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0 0.5 1 1.5 2+ Hospitalization 16% Improvement Relative Risk Recovery 34% Change in viral load from.. 2% no CI HCQ  Mitjà et al.  EARLY TREATMENT  RCT Is early treatment with HCQ beneficial for COVID-19? RCT 293 patients in Spain (March - May 2020) Improved recovery with HCQ (not stat. sig., p=0.38) Mitjà et al., Clinical Infectious Dise.., Jul 2020 Favors HCQ Favors control

Hydroxychloroquine for Early Treatment of Adults with Mild Covid-19: A Randomized-Controlled Trial

Mitjà et al., Clinical Infectious Diseases, ciaa1009, doi:10.1093/cid/ciaa1009
Jul 2020  
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HCQ for COVID-19
1st treatment shown to reduce risk in March 2020
*, now known with p < 0.00000000001 from 422 studies, recognized in 42 countries.
No treatment is 100% effective. Protocols combine complementary and synergistic treatments. * >10% efficacy in meta analysis with ≥3 clinical studies.
4,000+ studies for 60+ treatments.
This paper has conflicting values, table S2 shows 12 control hospitalizations, while table 2 shows 11. The original report for this paper had more conflicting values, with values reported in Table 2 and the abstract corresponding to 12 control hospitalizations, while others corresponded to 11 control hospitalizations. The counts in table S2 also do not match - n=290 is given for secondary endpoints but the three groups add up to n=238. The sum of the secondary endpoint counts for the control group in table 2 do not match the group size. One missing patient may be the 12th control hospitalization but there are 2 more missing.
There was a 16% reduction in hospitalization and 34% reduction in the risk of no symptom resolution, without statistical significance due to small samples.
Treatment delay is unknown at this time. They report a delay of up to 120 hours after symptoms plus an additional unspecified delay where medication was provided to patients at the first home visit. Authors did not respond to our request for details. Authors do not break down results by treatment delay.
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
Undetectable viral load was changed to 3 log10 copies/mL potentially masking effectiveness. For viral load authors use nasopharyngeal swabs, we note that viral activity in the lung may be especially important for COVID-19, and that research has shown HCQ concentrations can be much higher in the lung compared to plasma We also note that viral detection by PCR does not equate to viable virus Accuracy of the tests is not provided.
Nasopharyngeal viral load analysis issues include test unreliability and temporo-spatial differences in viral shedding
293 low-risk patients with no deaths. No serious adverse events. We asked for more details on the treatment delay and viral load change but received no response.
Also see this open letter:
Although the 16% lower hospitalization is not statistically significant, it is consistent with the significant 15% lower hospitalization [6‑24%] from meta analysis of the 65 hospitalization results to date.
risk of hospitalization, 16.0% lower, RR 0.84, p = 0.64, treatment 8 of 136 (5.9%), control 11 of 157 (7.0%), NNT 89.
risk of no recovery, 34.0% lower, RR 0.66, p = 0.38, treatment 8 of 136 (5.9%), control 14 of 157 (8.9%), NNT 33.
relative change in viral load from baseline, 2.0% better, RR 0.98, treatment 136, control 157, day 7.
Effect extraction follows pre-specified rules prioritizing more serious outcomes. Submit updates
Mitjà et al., 16 Jul 2020, Randomized Controlled Trial, Spain, peer-reviewed, 46 authors, study period 17 March, 2020 - 26 May, 2020, dosage 800mg day 1, 400mg days 2-7.
