Ophthalmic data on TQ
This study reported ophthalmic data from a clinical efficacy and safety trial of TQ monotherapy versus CQ/PQ sequential therapy in patients with P. vivax malaria. It is the first study to show that short-course (3-day) TQ can cause mild keratopathy. The study also collected data to evaluate for possible retinopathy, though results were inconclusive. The 1200 mg total TQ dose was evaluated to see whether higher doses were more effective for radical cure as monotherapy, but also provides a vital safety dataset at four times the single TQ dose (300 mg) used in Phase III trials for P. vivax radical cure in combination with CQ (1500 mg free base). The information from this study thus continues to build the ocular safety database for this important new drug.
In the TQ group, by direct slit-lamp examination, keratopathy was reported in 14/44 (31.8%) evaluable patients. In these patients, there was no effect on vision and the keratopathy observed was considered to be benign and reversible. Structurally, TQ has cationic amphiphilic characteristics such that an effect on the cornea might be expected. Phospholipidosis is associated with amphiphilic drugs, such as aminoquinoline antimalarials, and can result in accumulation of intracellular phospholipids which cannot be metabolized by lysosomal phospholipases. These deposits are known to occur with CQ in the corneal epithelium and superficial stroma [
17]. They may first appear as a Hudson-Stähli line or an increase in a preexisting Hudson-Stähli line. They are more commonly seen as a whorl-like pattern known as cornea verticillata, which can be seen with other amphiphilic drugs, such as amiodarone or chlorpromazine [
17]. In this study, keratopathy appeared after only three large TQ doses (total dose 1200 mg). This may be related to the TQ half-life of about 17.5 days (range 4–36 days) and a large volume of distribution, suggesting extensive tissue binding [
25‐
27]. However, whether there is a direct relationship between TQ pharmacokinetics and keratopathy has yet to be determined.
Because direct examinations were assessed from the cornea to the retina, the presence of keratopathy could have unintentionally unblinded the study. However, that there were more reports of retinal abnormalities described as mild mottling of the retinal pigment epithelium or hypopigmentation in the TQ (10/44, 22.7%) versus CQ/PQ (2/24, 8.3%) group; that 7 TQ patients had both keratopathy and retinopathy versus none in the CQ/PQ group; and that retinal changes remote from macula at Day 28 and Day 90 versus baseline in one TQ patient suggested increasing morphological changes (despite no clinically relevant changes in visual acuity or decreased visual field sensitivity) indicates that possible correlations between keratopathy and retinopathy, and in one case early progressive retinal epithelium changes, related to TQ cannot be ruled out.
Visual field testing (Humphrey™ 10-2) was the most sensitive objective test of retinal toxicity used in this study [
15,
21]. Post-baseline, a similar frequency of mildly decreased sensitivity was seen; 7/44 (15.9%) with TQ and 3/24 (12.5%) with CQ/PQ. In all cases, changes were < 5 dB; below the threshold considered clinically relevant. In all but three cases, there were no concurrent findings on retinal examination. In the CQ/PQ group, all of the abnormal Humphrey™ 10-2 tests had resolved by Day 90. In the TQ group, four patients had abnormal Humphrey™ 10-2 tests at Day 90; of these, one patient continued to have a decreased sensitivity from Day 28 (in both eyes) and three patients had abnormal results emerging at this assessment (in one eye only). It is not clear why such findings should appear so late during follow-up in these three patients.
The current study was limited by the recommended methods at the time that it was conducted, whereas more sensitive tests to evaluate drug ocular toxicity are now available. Recent guidelines from the American Academy of Ophthalmology (AAO) recommend Humphrey™ 10-2 fields for screening after prolonged CQ treatment plus the use of one or more of the following objective tests: multifocal electroretinogram (mfERG), spectral domain optical coherence tomography (SD-OCT), and fundus autofluorescence (FAF) [
15]. When Humphrey™ 10-2 fields are performed independently, even the most subtle changes are an indication for objective testing. The study reported in this paper was conducted before this AAO guidance, and is limited in its conclusions as these investigations were not performed [
15]. Also, guidelines suggest using a person’s height for calculating drug dose, rather than body weight, as this can lead to overmedication with CQ in obese patients [
28,
29]. A study investigating ocular toxicity with TQ versus placebo in healthy volunteers has recently been completed and includes SD-OCT and FAF in addition to standard clinical assessments (ClinicalTrials.gov Identifier: NCT02658435). Conducting these assessments within a malaria treatment clinical trial would be challenging as the necessary facilities would not normally be available at the point of care.
The first study to report ocular safety of TQ was conducted in healthy volunteers receiving TQ 200 mg weekly for 6 months in Bethesda, MD and Chiltern, UK [
30], though is not directly comparable to the current study as different macular function tests were used and there were no clinical retinal examinations, only retinal photography. In the 70 subjects receiving TQ available for assessment, there was no effect on night vision (low-contrast visual acuity test, mesopic contrast threshold tests, and scotopic contrast test) compared with 32 subjects receiving placebo [
30]. Forward light scatter test and macular functions were also similar between the two groups after 6 months of TQ therapy [
30]. Based on digital retinal photographs, retinal abnormalities were noted in one patient in each study arm. In the subject receiving TQ, a single area of retinal hyperpigmentation was detected at follow-up, without any decline in visual acuity, foveal sensitivity, or change in visual field, and remained unchanged for 11 months after therapy cessation [
30]. The subject receiving placebo had a retinal abnormality noted at 12 weeks that resolved within 2 months. Independent retinal photograph grading was performed for 39 subjects receiving TQ and 21 in the placebo group with no findings of changes in retinal morphology or any objective signs of toxicity [
30]. Humphrey™ 10-2 tests were performed, with no apparent trends in the rate of timing of abnormal results [
30]. However, one subject receiving TQ (
n = 56) was withdrawn at week 3 for an abnormal Humphrey™ 10-2 test; there was no effect on vision and the mild decrease in macular sensitivity resolved spontaneously [
30].
