key: cord-0898235-wtb51big
authors: Accinelli, Roberto Alfonso; Ynga-Melendez, Grisel Jesús; Leon-Abarca, Juan Alonso; López, Lidia Marianella; Madrid-Cisneros, Juan Carlos; Mendoza-Saldaña, Juan Diego
title: Hydroxychloroquine / azithromycin in COVID-19: The association between time to treatment and case fatality rate
date: 2021-09-14
journal: Travel Med Infect Dis
DOI: 10.1016/j.tmaid.2021.102163
sha: 54016e470c82f49c6df0f4c22e894267e41e7b57
doc_id: 898235
cord_uid: wtb51big

BACKGROUND: Currently, there is no formally accepted pharmacological treatment for COVID-19. MATERIALS AND METHODS: We included COVID-19 outpatients of a Peruvian primary care center from Lima, Peru, who were treated between April 30 - September 30, 2020, with hydroxychloroquine and azithromycin. Logistic regression was applied to determine factors associated with case-fatality rate. RESULTS: A total of 1265 COVID-19 patients with an average age of 44.5 years were studied. Women represented 50.1% of patients, with an overall 5.9 symptom days, SpO2 97%, temperature of 37.3 °C, 41% with at least one comorbidity and 96.1% one symptom or sign. No patient treated within the first 72 h of illness died. The factors associated with higher case fatality rate were age (OR = 1.06; 95% CI 1.01–1.11, p = 0.021), SpO2 (OR = 0.87; 95% CI 0.79–0.96, p = 0.005) and treatment onset (OR = 1.16; 95% CI 1.06–1.27, p = 0.002), being the latter the only associated in the multivariate analysis (OR = 1.18; 95% CI 1.05–1.32, p = 0.005). 0.6% of our patients died. CONCLUSIONS: The case fatality rate in COVID-19 outpatients treated with hydroxychloroquine/azithromycin was associated with the number of days of illness on which treatment was started.

The rapid spread of the virus referred to as severe acute respiratory syndrome coronavirus 2 vitro studies. (14) One of these studies demonstrated that CQ is an effective inhibitor of 120 replication of the coronavirus SARS-CoV. These cell culture experiments demonstrated 121 that the IC50 for the antiviral activity of CQ was significantly lower than its cytostatic 122 activity, which was reflected in a high selectivity index of 30. Specifically, these studies 123 indicated that the maximal concentration of its antiviral action (8.8 µM) was much lower, 124 than the concentration required for its mean cytotoxic effect (261. The present study analyzed anonymized data from the database of COVID-19 patients  169   attended at the CMI Tahuantinsuyo Bajo, a primary care facility in the city of Lima,  170 between April 30 and September 30, 2020. 171

Patients arrived at a dedicated triage site for patients with suspected COVID-19 infection. 172

There, vital signs were taken, including SpO2, and the attending physicians took the patient 173 history and performed a clinical examination to determine whether they met COVID-19 174 patient clinical criteria according to the guidelines of the Peruvian Ministry of Health. All 175 patients were registered in the respective epidemiological data file and the information 176 included vital signs, comorbidities, symptoms and treatment onset, consisting of 200 mg 177 HCQ every 8 hours for 7 to 10 days in combination with 500 mg AZIT on the first day, 178 followed by 250 mg for 4 days. Data on days from symptom onset to treatment was 179 collected as well. The patients were followed up with daily telephone controls and if any 180 symptoms of deterioration or side effects appeared, they were summoned to the clinical 181 facility. Follow-up was carried out not only with the patients but also with their contacts, 182 with the aim of providing treatment as soon as the first symptoms appeared. Every day the 183 epidemiology team recorded and shared patient's information to the physician coordinating 184 the COVID-19 registry. The information was transcribed into an Excel spreadsheet and the 185 cases were followed up after discharge until they were sure of their condition. If the 186 information could not be obtained by telephone, a home visit was done by the rapid a 187 response team also stablished under Peruvian COVID-19 guidelines. 188

