Summary: Background: There is no specific antiviral therapy recommended for the disease caused by SARS-CoV-2 (COVID-19). Recent publications have drawn attention to the possible benefit of chloroquine (CQ). Our study aimed to comprehensively evaluate the safety and efficacy of two different CQ dosages in patients with established severe COVID-19. Methods: We performed a parallel, double-blinded, randomized, phase IIb clinical trial, aiming to assess safety and efficacy of two different CQ dosages as adjunctive therapy of hospitalized patients with SARS in Manaus, Brazilian Amazon. Eligible participants were allocated to receive orally or via nasogastric tube high dose CQ (600mg CQ twice daily for 10 days or total dose 12g); or low dose CQ (450mg for 5 days, twice daily only on the first day, or total dose 2.7g). In addition, all patients received ceftriaxone and azithromycin. This study was registered with ClinicalTrials.gov , number NCT04323527 . Findings: Out of a pre-defined 440 patients sample size, 81 patients were enrolled. The high dosage CQ arm presented more QTc>500ms (18.9%), and a trend toward higher lethality (39%) than the lower dosage. Fatality rate until day 13 was 27% (95%CI=17.9-38.2%), overlapping with the CI of historical data from similar patients not using CQ (95%CI=14.5-19.2%). In 27 patients with paired samples, respiratory secretion at day 4 was negative in only six patients (22%). Interpretation: Preliminary findings suggest that the higher CQ dosage (10-day regimen) should not be recommended for COVID-19 treatment because of its potential safety hazards. Such results forced us to prematurely halt patient recruitment to this arm. Given the enormous global push for the use of CQ for COVID-19, results such as the ones found in this trial can provide robust evidence for updated COVID-19 patient management recommendations. Funding: This study was funded by the Government of the Amazonas State, Farmanguinhos (Fiocruz), SUFRAMA, CAPES, FAPEAM, and federal funds granted by a coalition of Brazilian senators. Research in context: Evidence before this study: Before the CloroCovid-19 trial began, to our knowledge, there were no published reports of robust clinical studies on the safety and/or efficacy of chloroquine (CQ) and/or hydroxychloroquine (HCQ) for the treatment of COVID-19 during the recent 2020 pandemic. We searched PubMed and also MedRxiv.org (pre-print server for health sciences, without peer review), without any language restrictions and including Chinese publications, for studies published between Dec 2019 and April 5, 2020, using the search terms ‘COVID-19, coronavirus, SARS-Cov-2’. We found three non-randomized studies with limited sample sizes in which (1) HCQ use led to a decrease in SARS-Cov-2 detected in respiratory secretions five days after treatment, together with azithromycin (France, 36 patients); (2) HCQ use shortened time to clinical recovery (China, 62 patients); and (3) CQ was superior to control treatment in inhibiting the exacerbation of pneumonia, improving lung imaging findings, and promoting virus-negative conversion and shortening the disease course (China, 100 patients). We found no published studies comparing different dosages of CQ/HCQ and their thorough safety assessment. Added value of this study: In a larger patient population, we found that a higher dosage of CQ for 10 days presented toxicity red flags, particularly affecting QTc prolongation. The limited sample size recruited so far does not allow to show any benefit regarding treatment efficacy, however the higher fatality associated with the higher dosage by day 13 of follow-up resulted in a premature halting of this arm. This is the first double-blinded, randomized clinical trial addressing different dosages of CQ for the treatment of severe patients with COVID-19 in the absence of a control group using placebo. Due to the impossibility of not using the drug recommended at the national level, we used historical data from the literature to infer comparisons for lethality endpoints. Follow-up until day 28 is ongoing with a larger sample size, in which long-term lethality will be better estimated. Implications of all the available evidence: The preliminary findings from CloroCovid-19 trial suggest that the higher dosage of CQ (12 g total dose over 10 days) in COVID-19 should not be recommended because of safety concerns regarding QTc prolongation and increased lethality, in the Brazilian population, and more often in older patients in use of drugs such as azithromycin and oseltamivir, which also prolong QTc interval. Among patients randomized to the lower dosage group (5 days of treatment, total dose 2.7 g), given the limited number of patients so far enrolled, it is still not possible to estimate a clear benefit of CQ in patients with severe ARDS. Preliminary data on viral clearance in respiratory secretions in our confirmed cases are also indicative of little effect of the drug at high dosage. More studies initiating CQ prior to the onset of the severe phase of the disease are urgently needed.

Objectives: to compare the metabolic, anthropometric, tobacco and alcohol consumption indicators considered as risk factors for cardiovascular diseases, as well as the demographic and socioeconomic characteristics between indigenous from Rio Negro, Sateré-Mawé, mixed-race/black and white people living in the city of Manaus. Methods: a cross-sectional observational study guided by the STROBE tool. There was a sample of 191 adults of both sexes. Anthropometric measurements, blood pressure and biochemical analyzes were performed. Statistical test was applied to cross color/race/ethnicity variable with the investigated variables. Results: indigenous had better metabolic and anthropometric indicators related to cardiovascular diseases than mixed-race/black and white, as well as Sateré-Mawé in relation to Rionegrinos (from Rio Negro). Conclusions: the main differences were obesity, dyslipidemia, pre-systemic arterial hypertension/systemic arterial hypertension, and increased circumferences, with a worse situation for mixed-race/black people. The findings indicate differences in risk factors between race/color and ethnicity groups evaluated.

