presentation. The mean (SD) time of presentation from initiation of ledipasvir-sofosbuvir was 8.8 (5.5) months. All patients were treated with ledipasvir-sofosbuvir for 12 weeks. Five of the patients presented after treatment was complete. With the exception of 1 individual, the patients had no history of uveitis and a negative systemic uveitis workup, including testing for syphilis, tuberculosis, and sarcoidosis. The other patient had a history of uveitis of unknown causative mechanism. For sarcoidosis, tests of angiotensin-converting enzyme and lysozyme were completed. Additionally, complete blood cell count, complete metabolic panel, quantiferon gold, HIV, antinuclear antibody , and syphilis enzyme immunoassay tests were all obtained on all patients.

Five patients (83.3%) presented with blurry vision. Two (33.3%) presented with pain. Additionally, 1 patient presented with photophobia and 1 with a scotoma. The main ocular findings were peripheral vasculitis, which was venular in nature (n = 8 of 9 eyes), papillitis (n = 7 of 9 eyes), and cystoid macular edema (n = 6 of 9 eyes). Additionally, vitritis (n = 2 of 9 eyes) and iritis (n = 1 of 9 eyes) were seen.

One patient had a history of chronic noninfectious anterior uveitis that had been controlled for more than 1 year while receiving cyclosporine and low-dose oral prednisone. Within 2 months of initiating ledipasvir-sofosbuvir treatment, this patient developed posterior uveitis notable for vasculitis and cystoid macular edema.

Another patient had started receiving ledipasvir-sofosbuvir 1 month prior to uncomplicated cataract surgery, and persistent inflammation in the surgical eye was attributed to postoperative inflammation. However, when optical coherence tomography and fluorescein angiography were obtained, it was clear that the patient had uveitis and cystoid macular edema in the nonsurgical eye as well.

Two patients (33%) were observed, and 2 were treated with topical therapy. One patient was treated with oral corticosteroids, and the remaining patient was treated with both oral corticosteroids and continuing receiving the same dose of immunomodulatory therapy previously prescribed. The median follow-up was 8 (range, 4-13) months. The median final visual acuity ranged was 20/40 (range, 20/20-20/200). Three patients (50%) had improved inflammation, 1 (16.7%) had resolved inflammation, and 2 (33.3%) continued to have inflammation. Two patients (33.3%) were still receiving treatment at the most recent examination. The Table summarizes individual patient characteristics, presentations, and findings. The Figure is a widefield fluorescein angiography showing neuritis and peripheral vasculitis seen on presentation of a patient after treatment with ledipasvir-sofobuvir.

Table. Individual Patient Characteristics, Presentations, and Findings.

Patient No.	Time Since Starting Ledipasvir-Sofosbuvir, mo	Presenting Symptoms	Affected Eye	Presenting Best-Corrected Visual Acuity	Main Findings	Treatment	Most Recent Visual Acuity	Most Recent Findings
1	10	Blurry vision	OD	20/50 OD	Cystoid macular edema OD	Topical NSAID	20/25 OD	Improved
2	9	Scotoma	OD	20/25 OD	Vasculitis, papillitis OD	Observation	20/25 OD	Resolution
3	11	Blurry vision	OU	20/70 OU	Cystoid macular edema OD, vasculitis, papillitis OU	Oral steroids	20/70 OU	Improved
4	5	Blurry vision	OU	20/60 OD; 20/40 OS	Iritis OD, cystoid macular edema, papillitis, vasculitis OU	Topical steroids	20/200 OD; 20/80 OS	Persistent inflammation
5	1	Blurry vision, Photophobia, photopsia	OU	20/30 OD; 20/40 OS	Cystoid macular edema, chorioretinitis OD, papillitis, vasculitis OU	Oral steroids	20/25 OD; 20/40 OS	Persistent inflammation
6	17	Blurry vision	OS	20/20 OS	Cystoid macular edema, vasculitis OS	Observation	20/20 OS	Improved

Abbreviation: NSAID, nonsteroidal anti-inflammatory drug.

Figure. Fluorescein Angiography Showing Papillitis and Peripheral Vasculitis on Presentation of a Patient After Treatment With Ledipasvir-Sofosbuvir.

A, Right eye of a patient with papillitis and vasculitis; B, left eye of a patient with papillitis and neuritis.

Discussion

Ledipasvir-sofosbuvir has caused a change in the treatment of chronic HCV inflammation. In the first decade of this century, there were approximately 170 million individuals with chronic HCV.

However, it seems likely that there is an association between the medication and a posterior-predominant uveitis. The demographics of this group are atypical for the initial presentation of noninfectious uveitis, in that 5 of the 6 patients were older men. Of note, 3 of 6 patients were seen in a Veterans Affairs setting, which likely explains some of the male predominance.

Five patients did not have any history of uveitis or systemic rheumatic disease. However, 1 patient did have a history of chronic noninfectious anterior uveitis that had been controlled for more than 1 year with cyclosporine and low-dose oral prednisone. Within 2 months of initiating ledipasvir-sofosbuvir, this patient developed posterior uveitis notable for vasculitis and cystoid macular edema.

Another patient started receiving ledipasvir-sofosbuvir 1 month prior to uncomplicated cataract surgery, and persistent inflammation in the surgical eye was attributed to postoperative inflammation. However, when optical coherence tomography and fluorescein angiography were obtained, it was clear that the patient had cystoid macular edema in the nonsurgical eye as well. In retrospect, we believe this bilateral presentation may be more consistent with inflammation secondary to ledipasvir-sofosbuvir.

Mechanistically, both targets of ledipasvir-sofosbuvir, nonstructural protein 5A and nonstructural protein 5B, are viral proteins mostly involved in viral RNA replication.² Because the medications do not have a direct cytotoxic effect, one would not expect an increase in the lysis of infected cells, such as those seen in Mazzotti or Jarisch-Herxheimer reactions. Also, no associations were reported with interferon and ribavirin treatments for HCV and uveitis. Therefore, we suspect the inflammatory reaction is directly owing to ledipasvir-sofosbuvir.

Most of the patients had a mild course. All except 1 patient were not receiving systemic treatment at the time of the most recent follow-up visit. One patient did have decreased visual acuity owing to prolonged cystoid macular edema.

Limitations

We acknowledge that this case series is small. A cause-and-effect association cannot be determined. This information also cannot confirm any other statistical association.

Conclusions

We report a case series of ledipasvir-sofosbuvir with posterior uveitis. Although most cases had a mild course that improved with treatment, some patients were affected by cystoid macular edema. However, these 6 cases suggest further surveillance for this outcome should be considered.