Introduction: In Latin America, Peru is the most impacted country due to COVID-19 pandemic. Given the authorized nationwide use of hydroxychloroquine, azithromycin, ivermectin and dexamethasone in COVID-19 patients, we aimed to evaluate their effectiveness alone or combined to prevent 30-day mortality among COVID-19 hospitalized patients without life-threatening illness. Methods: Design. Retrospective cohort study using digital clinical records to emulate a target trial. Setting. Nationwide data of mid- and high-level complexity hospitals from the Peruvian Social Health Insurance (EsSalud) between April 1 and July 19, 2020. Participants. Patients aged 18 years with confirmed SARS-CoV-2 infection by PCR, and non-severe pneumonia at admission. Interventions. We compared five treatment groups to the standard of care treatment regimen (control group) within 48 hours of admission to hospital: hydroxychloroquine/chloroquine alone (HCQ), ivermectin alone (IVM), azithromycin alone (AZIT), HCQ + AZIT group, and IVM + AZIT group with doses recommended by the Peruvian Ministry of Health. Main outcomes measures. The primary outcome was all-cause mortality rate, the secondary outcomes were survival without ICU rate, and survival without oxygen prescription rate. Analyses were adjusted for confounding factors by inverse probability of treatment weighting. A doubly-adjustment method was done for sensitivity analysis. Results: Among 5683 patients eligible for analysis, 200 received hydroxychloroquine or chloroquine within 48 hours of hospital admission, 203 received ivermectin, 1600 received azithromycin, 692 received hydroxychloroquine or chloroquine plus azithromycin, 358 received ivermectin plus azithromycin and 2630 received standard of care. AZIT + HCQ group was associated with 84% higher all-cause mortality hazard rate compared to standard care (wHR = 1.84, 95% CI: 1.12-3.02). Consistently, AZIT + HCQ treatment was associated with survival without transfer to ICU (wHR = 1.49, 95% CI: 1.01-2.19) and survival without oxygen prescription (wHR = 1.70, 95% CI: 1.07-2.69). HCQ treatment was associated with 77% higher all-cause mortality or oxygen prescription hazard rate compared to standard treatment (wHR = 1.77, 95% CI: 1.01-3.11). Surprisingly, we observed that IVM treatment was associated with less survival rate without transfer to ICU in the weighted analysis (wHR = 1.58, 95% CI:1.11-2.25) By last, we did not find evidence of effect on reduce all-cause mortality or increase survival rate without transfer to ICU or survival rate without oxygen prescription for AZIT group neither AZIT + IVM group in all analyses. Conclusion: The results of our target trial emulation match with previous findings of randomized clinical trials and observational studies, which showed no beneficial effects of hydroxychloroquine, ivermectin, azithromycin, or their combinations.

中文翻译：

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住院COVID-19患者中羟氯喹，阿奇霉素和伊维菌素的实际效果：使用来自秘鲁全国医疗系统的观察数据进行的目标试验模拟结果

简介：在拉丁美洲，由于COVID-19大流行，秘鲁是受影响最大的国家。鉴于已在全国范围内授权在COVID-19患者中使用羟氯喹，阿奇霉素，伊维菌素和地塞米松，我们的目标是评估它们的有效性或联合使用以预防住院的COVID-19患者30天死亡率，而不会危及生命。方法：设计。使用数字临床记录模拟目标试验的回顾性队列研究。设置。2020年4月1日至7月19日之间，来自秘鲁社会健康保险（EsSalud）的全国中高层综合医院数据。18岁的患者经PCR确诊为SARS-CoV-2感染，入院时为非严重肺炎。干预措施。我们将入院后48小时内的五个治疗组与护理治疗方案的标准（对照组）进行了比较：单独的羟氯喹/氯喹（HCQ），单独的伊维菌素（IVM），单独的阿奇霉素（AZIT），HCQ + AZIT组和IVM + AZIT组的剂量由秘鲁卫生部推荐。主要结果指标。主要结局是全因死亡率，次要结局是无ICU率的生存率和无氧处方率的生存率。通过权重的逆概率对混杂因素进行分析调整。使用双调整方法进行灵敏度分析。结果：在5683名符合分析条件的患者中，其中200例在入院48小时内接受了羟氯喹或氯喹治疗，203例接受了伊维菌素治疗，1600例接受了阿奇霉素治疗，692例接受羟氯喹或氯喹加阿奇霉素治疗，358例接受伊维菌素加阿奇霉素治疗，2630例接受标准护理。与标准护理相比，AZIT + HCQ组的全因死亡率危险率高84％（wHR = 1.84，95％CI：1.12-3.02）。一致地，AZIT + HCQ治疗与不转移至ICU的生存率（wHR = 1.49，95％CI：1.01-2.19）和无氧处方的生存率（wHR = 1.70，95％CI：1.07-2.69）相关。与标准治疗相比，HCQ治疗的全因死亡率或氧气处方危险率高77％（wHR = 1.77，95％CI：1.01-3.11）。出乎意料的是，我们在加权分析中观察到IVM治疗与较低的生存率相关，而未转移至ICU（wHR = 1.58，95％CI：1.11-2.25）我们没有发现降低AZIT组全因死亡率或提高生存率而不转移至ICU或没有氧气处方的生存率的证据，所有分析均未对AZIT + IVM组有效。结论：我们的目标试验模拟结果与之前的随机临床试验和观察性研究结果相吻合，没有发现羟氯喹，伊维菌素，阿奇霉素或其组合的有益作用。