Abstract
Introduction
Several antiretroviral drugs are being considered for the treatment of COVID‐19, the disease caused by a newly identified coronavirus, (SARS‐CoV‐2). We systematically reviewed the clinical outcomes of using antiretroviral drugs for the prevention and treatment of coronaviruses and planned clinical trials.
Methods
Three databases were screened from inception to 30 March 2020 for studies reporting clinical outcomes of patients with SARS, MERS or COVID‐19 treated with antiretrovirals.
Results
From an initial screen of 433 titles, two randomized trials and 24 observational studies provided clinical outcome data on the use of antiretroviral drugs; most studies reported outcomes using LPV/r as treatment. Of the 21 observational studies reporting treatment outcomes, there were three studies among patients with SARS, six studies among patients with MERS and 12 studies among patients with COVID‐19. In one randomized trial 99 patients with severe COVID‐19 illness were randomized to receive LPV/r (400/100 mg twice a day) and 100 patients to standard of care for 14 days: LPV/r was not associated with a statistically significant difference in time to clinical improvement, although LPV/r given within 12 days of symptoms was associated with shorter time to clinical improvement; 28 day mortality was numerically lower in the LPV/r group (14/99) compared to the control group (25/100), but this difference was not statistically significant. The second trial found no benefit. The certainty of the evidence for the randomized trials was low. In the observational studies 3 out of 361 patients who received LPV/r died; the certainty of evidence was very low. Three studies reported a possible protective effect of LPV/r as post‐exposure prophylaxis. Again, the certainty of the evidence was very low due to uncertainty due to limited sample size.
Conclusions
On the basis of the available evidence it is uncertain whether LPV/r and other antiretrovirals improve clinical outcomes or prevent infection among patients at high risk of acquiring COVID‐19.
Keywords: antiretroviral therapy, HIV, MERS, SARS, coronavirus, COVID‐19
1. INTRODUCTION
Several antiretroviral drugs are being considered for use in the treatment of COVID‐19, the disease caused by a newly identified coronavirus, (SARS‐CoV‐2). Protease inhibitors have been considered as candidate therapy because they inhibit enzymes that activate envelope glycoproteins as part of the process of viral entry into cells [1]. The use of lopinavir/ritonavir (LPV/r) has been supported by data from in vitro studies, animal models and positive clinical outcomes when LPV/r was given to patients infected with severe acute respiratory syndrome (SARS) and Middle East Respiratory Syndrome (MERS) diseases also caused by coronaviruses [2, 3, 4, 5]. Other antiretrovirals have been proposed based on virtual screening and in vitro studies, and several clinical trials are planned. Lopinavir/ritonavir (LPV/r) is included in rapid guidance issued by researchers from Wuhan University based on clinical use during prior epidemics of severe acute respiratory syndrome (SARS) and MERS coronavirus (CoV) infections [6].
This systematic review summarizes the clinical outcomes of using antiretroviral drugs for the prevention and treatment of coronaviruses and planned clinical trials.
2. METHODS
Based on in vitro activity, molecular docking studies, or reported use in prior reviews the following drugs were screened [7, 8, 9, 10, 11]: lopinavir/ritonavir, emtricitabine, tenofovir, atazanavir, ritonavir, darunavir, nelfinavir, indinavir, saquinavir, lamivudine and zidovudine (Search strategy provided in Appendix S1).
Three databases – Medline via PubMed, EMBASE and the Cochrane Library – were screened from inception to 30 March 2020 for studies reporting clinical outcomes of patients with SARS, MERS or COVID‐19 treated with antiretrovirals; studies using antiretrovirals for the prevention of these infections were also sought. The WHO database of publications on COVID‐19 was also searched https://www.who.int/emergencies/diseases/novel-coronavirus-2019/global-research-on-novel-coronavirus-2019-ncov.
Any study design that reported clinical outcome data was included, and there were no language restrictions. Clinicaitrials.gov and Chictr.org.cn were searched for ongoing and completed trials. Data are summarized per study, but not pooled in meta‐analysis due to the limited number of studies reporting outcomes for each disease. The review was conducted by a single reviewer (NF), with data extraction validated by a second reviewer (AR). The quality (or certainty) of the evidence was assessed using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach [12].
