Safety and Efficacy of Hydroxychloroquine for Treatment of Non-Severe COVID-19 in Adults in Uganda:

Updated: Sep 19, 2021

Background

Several repurposed drugs such as hydroxychloroquine (HCQ) have been investigated for the treatment of COVID-19, but none was confirmed to be efficacious. While in vitro studies have demonstrated antiviral properties of HCQ, data from clinical trials were conflicting regarding its benefit for COVID-19 treatment. Drugs that limit viral replication may be beneficial in the earlier course of the disease thus slowing progression to severe and critical illness.

Design

We conducted a randomized open-label Phase II clinical trial from October -December 2020.

Methods

Patients diagnosed with COVID-19 using RT-PCR were included in the study if they were 18 years and above and had a diagnosis of COVID-19 made in the last 3 days. Patients were randomized in blocks, to receive either HCQ 400mg twice a day for the first day followed by 200mg twice daily for the next 4 days plus standard of care (SOC) treatment or SOC treatment alone. SARS COV-2 viral load using nasal/oropharyngeal swabs was performed at baseline, day 2, 4, 6, 8, and 10. The primary outcome was median time from randomization to SARS COV-2 viral clearance by day 6.

Results

Of the 105 participants enrolled, 55 were assigned to the intervention group (HCQ plus SOC) and 50 to the control group (SOC only). Baseline characteristics were similar across treatment arms. Viral clearance did not differ by treatment arm, 20 and 19 participants respectively had SARS COV-2 viral load clearance by day 6 with no significant difference, median (IQR) number of days to viral load clearance between the two groups was 4(3-4) vs 4(2-4): p=0.457. There were no significant differences in secondary outcomes (symptom resolution and adverse events) between the intervention group and the control group. There were no significant differences in specific adverse events such as elevated alkaline phosphatase, prolonged QTc interval on ECG, among patients in the intervention group as compared to the control group.


Safety and Efficacy of Hydroxychloroquine for Treatment of Non-Severe COVID-19 in Adults in Uganda:

Study Site We conducted a randomized open-label Phase II clinical trial entitled Hydroxychloroquine for Treatment of Non-Severe COVID-19 (HONEST trial) from October -December 2020. The study was conducted at the Namboole nontraditional isolation facility where patients with asymptomatic or mild COVID-19 with no comorbidities were isolated and managed. Namboole stadium, a multipurpose stadium located 10 km east of the central business district of Kampala city, was remodeled into a COVID-19 isolation and treatment facility for patients with asymptomatic and mild COVID-19 due to escalating numbers in the country.

Study design and population Diagnosis of COVID-19 was performed using RT-PCR at the government-approved laboratories. Patients diagnosed with COVID-19 were included in the study if they were 18 years and above and had a diagnosis of COVID-19 made in the last 3 days. Patients were excluded if they had known allergies to HCQ or chloroquine, were on medications that have clinically significant interactions with HCQ, had a positive rapid test for malaria, were diagnosed with severe/critically ill COVID-19 (WHO Ordinal Scale of ≥ 5), had QTc prolongation of > 450ms for males and > 470ms for females, were pregnant or breastfeeding or were on chronic HCQ use. Participants found to have hypo- or hyperkalemia at baseline were withdrawn from the study.


Discussion

In this randomized, open-label, clinical trial to determine the safety and efficacy, of HCQ for treatment of non-severe SARS CoV-2 PCR-positive adults in Uganda, we found no difference in the proportion of participants who had PCR negative conversion, a 50% reduction in SARS-CoV-2 viral load (based on Ct values) after 6 days of treatment, or the resolution of symptoms by day 10 of treatment when we compared participants who were randomized to receive HCQ and participants receiving SOC. The novel coronavirus, SARS-CoV-2, which causes COVID-19, is the seventh human coronavirus described to date. By 3 July 2020, more than 11 million COVID-19 infections were reported worldwide resulting in more than 450,000 deaths.10 Since March 2020, various therapies have been evaluated in clinical trials with the adoption of some in clinical guidelines. One of these therapies, HCQ, was first used in 1955 and is considered to have a superior safety profile over chloroquine.11 In vitro studies suggest that HCQ prevents SARS-CoV-2 binding to gangliosides, subsequently preventing binding with the Angiotensin-converting enzyme receptor (ACE-2), required for viral entry into cells.12 By incorporating into endosomes and lysosomes, the drug increases the pH of intracellular compartments, resulting in defective protein degradation, endocytosis, and exocytosis required for viral infection, replication, and propagation.13 HCQ was shown to inhibit a broad range of viruses including coronaviruses (SARS-CoV-1 and Middle East respiratory syndrome-CoV) in cell culture,14 15 however, evidence from Hamster models suggested that HCQ did not demonstrate an effect on reducing SARS-CoV-2 virus levels.16 By 13 April 2021, 62 trials of HCQ for the treatment of COVID-19 had been completed.17 The efficacy of HCQ has been explored in both mild-moderate and severe COVID-19 disease. Similar to our study, Chen and colleagues did not find statistically significant differences in PCR conversion rate by day 7 and no difference was observed in clinical outcomes.18 The SOLIDARITY trial conducted in multiple countries did not demonstrate mortality benefit among hospitalized patients who were treated with HCQ.19 In a trial evaluating the efficacy of HCQ and standard of care vs standard of care alone, Tang and colleagues showed that the addition of HCQ did not result in a significantly higher probability of negative PCR conversion by 28 days.20 In outpatient settings, HCQ has also shown mixed efficacy when used as post-exposure prophylaxis with one study in India showing a relative reduction in the incidence of COVID-1921 while two other trials in the United States and Canada did not demonstrate any benefit in the prevention of COVID-19.22 23 Further, the use of once or twice weekly or daily (over 8 weeks) HCQ as pre-exposure prophylaxis among health care workers did not significantly reduce the incidence of laboratory-confirmed SARS-CoV-2 infection.24 25 A recent metanalysis showed that there was insufficient evidence to demonstrate the efficacy of HCQ in reducing short-term mortality or risk of hospitalization among outpatients with SARS-CoV-2 infection.26 One study combining HCQ with azithromycin demonstrated significantly reduced viral titers at day 6 resulting in a shortened time to clinical recovery and cough remission,5 however, the sample size was small, and the severity of the disease was not clearly stated. Although the U.S. Food and Drug Administration had issued an Emergency Use Authorization for the use of HCQ to treat COVID-19 in adolescents and adults on 28 March 2020,27 this authorization was later revoked on April 15, 2020, due to growing evidence of cardiac adverse events along with evidence suggesting that the drug was unlikely to be effective in treating COVID-19.

Ethics approval and consent to participate

Ethics approval was obtained from the Makerere University School of Medicine Research and Ethics Committee REF 2020-137), the Uganda National Council for Science and Technology (RESCLEAR/05), and the National Drug Authority (CTA 0143). Written informed consent was obtained from all study participants and the trial was conducted according to Good Clinical Practice Guidelines by the Declaration of Helsinki.

Credited to Pauline Byakika-Kibwika


 






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