The treatment started as soon as the attending physician determined that the patient 189 exhibited symptoms that met the COVID-19 patient clinical criteria according to the 190 J o u r n a l P r e -p r o o f guidelines of the Peruvian Ministry of Health. Some of these patients arrived at the hospital 191 with a positive test, but most did not. Those that were not tested before arrival were asked 192 to take the test. This test was not readily available at the center, albeit it continues to be 193 offered at no cost at some government testing sites. Given that during the study period it 194 could take almost a week to process and register the result of the NAAT test, and because 195 tests tend to be less accurate within three days of exposure, the treatment regimen was SpO2 of 97%, temperature of 37.3°C, with 41% with at least one comorbidity and 96.1% 216 with at least one symptom or sign (Table 1) . The most common comorbidities were obesity 217 (17.3%), hypertension (8.3%), chronic respiratory disease (7.2%) and diabetes (6.1%) 218

( Table 2 ). The most common symptoms were cough (85.1%), malaise (81.7%), sore throat 219 (76.7%), sensation of thermal rise (54.2%) and dyspnea (33.8%) ( Table 3) . 220

At follow-up, there were 7 deaths in total, all men with a mean age of 57.7 years, SatO2 221 96%. Four of the deceased patients carried one known comorbidity (hypertension, obesity, 222 diabetes and chronic respiratory disease), three had no comorbidity. The one aged 29 years 223 old had obesity and a 98% SpO2 at first encounter, while the patient age 39 years old had 224 no known comorbidities and a 98% SpO2.The most common symptoms were cough 225 (100%), malaise (100%), sore throat (85.7%), dyspnea (71.4%), nasal congestion (42.9%) 226 and febrile sensation (42.9%) ( Table 3 ). Logistic regression showed that those factors 227 associated with higher mortality were age (OR 1.06; 95% CI 1.01-1.11, p=0.021), SpO2 228 (OR 0.87; 95% CI 0.79-0.96, p=0.005) and number of days until the start of treatment (OR 229 1. 16; 95% CI 1.06-1.27, p=0.002). However, in a multivariate analysis the time of illness 230 elapsed before receiving treatment was the only factor associated with higher mortality (OR 231 1.18; 95%CI 1.05-1.32, p=0.005) (Table 4) . 232

The case-fatality rate of this cohort of patients treated with HCQ-AZIT was 0.6. No female 233 patient died and the mortality among males was 1.12%. (Table 5) . 234

Remarkably, none of those treated in the first 72 hours of illness onset died. Deaths 235 occurred on days four, when two died, and on days six, seven, eight, twelve and thirty-one 236 after onset. All but nine patients (0.72%) reported having sought care within the first 20 237 J o u r n a l P r e -p r o o f days of symptom onset (Table 6 ). The proportion of patients seen within the first 72 hours 238 was different than the proportion of patients that arrived with longer duration of illness 239 [28.06% (95% CI:25.65-30.61%) vs 71.94%, (95% CI: 69.39-74.35%), p<0.0001] ( Figure  240 1). The percentage of case fatality increased progressively with the number of days after 241 treatment initiation (p=0.0039), reaching 0.89% (95% CI: 0.1-6.12%) among those who 242 received treatment from day 10 to 12 of illness ( Figure 2) . Importantly, no patients had 243 cardiovascular side effects or had to be hospitalized for any effect attributable to the use of 244 HCQ/AZT, but there were 0.79% (10/1265) who had their scheme suspended due to side 245 effects, being nausea the most frequent present in 5 patients. (Table 1 ) 246 247

Of the 1265 COVID-19 patients treated at Tahuantinsuyo Bajo with HCQ-AZIT, 0.6% died 249 (Table 1) . This outcome is consistent with the first European study that used the same 250 treatment regimen for 1061 patients. The case-fatality rate in this healthcare center was 251 0.75%. (28) The mortality rate among the 1265 patients treated with this specific regimen 252 was six times lower than the national average. With HCQ/AZIT treatment, mortality in male patients did not exceed 1% in the group 346 younger than 80 years of age, while 16.67% in those older than 80 years. (Table 5) The case-fatality rate with this treatment regimen was 0.6%, which was significantly lower 399 than the national average. There is a large discrepancy between the case-fatality rate 400 reported in this study and the rest of the country. Peruvian government put in its guidelines 401 HCQ-AZT as one of the treatments for these patients. J o u r n a l P r e -p r o o f 

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