Side effects of hydroxychloroquine prophylaxis against COVID-19 in healthcare workers.

Dear Editor,

Hydroxychloroquine (HCQ) is an antimalarial drug with anti-inflammatory, antiproliferative, and immunomodulatory properties. HCQ has been demonstrated to have an anti-Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) activity in vitro. Indian Council of Medical Research (ICMR) issued guidelines for the prophylactic use of HCQ for Healthcare Workers (HCW) and high-risk contact of COVID-19 positive patients. HCQ mainly causes gastrointestinal, dermatological, neurological, retinal, and cardiac side effects., These side effects are mild and not considered as life-threatening except QT prolongation. Most side effects are documented with prolonged use and not at a low dose (once weekly) being planned for prophylaxis.

We conducted a retrospective analysis of the side-effect profile of HCQ taken as prophylaxis against COVID-19 by HCWs at a tertiary care hospital in southern India from June 2020 to July 2020. Participants were included if they were HCWs who were advised to take HCQ prophylaxis as per guidelines issued by ICMR dated 23 Mar 2020 (revised 22 May 2020). Inclusion criteria were if they had taken at least one dose of HCQ and willing to participate in the study. Exclusion criteria were HCWs already taking HCQ for any other disease, having known retinopathy, known Glucose-6-phosphate deficiency, known hypersensitivity to HCQ, and known prolonged baseline QTc interval. The dose of HCQ was 400 mg BD on day one followed by 400 mg once in a day every week, and to be taken with meals. All the doses were supervised. The data was collected through online Google Forms. Responses regarding demographic details, prior known illness, counseling before starting prophylaxis, the reason for stopping prophylaxis, and side effects of HCQ were collected. Participants were encouraged to come back for an ECG after at least a week of the first dose or any time after that while on drug. The sample size was calculated using the formula n = Z2 P (1−P)/d2. In this Z was 1.96 (at 95% confidence level) and precision (d) was 0.05. Taking prevalence (P) of the most common side effect (nausea 10.24%) from the HyPE study, a sample size of 142 participants was calculated. The sampling method used was nonprobability stratified. Online digital consent was taken from all the participants. Descriptive statistics were used to analyze the data. Google Forms were sent to 266 individuals meeting the inclusion criteria, out of which 230 responded. Five responses were rejected as they were incomplete, and data from 225 individuals were analysed.

Males constituted 193 (85.8%) of the study subjects. The mean age of the participants was 33 ± 7.9 years. The majority of the participants were paramedics (118, 52.4%). Nearly 50% (105) were having at least a graduate degree. Of the participants, 16 had known prior illness (diabetes mellitus: 5, hypertension: 3, coronary artery disease: 2, migraine: 2, allergic rhinitis: 2, chronic obstructive pulmonary disease, hypothyroidism, and hypertriglyceridemia: 1, and B cell lymphoma: 1). The mean duration of prophylaxis was 5.69 ± 2.63 weeks and the mean duration among those who discontinued the prophylaxis was 5.77 ± 2.61 weeks. Sixty-three (28%) participants discontinued the prophylaxis. The commonest reason for discontinuation of prophylaxis was side effects (30, 13.3%). A total of 57 (25.3%) participants experienced one or more side effects. Table 1 shows the frequency of the side-effect profile. The commonest side effect was headache (12%) and abdominal discomfort (12%). A follow-up ECG was available for 60 individuals during the course of prophylaxis. Only one participant had raised QTc interval, and none developed arrhythmia during the study period with a mean QTc interval 0.411 ± 0.051 s.

Table 1

Profile of side effects hydroxychloroquine.

Side Effects	Number	Percentage
Abdominal discomfort	27	12
Nausea/vomiting	6	2.7
Loose stools	3	1.3
Constipation	1	0.4
Abdominal bloating	2	0.8
Skin rashes	2	0.8
Alopecia	3	1.3
Photosensitivity	1	0.4
Palpitations	5	2.2
Chest discomfort	1	0.4
Headache	27	12
Dizziness	10	4.4
Sleep disturbances	2	0.8
Nervousness	2	0.8
Myalgia	1	0.4

Our study has shown that a quarter of our HCWs who took at least one dose of HCQ prophylaxis for the prevention of COVID-19 infection as per the laid down guidelines experienced some form of side effects. Half of these participants discontinued prophylaxis due to the side effects.

An ICMR study of 1323 HCW receiving HCQ prophylaxis during the COVID-19 pandemic shows that 214 (16.17%) participants developed side effects. Common side effects reported were abdominal pain (7.3%), nausea (8.9%), vomiting (1.5%), hypoglycemia (1.7%), and cardiovascular effects (1.9%). Another study from India known as HyPE study reported 30.7% events as adverse drug reaction with common side effects being abdominal pain (7.2%), nausea (10.2%), decreased appetite (4.8%), diarrhea (7.2%), vomiting (1.2%) headache (6.0%), dizziness (3.6%), palpitations (3.6%), and chest pain (1.2%).

The chief limitations of our study were retrospective nature, small sample size with lack of follow-up, no control arm to compare the results, recall bias, and lack of upfront evaluation at the start of HCQ.

Our study highlights the facts brought out in previous observations that side effects of HCQ taken in prophylactic doses for COVID-19 are frequent but mild.