Discussion
The use of HCQ early in the Covid-19 pandemic resulted in a substantial
increase in suspected ADR reporting associated with this medication. The
rise in HCQ use [14][15]–[17], along with the concerns
about its administration to Covid patients in spite of the lack of
sufficient scientific evidence, and the fact that everybody’s eyes were
focused on any aspects related to the pandemic because of the worldwide
mass media coverage may have played a part in this increment in
suspected ADR reporting. The subsequent decline in reporting is likely
to be related to calls to caution [7] as well as to the publication
of findings against HCQ [4],[5].
Both the patient profile and HCQ use pattern proved different in our two
groups (i. e, Covid and no-Covid patients). In the case of no-Covid
patients, the cases most often corresponded to middle-aged women treated
with low daily HCQ doses in a majority of cases. These patients did not
receive high daily doses (≥ 800 mg/day), even though the total
administered dose was considerably higher (median: 21,600), which is
consistent with the fact that the treatment length was substantially
longer. It should be underscored that, in both groups, a high percentage
of case notifications did not include any data on the administered
doses. Though important, the completion of the box ‘Administered doses’
in the report form is not obligatory to validate the notifications
submitted to SEFV-H. As expected, the main indications were rheumatic
conditions, arthropathies, and lupus erythematosus; however, we also
found off-label HCQ indications. Nearly half of patients took only HCQ,
and reported co-medications were principally corticoids, other
immunosuppressants, and painkillers. By active ingredient, methotrexate,
prednisone, enoxaparin, and mycophenolate were the most frequently
administered to these patients. Most of cases of Covid patients were
males, aged approximately a decade over their no-Covid counterparts,
who, in a majority of cases, were given medium daily HCQ doses, and a
low total dose in 100% of cases, a finding that is consistent with the
fact that the length of their treatment was considerably shorter.
Virtually all patients were treated with medications other than HCQ,
notably antimicrobials, corticoids, and immunosuppressants. By active
ingredient, azithromycin and the lopinavir+ritonavir combination were
the most frequently combined with HCQ in a high percentage of Covid
patients. This finding mirrors the kind of patients who were treated
with HCQ as well as the usual HCQ administration guidelines
[7],[18],[19]. These differences in patient features,
indications, HCQ doses and treatment length and use of medications other
than HCQ have by themselves the potential to change the safety profile
of the drug, as was the case of the modifications of ADR profile we
found in our study.
Firstly, there was a 24% excess of serious cases among Covid patients.
Covid patients on HCQ were, by definition, persons who have been
admitted to a hospital, and, therefore, it is assumed that they suffer
from a more serious disease, which may contribute to explain why Covid
patients in our study were in worse health condition. On the other hand,
because of the work overload of hospital healthcare professionals in
Spain in that time, it is reasonable to assume that only the most severe
ADRs were reported to the pharmacovigilance system. The overall profile
of ADRs potentially associated with HCQ we found in no-Covid patients
approximated to that in earlier studies [7],[20]. In no-Covid
patients on HCQ, the prevailing ADRs are cutaneous in nature, followed
by eye disorders, general health problems, nervous system disturbances,
and gastrointestinal disorders; while in Covid patients the most
frequent ADRs are hepatobiliary disorders, followed by gastrointestinal,
cardiac, general disorders and intoxications, and skin disorders.
Importantly, in the present study, the main differences between the two
groups corresponded to hepatobiliary, gastrointestinal, ocular and
cardiac disorders, which are usually reported more frequently in Covid
cases, on the one hand, and skin and nervous system disorders, the
reporting frequency of which was higher in no-Covid cases, on the other
(Figure 3).
The percentage of hepatobiliary disorders reported among the Covid cases
is a striking finding in our study. According to the reports released by
SEFV-H during the Covid-19 pandemic, most of hepatobiliary disorder
notifications came from only a single hospital, in which active
pharmacovigilance surveillance specifically for hepatotoxicity was
conducted [21], therefore hepatobiliary ADRs might be
overrepresented. Furthermore, it should be borne in mind that SARS-Cov-2
infection itself is associated with liver damage [22], which
suggests that, in our study, this finding may be flawed by an indication
bias. Nevertheless, earlier studies have also reported hepatobiliary
disorders to rank either first or second in frequency among Covid
patients on HCQ, particularly when this drug is combined with other
medications [23]–[25]. The disproportionality analysis we
conducted showed that there was an association between HCQ treatment and
both overall liver and severe liver disturbances only during the
pandemic period (Table 2).