3. RESULTS AND DISCUSSION
3.1. Antiretroviral drugs for treatment
From an initial screen of 433 titles, two randomized controlled trials and 21 observational studies provided clinical outcome data on the use of antiretroviral drugs for treatment, and 3 studies reported outcomes for prevention. Three studies were excluded: one because cause of infection was unclear [13], one because the original study was retracted during the conduct of this systematic review [14] and one because lamivudine was given to control chronic hepatitis B infection and its use could not be linked to SARS outcomes [15]. Among the included studies, the majority reported outcomes using LPV/r as treatment; two two studies reported outcomes among HIV‐positive individuals who were on a combination antiretroviral drugs for management of HIV [16, 17].
Characteristics of included studies and patient outcomes are summarized in Table 1.
Table 1.
Clinical studies evaluating LPV/r for MERS, SARS and Covid‐19
Author Country |
Population Study design |
Intervention | Co‐interventions | Timing/duration of therapy | Comparitor | Mortality | Details |
---|---|---|---|---|---|---|---|
Treatment | |||||||
SARS | |||||||
Chan 2003 [2] China |
75 adults Matched cohort study |
LPV/r 400/100 Q12H + standard treatment protocol | Ribavarin either as cotreatment with LPV/r or as rescue therapy, pulse Methylprednisone 3 mg/kg/day or tailing hydrocortisone therapy 21 days 100 to 200 mg/day + mechanical ventilation if required | 10 to 14 days depending on severity | 977 matched controls from hospital data |
LPV/r: 5/75 died Control: 147/977 died |
Reduction in mortality: 2.3% (0% to 6.8%) vs. 15.6% (9.8% to 22.8%) Reduction in intubation rate: 0% vs 11% (7.7% to 15.3%) |
Chu 2004 [18] China |
41 adults Case‐control study with historical controls |
LPV/r 400/100 Q12H as initial therapy (n = 12), time of onset of symptoms 3.5 days. For rescue treatment (n = 29) time of onset of symptoms 14 days | Ribavarin and IV steroids | 14 days | 111 historical controls |
LPV/r: 0/41 died Control: 7/111 died |
Treatment group: 21‐day mortality/ARDS: 0/41, ARDS/death before 21 days: 1/44; Historical controls: 21 day mortality/ARDS: 7/111, ARDS/death before 21 days: 32/111 |
Wong 2004 [17] China |
30‐year‐old man Case report |
Abacavir 300 mg Q12H, efavirenz 600 mg once daily, TDF 300 mg Q12H, LPV/r 4 x 133.3 mg/33.3 mg |
Ribavirin 1200 mg three times a day and prednisolone 25 mg three times a day 3TC (for hepatitis flare) |
ARVs provided for HIV treatment | n/a | 0/1 died | Recovered |
MERS | |||||||
Spanakis 2014 [19] Greece |
69‐year‐old man Case report |
LPV/r 400/100 Q12H | peg‐interferon 180 mcg 1/wk for 12 days, RBV, empirical antibiotics | 2 months and 6 days; RBV d/c on day 20 | n/a | LPV/r: 1/1 died | Died due to Septic Shock + MODS; incidental diagnosis of adenocarcinoma colon |
Meyer 2015 [20] Austria |
29‐year‐old woman Case report |
LPV/r | Supportive intensive care therapy | nr | n/a |
LPV/r 0/1 died |
Complete clinical recovery |
Shalhoub 2015 [16] Saudi Arabia |
51‐year‐old man Case report |
TDF/FTC 300/200 mg once daily + ATV/r 300 mg/100 mg) once daily |
Supportive intensive care therapy IFN 2a 180 mcg 1/wk, RBV (loading dose of 2 gm, followed by 600 mg orally every 12 hours) Treatment for CMV prophylactic trimethoprim/sulfamethoxazole 960 mg daily |
ARVs initiated for HIV treatment | n/a | 0/1 died | Recovered |
Kim 2016 [22] Rep Korea |
