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Antivirals have demonstrated efficacy in treating other infectious diseases in early stages of disease, reducing morbidity, mortality, and the likelihood of onward transmission. At the time of writing, more than 1900 clinical trials are registered globally to assess the efficacy and safety of candidate therapeutics for COVID-19. The majority of these trials are designed to evaluate the comparative efficacy and safety of candidate therapeutics for the treatment of COVID-19 to prevent death among populations of hospitalized patients with advanced disease. Yet, emerging epidemiological evidence now indicates that the majority of those infected with the SARS-CoV-2, while still infectious, experience minimal or mild disease symptomology. Like HIV and hepatitis C that pioneered treatment as prevention, there is a missed opportunity for trials of early pharmaceutical intervention for COVID-19 disease evaluating not only reductions in morbidity and mortality but also transmissibility. We discuss this clinical research gap within an historical context of viral treatment as prevention for HIV and hepatitis C, and comment on the challenges and opportunities for clinical research of candidate therapeutics for early COVID-19 disease.

High adherence to antiretroviral therapy is crucial to the success of HIV treatment. We evaluated comparative effectiveness of adherence interventions with the aim of informing the WHO's global guidance on interventions to increase adherence.

The scale of waste in research funding systems is large and detrimental to research capacity. Both incompleteness and non-publication of Randomised Controlled Trials (RCTs) have been increasingly reported in the literature. This is a serious consequence as RCTs demand monumental amounts of healthcare resources leading to wastage. Most importantly, both under-reporting and non-publication can distort the evidence landscape and obscure rationale behind clinical decisions.

IMPORTANCE: Data on the efficacy of hydroxychloroquine or lopinavir-ritonavir for the treatment of high-risk outpatients with COVID-19 in developing countries are needed. OBJECTIVE: To determine whether hydroxychloroquine or lopinavir-ritonavir reduces hospitalization among high-risk patients with early symptomatic COVID-19 in an outpatient setting. DESIGN, SETTING, AND PARTICIPANTS: This randomized clinical trial was conducted in Brazil. Recently symptomatic adults diagnosed with respiratory symptoms from SARS-CoV-2 infection were enrolled between June 2 and September 30, 2020. The planned sample size was 1476 patients, with interim analyses planned after 500 patients were enrolled. The trial was stopped after the interim analysis for futility with a sample size of 685 patients. Statistical analysis was performed in December 2020. INTERVENTIONS: Patients were randomly assigned to hydroxychloroquine (800 mg loading dose, then 400 mg daily for 9 days), lopinavir-ritonavir (loading dose of 800 mg and 200 mg, respectively, every 12 hours followed by 400 mg and 100 mg, respectively, every 12 hours for the next 9 days), or placebo. MAIN OUTCOMES AND MEASURES: The primary outcomes were COVID-19–associated hospitalization and death assessed at 90 days after randomization. COVID-19–associated hospitalization was analyzed with a Cox proportional hazards model. The trial included the following secondary outcomes: all-cause hospitalization, viral clearance, symptom resolution, and adverse events. RESULTS: Of 685 participants, 632 (92.3%) self-identified as mixed-race, 377 (55.0%) were women, and the median (range) age was 53 (18-94) years. A total of 214 participants were randomized to hydroxychloroquine; 244, lopinavir-ritonavir; and 227, placebo. At first interim analysis, the data safety monitoring board recommended stopping enrollment of both hydroxychloroquine and lopinavir-ritonavir groups because of futility. The proportion of patients hospitalized for COVID-19 was 3.7% (8 participants) in the hydroxychloroquine group, 5.7% (14 participants) in the lopinavir-ritonavir group, and 4.8% (11 participants) in the placebo group. We found no significant differences between interventions for COVID-19–associated hospitalization (hydroxychloroquine: hazard ratio [HR], 0.76 [95% CI, 0.30-1.88]; lopinavir-ritonavir: HR, 1.16 [95% CI, 0.53-2.56] as well as for the secondary outcome of viral clearance through day 14 (hydroxychloroquine: odds ratio [OR], 0.91 [95% CI, 0.82-1.02]; lopinavir-ritonavir: OR, 1.04 [95% CI, 0.94-1.16]). At the end of the trial, there were 3 fatalities recorded, 1 in the placebo group and 2 in the lopinavir-ritonavir intervention group. CONCLUSIONS AND RELEVANCE: In this randomized clinical trial, neither hydroxychloroquine nor lopinavir-ritonavir showed any significant benefit for decreasing COVID-19–associated hospitalization or other secondary clinical outcomes. This trial suggests that expedient clinical trials can be implemented in low-income settings even during the COVID-19 pandemic. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04403100

In the Original Publication of the article, Copyright license type was erroneously published.