A previous study of long-term TQ prophylaxis described ocular effects. In the study, Australian soldiers received TQ 200 mg weekly for 6 months. Whorl-like formations and mild vortex keratopathy were observed in 69/74 (93.2%) subjects [
20]. The changes were reversible and resolved by 1 year and did not adversely affect visual acuity [
20]. In these subjects, retinal abnormalities were also noted on clinical examination in 27/69 (39.1%) receiving TQ (e.g. granularity/pigmentation of the retinal pigment epithelium or hard drusen) versus 4/17 (23.5%) receiving mefloquine (MQ). Retinal FFAs were performed on subjects with possible retinal findings; 14 receiving TQ, 1 receiving MQ. Of these, four TQ subjects and one MQ subject had FFAs that were considered possibly abnormal [
20]. However, review of these data by an Independent Expert Ophthalmology Review Board concluded that the retinal findings could have been normal variations and that there was no evidence of drug-related visual disturbances. The study was limited in that retinal fundoscopic examinations were unmasked at follow-up because the presence of corneal deposits was already known to investigators. Also, there were no baseline data present for comparison. Humphrey™ 10-2 results were normal in all subjects (
N = 63) in the TQ group and in 15/16 (93.8%) of subjects in the MQ group [
20]. These data, taken together with the Bethesda volunteer study described above, provided no conclusive evidence of early retinal changes related to TQ, though the number of subjects examined was small. Note that subjects receiving prophylaxis received much larger TQ doses, and for longer, than for
P. vivax radical cure.
Compared to the prophylaxis study in Australian soldiers, the shorter TQ dose duration used in the current trial might have led to the decreased frequency and severity of the ocular findings noted. However, our results are consistent with a trial in healthy volunteers in the USA and UK, in which 15/60 (25.0%) subjects given TQ 200 mg weekly for 6 months had mild keratopathy compared with 4/25 (16.0%) in the placebo arm [
30]. The differences between these studies may reflect differences in data collection methods, data quality, environmental exposure, ethnic or other unknown factors. Sufficient data are not yet available to allow comment on the relationship between TQ dose and duration and the incidence of keratopathy.
In studies investigating
P. vivax radical cure, two older reports of the effect of TQ at doses ranging from 500 mg single dose to 2100 mg over 7 days after treatment with CQ (
N = 90) did not include ophthalmic safety data specifically [
8,
9]. However, 4/90 (4.4%) patients receiving TQ experienced an eye-related adverse event (one each of conjunctivitis, eye irritation, blurred vision and ocular hyperemia); there were no instances in the comparator groups (CQ and CQ/PQ) [
31]. A recent, much larger Phase IIb randomized dose-ranging trial included 329 patients with
P. vivax malaria who received TQ doses of 50 mg, 100 mg, 300 mg or 600 mg as a single-dose plus 3-day CQ (total CQ dose 1500 mg free base equivalent) or CQ/PQ or CQ alone [
14]. Adverse events attributed to eye disorders occurred in 5/225 (2.2%) of patients that received TQ/CQ (2 conjunctivitis, 2 eye pain, 1 blurred vision, 1 conjunctivial hyperemia) versus 2/50 (4.0%) with CQ/PQ (both blurred vision) and 2/54 (4.0%) with CQ alone (both blurred vision) [
14]. Ophthalmic assessments were conducted in 93 patients overall, with no reports of keratopathy in any treatment group [
14]. There were mild post-baseline transient changes in the results of the Humphrey visual field test in 7/61 (11%) patients receiving TQ/CQ, 1/15 (7%) with CQ/PQ, and in 1/17 (5.9%) with CQ alone. In all cases, these findings had resolved by Day 180 of the study. There were no other clinically important ophthalmic findings [
14].
In the current study, despite the known ocular toxicity of CQ, keratopathy or clinically relevant ocular changes were not reported in the CQ/PQ group. These findings are consistent with the short (3-day) dose duration of CQ in antimalarial therapy. Ocular complications, such as corneal opacity, reversible retinal lipidosis, and irreversible receptor cell degeneration have been documented with CQ, generally during extended use in rheumatoid diseases [
15,
17,
32,
33]. The risk of ocular complications increases with therapy duration, and CQ doses of 250 mg or below are rarely associated with ocular side effects if used for less than 6 months [
15,
17]. A retrospective study of CQ ocular toxicity among 155 Thai patients aged 10–70 years, who received treatment for 6–14 years with a cumulative dose of 26–1771 g, found that early retinal toxicity occurred at 9 months of treatment, with an overall prevalence of keratopathy of 9.0% (17/155) and retinopathy of 14.2% (22/155), without correlation between keratopathy and retinopathy [
32]. Rheumatologists have switched from using CQ to hydroxychloroquine (HCQ) because of its better safety profile in long-term use. The risk of developing HCQ retinopathy is rare and the cumulative dose appeared to be a more important factor than daily dosage [
19]. Retinal toxicity associated with CQ and HCQ may continue to progress despite cessation of the drug therapy [
19]. The largest study, in 400 Greek patients with rheumatoid arthritis or systemic lupus treated with < 6.5 mg/kg/day HCQ for a mean of 8.7 years reported the incidence of irreversible retinal toxicity as 0.5% [
34].