64‐year‐old man Case Report |
LPV/r 400/100 Q12H | Ribavarin 2 g LD, 1.2 g TID, IFN 2alpha 180 mcg/0.5 mL from day 4 of admission, Empirical therapy with piperacillin/tazobactam and azithromycin from Day 1 of admission | 7 days | n/a | LPV/r: 0/1 died | Discharged on day 13 due to clinical improvement |
Choi 2016 [3] Rep Korea |
120 adults Retrospective observational study |
138 patients received antivirals among whom 120 received LPV/r‐containing regimens |
Antibiotics, haemodialysis, ECMO and convalescent sera. >80% of patients given LPV/r also received IFN | Median time from onset of illness to treatment was 6 days | n/a | LPV/r: 24/120 died | Median interval from symptom onset to death was 14 days |
Saudi Arabia |
41 patients Retrospective observational study |
41 patients received LPV/r | IFN, RBV and antibiotics | nr | n/a |
LPV/r 17/41 died |
|
COVID‐19 | |||||||
Cao 2020 [23] China |
199 patients Randomized trial |
100 adult patients received LPV/r 400/100 Q12H | Supportive care | 14 days | Supportive care alone |
LPV/r 14/99 died Control 25/100 |
LPV/r not associated with a statistically significant difference in time to clinical improvement |
Li 2020 [24] China |
21 adult patients received LPV/r Randomized trial |
LPV/r 200/500 Q12H |
Some patients received gama globulin. All patients received supportive care and oxygen therapy if needed |
7 to 14 days |
16 received arbidol 7 received no antivirals |
LPV/r 0/21 died |
Mild/moderate cases enrolloed. More patients treated with LPV/r progressed to severe/critical status |
Wang 2020 [28] China |
4 adult patients Case series |
LPV/r 400/100 Q12H | Umifenovir (Arbidol), SFJDC | 6 to 15 days | n/a | LPV/r: 0/3 died | Outcome of 1 patient unknown |
Lim 2020 [25] Rep Korea |
54‐year‐old man Case report |
LPV/r 400/100 Q12H from day 8 of admission, day 10 from onset of symptoms |
Other treatments included: Azithromycin, ceftriaxone, levofloxacin/ Tazobactam and 1 dose of Peramivir |
10 days | n/a | LPV/r: 0/1 died | Patients showed clinical improvement following initiation with LPV/r |
Han 2020 [26] China |
47‐year‐old man Case report |
LPV/r 400/100 daily on day 4 of illness | Methylprednisolone (40 mg daily), IFN alfa‐2b (10 million IU daily), ambroxol hydrochloride (60 mg daily) and moxifloxacin hydrochloride (0.4 g daily | Unclear, but discharged after 10 days | n/a | LPV/r: 0/1 died | Patient received LPV/r and was discharged on day 10. |
Kim 2020 [27] Rep Korea |
35‐year‐old woman Case report |
LPV/r 800/200 daily | Oxygen supplementation | Unclear but fever persisted for 10 days | n/a | LPV/r: 0/1 died | |
Young 2020 [29] Singapore |
5 adults Retrospective cohort |
5 patients treated with LPV/r (200 mg/100 mg Q12H for up to 14 days) | Oxygen supplementation | within 1 to 3 days of desaturation | n/a |
LPV/r: 0/5 died 3/5 improved 2/5 developed progressive respiratory failure |
4/5 patients developed nausea, vomiting, and/or diarrhoea, and 3 developed Abnormal liver function test results. Only 1 completed the full 14‐day treatment course |
Chen 2020 [31] China |
99 patients, of which 75 received LPV/r Retrospective cohort |
LPV/r 500 mg Q12H |
oseltamivir (75 mg every 12 hours, orally), ganciclovir (0·25 g every 12 hpurs, intravenously). Antibiotics |
3 to 14 days | n/a | 2/75 died |
57 remained in hospital 31 discharged 11 died |
Jun 2020 [32] China |
52 patients received LPV/r Retrospective cohort |
LPV/r Q12H for 5 days | IFN alpha‐2b and supportive care |
