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0 0.5 1 1.5 2+ Mortality 46% Improvement Relative Risk Hospitalization 17% Baseline PCR- risk of cases 32% Mitjà et al. HCQ for COVID-19 RCT PEP Favors HCQ Favors control
A Cluster-Randomized Trial of Hydroxychloroquine as Prevention of Covid-19 Transmission and Disease
Mitjà et al., NEJM, doi:10.1056/NEJMoa2021801 (date from earlier preprint)
26 Jul 2020    Source   PDF   Share   Tweet
For positive symptomatic cases, a greater effect is seen for nursing home residents, RR=0.49 [0.21 - 1.17], vs. overall 0.89, possibly because the exposure events are identified faster in this context, versus home exposure where testing of the source may be more delayed. The trial is too small for significance here. If the trend continued this result would be significant at p<0.05 after about 25% more patients were added.
There are 2 groups in this study: PCR+ at baseline (n=314) and PCR- at baseline (n=2000), which should be separated as they are different populations (primary outcome rates 18.6% and 22.2% compared to 3.0% and 4.3%). PCR+ already have COVID-19, so PEP analysis should be for the 2,000 PCR-, showing symptomatic COVID-19 of 4.3% (control) and 3.0% (treatment), RR 0.7, p=0.154.
The paper has different RR values here, stating that they are adjusted for contact-level variables. It is not clear how they are computed - the adjusted RR for the overall sample is 4% lower, for PCR+ it is 20% lower, but for PCR- it is 107% higher, even though PCR- represents 86% of the sample.
Hopefully, supplementary data will provide a breakdown on cases in this PCR- @baseline sample by number of days since exposure, and also provide relevant hospitalisation and death results.
Enrollment was up to 7 days after exposure, median 4 days. Treatment delay is unclear. The exposure event timing is not detailed. It appears to be based on the date of a positive test for a contact, which is likely to be much later than the actual exposure time. 13.1% were already positive at baseline, which is consistent with the actual exposure time being significantly earlier. PCR testing has a very high false-negative rate in early stages (e.g., 100% on day 1, 67% on day 4, and 20% on day 8 []), hence it is likely that a much higher percentage were infected at an unknown time before enrollment. Medication administration is not detailed. Sensitivity and specificity of the tests is not provided.
Given the delay identifying index cases, PCR test delay, and PCR false negative rate at early stages, the treatment delay in general was very long and could be over 2 weeks.
The RR for non-PCR positive at baseline is 0.74. Including the PCR-positive at baseline patients reduced this to 0.89. This is also consistent with earlier treatment being more effective.
The paper does not mention zinc. Zinc deficiency in Spain has been reported at 83% [], this may significantly reduce effectiveness. HCQ is a zinc ionophore which increases cellular uptake, facilitating significant intracellular concentrations of zinc, and zinc is known to inhibit SARS-CoV RNA-dependent RNA polymerase activity, and is widely thought to be important for effectiveness with SARS-CoV-2 [].
This study focuses on the existence of symptoms or PCR-positive results, however severity of symptoms is more important. Research has shown HCQ concentrations can be much higher in the lung compared to plasma [], which may help minimize the occurrence of severe cases and death.
There is a treatment-delay response relationship consistent with an effective treatment, however the authors only provide 3 ranges and do not break down the earliest treatment delay times.
The definition of COVID-19 symptoms is very broad - just existence of a headache alone or muscle pain alone was considered COVID-19. There was an overall very low incidence of confirmed COVID-19 (138 cases across both arms). There were no serious adverse events that were adjudicated as being treatment related. Authors exclude those with symptoms in the previous two weeks, however, those with symptoms up to several months before may still test PCR-positive even though there may be no viable virus.
There appears to be incorrect data. Table 2, secondary outcomes, control, hospital/vital records shows that 8 of 1042 is 9.7% (we get 0.8%).
Nasopharyngeal viral load analysis issues include test unreliability and temporo-spatial differences in viral shedding [].
Data from this study has been used to show that viral load is the primary factor in transmission: [].
risk of death, 45.6% lower, RR 0.54, p = 0.39, treatment 4 of 1,196 (0.3%), control 8 of 1,301 (0.6%), NNT 357, per supplemental appendix table S7, excluding patient that did not take any study medication and had an unknown cause of death.
risk of hospitalization, 16.8% lower, RR 0.83, p = 0.71, treatment 13 of 1,196 (1.1%), control 17 of 1,301 (1.3%), NNT 455, per supplemental appendix table S7, excluding patient that did not take any study medication and had an unknown cause of death.
baseline PCR- risk of cases, 32.0% lower, RR 0.68, p = 0.27, treatment 29 of 958 (3.0%), control 45 of 1,042 (4.3%), NNT 77.
Effect extraction follows pre-specified rules prioritizing more serious outcomes. Submit updates
Mitjà et al., 26 Jul 2020, Randomized Controlled Trial, Spain, peer-reviewed, 12 authors.
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