In Brazil, malaria caused by Plasmodium vivax presents control challenges due to several reasons, among them the increasing possibility of failure of P. vivax treatment due to chloroquine-resistance (CQR). Despite limited reports of CQR, more extensive studies on the actual magnitude of resistance are still needed. Short-time recurrences of malaria cases were analyzed in different transmission scenarios over three years (2005, 2010, and 2015), selected according to malaria incidence. Multilevel models (binomial) were used to evaluate association of short-time recurrences with variables such as age. The zero-inflated Poisson scan model (scanZIP) was used to detect spatial clusters of recurrences up to 28 days. Recurrences compose less than 5% of overall infection, being more frequent in the age group under four years. Recurrences slightly increased incidence. No fixed clusters were detected throughout the period, although there are clustering sites, spatially varying over the years. This is the most extensive analysis of short-time recurrences worldwide which addresses the occurrence of P. vivax CQR. As an important step forward in malaria elimination, policymakers should focus their efforts on young children, with an eventual shift in the first line of malaria treatment to P. vivax.

Virologic failure may occur because of poor treatment adherence and/or viral drug resistance mutations (DRM). In Brazil, the northern region exhibits the worst epidemiological scenarios for the human immunodeficiency virus (HIV). Thus, this study is aimed at investigating the genetic diversity of HIV‐1 and DRM in Manaus. The cross‐sectional study included people living with HIV on combined antiretroviral therapy and who had experienced virological failure during 2018‐2019. Sequencing of the protease/reverse transcriptase (PR/RT) and C2V3 of the viral envelope gp120 (Env) regions was analyzed to determine subtypes/variants of HIV‐1, DRMs, and tropism. Ninety‐two individuals were analyzed in the study. Approximately 72% of them were male and 74% self‐declared as heterosexual. Phylogenetic inference (PR/RT‐Env) showed that most sequences were B subtype, followed by BF1 or BC mosaic genomes and few F1 and C sequences. Among the variants of subtype B at PR/RT, 84.3% were pandemic (B_PAN), and 15.7% were Caribbean (B_CAR). The DRMs most frequent were M184I/V (82.9%) for nucleoside reverse transcriptase inhibitors (NRTI), K103N/S (63.4%) for nonnucleoside reverse transcriptase inhibitor (NNRTI), and V82A/L/M (7.3%) for protease inhibitors (PI). DRM analysis depicted high levels of resistance for lamivudine and efavirenz in over 82.9% of individuals; although, low (7.7%) cross‐resistance to etravirine was observed. A low level of resistance to protease inhibitors was found and included patients that take atazanavir/ritonavir (16.6%) and lopinavir (11.1%), which confirms that these antiretrovirals can be used—for most individuals. The thymidine analog mutations‐2 (TAM‐2) resistance pathway was higher in B_CAR than in B_PAN. Similar results from other Brazilian studies regarding HIV drug resistance were observed; however, we underscore a need for additional studies regarding subtype B_CAR variants. Molecular epidemiology studies are an important tool for monitoring the prevalence of HIV drug resistance and can influence the public health policies.

The high incidence of Zika virus (ZIKV) infection in the period of 2015–2016 in Brazil may have affected linear height growth velocity (GV) in children exposed in utero to ZIKV. This study describes the growth velocity and nutritional status based on the World Organization (WHO) standards of children exposed to ZIKV during pregnancy and followed up in a tertiary unit, a reference for tropical and infectious diseases in the Amazon. Seventy-one children born between March 2016 and June 2018 were monitored for anthropometric indices: z-score for body mass index (BMI/A); weight (W/A); height (H/A) and head circumference (HC/A); and growth velocity. The mean age at the last assessment was 21.1 months (SD ± 8.93). Four children had congenital microcephaly and severe neurological impairment. The other 67 were non-microcephalic children (60 normocephalic and 7 macrocephalic); of these; 24.2% (16 children) had neurological alterations, and 28.8% (19 children) had altered neuropsychomotor development. Seventeen (24.2%) children had inadequate GV (low growth velocity). The frequencies of low growth among microcephalic and non-microcephalic patients are 25% (1 of 4 children) and 23.9% (16 of 67 children); respectively. Most children had normal BMI/A values during follow-up. Microcephalic patients showed low H/A and HC/A throughout the follow-up, with a significant reduction in the HC/A z-score. Non-microcephalic individuals are within the regular ranges for H/A; HC/A; and W/A, except for the H/A score for boys. This study showed low growth velocity in children with and without microcephaly, highlighting the need for continuous evaluation of all children born to mothers exposed to ZIKV during pregnancy.