Introduction: Hydroxychloroquine (HCQ) emerged early in the course of the coronavirus disease 2019 (COVID-19) pandemic as a possible drug with potential therapeutic and prophylactic benefits. It was quickly adopted in China, Europe, and the USA. We systematically reviewed the existing clinical evidence of HCQ use for the prevention and treatment of COVID-19. Methods: We screened for clinical studies describing HCQ administration to treat or prevent COVID-19 in PubMed. We included randomized controlled trials (RCTs), non-randomized comparative cohorts, and case series studies that had all undergone peer review. Results: A total of 623 studies were screened; 17 studies evaluating HCQ treatment were included. A total of 13 were observational studies, and 4 were RCTs. In terms of effect on mortality rates, observational studies provided conflicting results. As a whole, RCTs, including one large British RCT that has not yet been Hydroxychloroquine for COVID-19 Rambam Maimonides Medical Journal 2 July 2020 Volume 11 Issue 3 e0025 published, showed no significant effect of HCQ on mortality rates, clinical cure, and virologic response. The use of HCQ as a post-exposure prophylactic agent was found to be ineffective in one RCT. Conclusion: There is no evidence supporting HCQ for prophylaxis or treatment of COVID-19. Many observational trials were methodologically flawed. Scientific efforts have been disappointingly fragmented, and well-conducted trials have only recently been completed, more than 7 months and 600,000 deaths into the pandemic.
Background: Viral culture is currently the most accurate method to demonstrate viability and infectivity of Severe acute respiratory syndrome Coronavirus (SARS–2 CoV). Routine clinical diagnosis, however, is mostly performed by PCR – based assays that do not discriminate between infectious and non–virus. Herein, we aimed to determine the correlation between positive viral cultures and either PCR positivity, the Cycle Threshold (Ct) or the number of viral copies. Methods: A systematic electronic literature search was performed and studies that reported both viral SARS–CoV–2 culture and PCR–based assays were included. A separate search for samples from blood, urine, stool, breast milk and tears were performed. To convert Ct values reported in the reviewed studies were to viral genomic copies, calibration experiments with four different reaction performed, using quantified RNA molecules. Results: A total 540 articles were reviewed, and 38 studies were included in this review. Out of 276 positive–culture of non-severe patients, 272 (98.55%) were negative ten days after symptoms onset, while PCR assays remained positive for up to 67 days. In severely ill or immunocompromised patients positive-culture was obtained up to 32 days and out of 168 cultures, 31 (18.45%) stayed positive after day 10. In non-severe patients, in Ct value greater than 30 only 10.8% were still culture–positive while in Ct >35 it was nearly universally negative. The minimal calculated number of viral genome copies in culture- positive sample was 2.5 X 103 copies / mL. These findings were similar in immunocompromised patients. Recovering positive culture from non–respiratory samples was sporadically obtained in stool or urine samples. Conversion of Ct values to viral genome copies showed variability between different PCR assays and highlighted the need to standardize reports to correctly compare results obtained in different laboratories. Conclusion: During the pandemic phase, non-severe COVID-19 patients who are recovering and are not immuno-suppressed, can be regarded as non–infectious, within 10 days from symptom onset, or with Ct value greater than 35 (or a calculated viral load lower than 1.2X103 copies / mL). These findings have important implications for recovering patients and asymptomatic patients, with respect to isolation criteria. The conversion of Cq values to viral genome copies described herein may be useful in future work, enabling a more standardized comparison between results reported in different studies from different laboratories.
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