A systematic review and meta-analysis on chloroquine and hydroxychloroquine as monotherapy or combined with azithromycin in COVID-19 treatment

Abstract

Many recent studies have investigated the role of either Chloroquine (CQ) or Hydroxychloroquine (HCQ) alone or in combination with azithromycin (AZM) in the management of the emerging coronavirus. This systematic review and meta-analysis of either published or preprint observational studies or randomized control trials (RCT) aimed to assess mortality rate, duration of hospital stay, need for mechanical ventilation (MV), virologic cure rate (VQR), time to a negative viral polymerase chain reaction (PCR), radiological progression, experiencing drug side effects, and clinical worsening. A search of the online database through June 2020 was performed and examined the reference lists of pertinent articles for in-vivo studies only. Pooled relative risks (RRs), standard mean differences of 95% confidence intervals (CIs) were calculated with the random-effects model. Mortality was not different between the standard care (SC) and HCQ groups (RR = 0.99, 95% CI 0.61-1.59, I² = 82%), meta-regression analysis proved that mortality was significantly different across the studies from different countries. However, mortality among the HCQ + AZM was significantly higher than among the SC (RR = 1.8, 95% CI 1.19-2.27, I² = 70%). The duration of hospital stay in days was shorter in the SC in comparison with the HCQ group (standard mean difference = 0.57, 95% CI 0.20-0.94, I² = 92%), or the HCQ + AZM (standard mean difference = 0.77, 95% CI 0.46-1.08, I² = 81). Overall VQR, and that at days 4, 10, and 14 among patients exposed to HCQ did not differ significantly from the SC [(RR = 0.92, 95% CI 0.69-1.23, I² = 67%), (RR = 1.11, 95% CI 0.26-4.69, I² = 85%), (RR = 1.21, 95% CI 0.70-2.01, I² = 95%), and (RR = 0.98, 95% CI 0.76-1.27, I² = 85% )] respectively. Exposure to HCQ + AZM did not improve the VQR as well (RR = 3.23, 95% CI 0.70-14.97, I² = 58%). The need for MV was not significantly different between the SC and HCQ (RR = 1.5, 95% CI 0.78-2.89, I² = 81%), or HCQ + AZM (RR = 1.27, 95% CI 0.7-2.13, I² = 88%). Side effects were more reported in the HCQ group than in the SC (RR = 3.14, 95% CI 1.58-6.24, I² = 0). Radiological improvement and clinical worsening were not statistically different between HCQ and SC [(RR = 1.11, 95% CI 0.74-1.65, I² = 45%) and (RR = 1.28, 95% CI 0.33-4.99), I² = 54%] respectively. Despite the scarcity of published data of good quality, the effectiveness and safety of either HCQ alone or in combination with AZM in treating COVID-19 cannot be assured. Future high-quality RCTs need to be carried out.PROSPERO registration: CRD42020192084.

Figure 1

PRISMA flow chart of studies screened and included.

Figure 2

(a) Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies. (b) Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

Figure 3

Pooled mortality in the Hydroxychloroquine ± Azithromycin groups versus standard care group.

Figure 4

Funnel plot of included studies highlighted the mortality of the Hydroxychloroquine regimen.

Figure 5

Duration of hospital stay of  Hydroxychloroquine ± Azithromycin versus standard care.

Figure 6

Forest plot for pooling risk ratios regarding virological cure rate on day four, 10 and 14 respectively.

Figure 7

Forest plot for pooling risk ratios regarding the overall virological cure rate.

Figure 8

The virological cure rate of Hydroxychloroquineand azithromycin versus standard care.

Figure 9

Need for mechanical ventilation of the Hydroxychloroquine ± Azithromycin versus standard care.

Figure 10

Forest plot for pooling std. mean differences of the time to a negative polymerase chain reaction.

Figure 11

Forest plot for pooling risk ratios regarding radiological improvement.

Figure 12

Side effects of the Hydroxychloroquine versus the standard care.

Figure 13

Clinical worsening of the Hydroxychloroquine versus the standard care