Additionally, gastrointestinal disorders are reportedly the most
frequent ones upon HCQ treatment initiation. This holds true for both
Covid and no-Covid patients [26]. In our study, the gastrointestinal
tract is the second most frequently involved system in Covid patients on
HCQ, which is in line with the results from a Portuguese prospective
study [23]. Indeed, in our study, HCQ treatment in Covid patients is
associated with “non-infectious diarrhoea”, “ischaemic colitis” and
“gastrointestinal perforation, ulceration, haemorrhage or obstruction”
(see Table 2). Of note, the latter HCQ gastrointestinal disturbance had
not been reported anywhere before Covid-19 pandemic [7].
Cardiac involvement represented one of the major safety concerns when
HCQ was used for Covid treatment, especially given its use in
combination with azithromycin.. [27]. In the present study, cardiac
derangements have been reported to occur twice more frequently in Covid
patients as compared with their no-Covid counterparts. In fact,
according to disproportionality analysis results, three cardiac
disturbances ranked first, second and third, with cardiac arrhythmias,
specifically TdP/QTp, ranking first; and this was the heart problem for
which we found the largest number of differences in relation to
disproportion between the two patient groups (Table 2). This striking
increase in TdP/QTp in these patients may result from the use of higher
HCQ doses [26] or, alternatively, may be due to the use of
concomitant medications such as azithromycin [27], as shown by the Ω
statistic estimation (Table 3). Likewise, it is an outstanding finding
that the summaries of product characteristics of some of the drugs
currently commercialised in Spain that contain HCQ do not include this
risk in spite of mass media information impact and safety statements
released by both regulatory authorities and scientific societies
[7],[28]. Concerning cardiomyopathy, which was a cardiac ADR
reported in our study, we did not find any important differences in ROR
for the two groups of patients, despite cardiomyopathy was associated
with lengthy treatment with HCQ [26].
When HCQ was first used as a therapy for COVID-19, another cause of
concern was the attendant risk of retinopathy. Although this is an
infrequent complication, eventually it can cause irreversible blindness.
According to current evidence, retinopathy is related to HCQ dose and
treatment length. So, the most recent clinical guidelines recommend not
to exceed 5mg/kg body weight/day in order to prevent this HCQ therapy
complication [19]. In Spain, with a patient mean weight of 70 kg,
this recommendation would correspond to a dose of 350 mg/day. In our
study, most of doses given to Covid patients exceeded this figure.
Nonetheless, we found that retinopathy was more prevalent in no-Covid
patients in both frequency and disproportionality. Therefore, it could
be assumed that the risk of eye disturbances is more strongly associated
with HCQ treatment length than is with the dose, which would be in
keeping with results from earlier studies [26].
Skin reactions have been reported most frequently in HCQ treatment for
no-Covid patients. They are well established reactions in patients on
HCQ, and may become apparent in the form of rashes, itching and/or
hyperpigmentation. However, some of these skin adverse reactions may be
more worrying, as is the case of Stevens-Johnson syndrome (SJS) or toxic
epidermal necrolysis (TEN), and acute generalised exanthematous
pustulosis (AGEP). In some cases, they manifest themselves with
psoriatic lesions and hair loss or discoloration [7],[29]. Such
HCQ-related skin reactions can be classified according to the
accumulated dose, the most common being reactions that become apparent
following the administration of high accumulated doses [29], which
is in keeping with our finding that skin adverse reactions were most
often reported in patients undergoing prolonged HCQ therapy, that is, in
no-Covid patients. However, when looking at severe skin reactions,
including blistering and exfoliative conditions, we noted that these
reactions were notified relatively more frequently in Covid patients,
and furthermore ROR was higher in the pandemic period (Table 2). HCQ
accumulated dose range in which skin reactions appear is very broad. In
fact, such reactions may become evident with accumulated doses as low as
3,000 or 4,000 mg, as is the case of some severe skin complications such
as AGEP or Drug reaction with eosinophilia and systemic symptoms (DRESS)
[29]. Thus, it can be speculated that HCQ-related skin reactions in
the setting of COVID-19 therapy either were less frequent but more
severe or, alternatively, only the most severe reactions were notified.