This PaperHCQAll
Hydroxychloroquine for Early Treatment of Adults with Mild Covid-19: A Randomized-Controlled Trial
PhD Oriol Mitjà, Marc Corbacho-Monné Bm, Maria Ubals Bm, PhD Cristian Tebe, PhD Judith Peñafiel, PhD Aurelio Tobias, PhD Ester Ballana, Andrea Alemany Bm, Núria Riera-Martí, Bm, Carla A Pérez Bm, PhD Clara Suñer, Pep Laporte Bm, Pol Admella Bm, MBA Jordi Mitjà, MBA Mireia Clua, Laia Bertran Ma, Maria Sarquella Ma, Sergi Gavilán Ba, [ Jordi, Ara Phd, PhD Josep M Argimon, Jordi Casabona, BM Gabriel Cuatrecasas, PhD Paz Cañadas, PhD Aleix Elizalde- Torrent, PhD Robert Fabregat, PhD Magí Farré, Anna Forcada Bm, PhD Gemma Flores-Mateo, MSc Esteve Muntada, MB Núria Nadal, Silvia Narejos, Aroa N Gil-Ortega Bn, Nuria Prat Bm, Jordi Puig Bn, Carles Quiñones Mpharm, PhD Juliana Reyes-Ureña, MSc Ferran Ramírez- Viaplana, PhD Lidia Ruiz, PhD Eva Riveira-Muñoz, Alba Sierra Bn, PhD César Velasco, PhD Rosa Maria Vivanco-Hidalgo, Alexis Sentís, Beiras Phd, PhD Bonaventura Clotet, MD Martí Vall-Mayans
BACKGROUND: No therapeutics have yet been proven effective for the treatment of mild-illness caused by SARS-CoV-2. We aimed to determine whether early treatment with hydroxychloroquine (HCQ) would be more efficacious than no-treatment for outpatients with mild Covid-19. METHODS: We conducted a multicenter, open label, randomized controlled trial in Catalonia (Spain) between March 17, and May 26, 2020. Eligible Covid-19 cases were non-hospitalized adult patients with recently confirmed SARS-CoV-2 infection and less than five days of symptoms. Patients were assigned to receive HCQ (800 mg on day 1, followed by 400 mg once daily for 6 days) or no antiviral treatment (not-placebo controlled). Study outcomes were the reduction of viral RNA load in nasopharyngeal swabs up to 7 days after treatment start, patient disease progression using the WHO scale up to 28 days, and time to complete resolution of symptoms. Adverse events were assessed up to 28 days. RESULTS: A total of 293 patients were eligible for intention-to-treat analysis: 157 in the control arm and 136 in the intervention arm. The mean age was 41.6 years (SD 12.6), mean viral load at baseline was 7.90 (SD 1.82) Log 10 copies/mL, and median time from symptom onset to randomization was 3 days. No significant differences were found in the mean reduction of viral load at day 3 (-1.41 vs. -1.41 Log 10 copies/mL in the control and intervention arm, respectively; difference 0.01 [95% CI -0.28;0.29]) or at day 7 (-3.37 vs. -3.44; d -0.07 [-0.44;0.29]). This treatment regimen did not reduce risk of hospitalization (7.1%, control vs. 5.9%, intervention; RR 0.75 [0.32;1.77]) nor shortened the time to complete resolution of symptoms (12 days, control vs. 10 days, intervention; p = 0.38). No relevant treatment-related AEs were reported. CONCLUSIONS: In patients with mild Covid-19, no benefit was observed with HCQ beyond the usual care.
A c c e p t e d M a n u s c r i p t 9 concomitant administration of DRV in some participants may have slightly increased plasma levels of HCQ, thereby leading to increased HCQ effect because DRVc is a weak inhibitor of the metabolic enzyme of HCQ, CYP2D6. Therefore, we do not expect the use of DRVc might have reduced the effect of HCQ. Third, owing to the urgency, the trial could not be masked with a placebo, which may affect the rate of AE declared (AEs are less often reported in a control, non-placebo group). Nevertheless, it did not affect the attrition numbers in the control arm. Moreover, to minimize the detection bias of the primary outcome (i.e., the viral load), the laboratory staff remained unaware of participants' allocation. Finally, the regional nature of the trial and overrepresentation of healthcare workers (>80%) may limit the generalization of our findings. Therefore, cautiousness should be taken when extrapolating our data to other countries or settings. HCQ and chloroquine have garnered unprecedented attention as potential therapeutic agents following inconclusive clinical trials in combination or not with azithromycin [9, 12] , uncontrolled case series [14] , and public figure endorsements [28] . While there is a growing body of scientific data against using HCQ for treating Covid-19 that includes a concern for harm, particularly cardiac disease, the potential for the treatment of mild Covid-19 with HCQ has been explored in this trial to provide..
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