The evidence on the risk of suicidal/self-injury behaviour has been
conflicting, and, up to date, there has been insufficient evidence
concerning the relationship of these psychiatric conditions to HCQ use
[30]. However, during the Covid-19 pandemic, it was one of the
causes of concern that led to change the summary of product
characteristics of HCQ. [31],[32]. While few cases had been
reported during the pre-pandemic period, this signal could have been
detected at that time. (Table 2).
Aside from the aforementioned psychiatric, hepatic and gastrointestinal
disorders and cardiac arrhythmias, we found further ADRs associated with
the use of HCQ in Covid patients that are usually overlooked or not are
observed so distinctly when HCQ is used for other indications, such as
dyslipidaemias, shock, ischaemic colitis, kidney disturbances,
noninfectious encephalopathy, and acute renal failure (Table 2). During
the pre-pandemic period, it had been reported malignant adverse
reactions, which may be explained by HCQ immunomodulatory effects.
However, these malignant ADRs should be interpreted cautiously.
Likewise, cytopaenias, including agranulocytosis, are well known HCQ
adverse reactions. Their disproportionality is lower in Covid patients,
which may be due to a shorter exposure time to the drug in these
patients. Concerning dyslipidaemias, it is remarkable that, in our
study, in all cases HCQ was given concomitantly with lopinavir +
ritonavir, medications for which dyslipidaemias are well established
ADRs. Therefore, it is reasonable to assume that, in the present study,
the use of lopinavir + ritonavir was a confounding factor.
Alternatively, these ADRs might be due to a true interaction, a
possibility suggested by the results we found with the Ω statistic.
We obtained significant estimators for interactions that, curiously
enough, only were found when HCQ was used to treat Covid patients. Some
of these interactions are known, such as the risk of TdP/QTp with the
concomitant use of azithromycin and, to a lesser extent, lopinavir and
ceftriaxone. On the contrary, other interactions are less known or even
unknown, like severe hepatic derangements and dyslipidaemias.
Pharmacovigilance database-based studies are flawed with obvious
limitations. The major drawback is probably under-reporting, which,
tough difficult to accurately estimate, has been reported to be as high
as 90% [33]. This, along with the lack of data on the comsuption of
the drug in question, prevent from accurately estimating the actual
incidence of the reported ADRs. Furthermore, the number of cases
notified to the database largely relies on a series of factors, such as
the involved medication (commercialisation time, use in the clinical
setting, current knowledge on the drug and so forth), and the reporting
person’s profile (available time, knowledge, expertise, and degree of
commitment with routine pharmacovigilance activities, etc.).
Additionally, the relevance and impact of all these limiting factors may
vary with time or other circumstances, as it was the case with Covid-19
pandemic. No doubt, public’s interest and concern, along with the mass
media focus, have markedly influence on ADR reporting during the
pandemic. On the other hand, it should be kept in mind that the Covid-19
pandemic had a major impact on the Spanish healthcare system running.
However, it is not possible to precisely understand the impact this
factor had on the ADR spontaneous reporting system and the
pharmacovigilance databases. Finally, the lacking clinical data in
notification forms is another constraint to be considered.
Still, spontaneous reporting systems presents several advantages: they
cover all types of authorised drugs; it is a simple, quick and
economical method enabling to generate hypotheses and identify new
potential safety concerns involving drugs, notably rare, infrequent or
unexpected events. Several studies showed that, despite their
shortcomings, spontaneous reporting systems have the potential to
identify early and efficiently emergent risks associated with the use of
medications [34]–[37].