ArdiboL: 34 patients No antivirals: 48 patients |
LPV/r: 0/52 |
No reported deaths LPV/r: 2/52 severe Abidol: 1/33 Control: 2/48 |
|
Liu 2020 [30] China |
10 patients received LPV/r Retrospective cohort |
LPV/r 400/100 Q12H |
Oxygen supplementation. I patient also received TDF for underlying liver disease. 9/10 also received IFN alpha‐2b |
5 days from onset of symptoms | n/a |
LPV/r: 0/10 |
|
Deng 2020 [33] China |
33 patients received LPV/r Retrospective cohort |
LPV/r 400/100 Q12H |
Some patients received corticosteroids Supportive care |
5 to 21 days | 16/33 patients also received arbidol |
LPV/r: 0/17 LPV/r/arbidol: 0/16 |
After 14 days, coronavirus no longer detected by PCR |
Liu 2020Liu 2020 [34] China |
56 patients, of which 53 patients received LPV/r Retrospective cohort |
LPV/r 400/100 Q12H | Some patients received IFH & traditional Chinese medicines | n/a |
3/56 Unclear Who received LPV/r |
Outcomes not linked to receipt of LPV/r | |
Wan [35] China |
135 adult patients Retrospective cohort |
LPV/r (dose not reported) |
All received interferon Some received corticosteroids and traditional Chinese medicine |
nr | n/a |
LPV/r 1/135 |
Patient who died considered severe case |
Cai [36] China |
45 patients received LPV/r Comparative cohort study |
LPV/r 400/100 Q12H | IFN‐α1b 60 μg twice daily | 14 days | Favipiravir | 0/45 died | |
Prevention | |||||||
Chen 2003 [38] China |
19 patients Individuals with HIV (AIDS) infected with SARS Retrospective cohort |
11/19 patients received ARVs: D4T/3TC/EFV = 3, d4T/3TC/NVP = 2, d4T/ddI/NVP = 3, Combivir/EFV = 1, Indinavir/EFV = 2 | Remaining 8 patients received treatment for opportunistic infections | 15 patients stayed for >1 month with SARS patients on the same floor. | n/a | LPV/r: 0/1 infected | All 19 HIV patients (with AIDS) on the floor tested negative for SARS |
Park 2019 [39] Rep Korea |
123 HCWs with unprotected exposure to a MERS‐CoV case of which 43 had a high‐risk exposure Retrospective case control study |
22 received PEP and 21 were not given PEP; PEP protocol was RBV + LPV/r initiated between day 1 and day 3 after last unprotected exposure to the patient | 2 HCWs in the non‐PEP group wore masks, 3 HCWs wore gloves as personal protective equipment | PEP given until day 14, initiated within 36 post exposure, median duration of PEP 12 days | Historical controls from 4 hospitals located far apart |
LPV/r: 0/22 infected Control: 6/21 infected |
6/43 had MERS‐CoV infection; Attack rate in PEP Vs non‐PEP groups: 0% Vs 28.6%, OR: 0.405 (0.274 to 0.599) |
Guo 2020 [40] China |
8 HIV positive individuals with COVID‐19 disease compared with 1166 without COVID‐19 disease |
947 patients received NNRTI‐ regimen 119 received LPV/r‐based regimen |
Use of protection measures unknown | All antiretrovirals taken as HIV treatment | HIV/AIDS patients in Wuchang and Qingshan district |
LPV/r: 0/8 infected |
Results not statistically significant |
3TC, lamivudine; ARDS, acute respiratory distress syndrome; ATV/r, ritonavir‐boosted atazanavir; D4t, stavudine; ECMO, extracorporeal membrane oxygenation; HCWs, Healthcare workers; IFN, Interferon alpha; IU, international units; IV, intravenous; LPV/r, boosted lopinavir/ritonavir; MERS, middle‐east respiratory syndrome; MODS, multiple organ dysfunction syndrome; n/a, not applicable; nCoV, novel coronavirus; nr, not reported; NVP, nevirapine; peg‐IFN, pegylated interferon; PEP, post‐exposure prophylaxis; Q12H, twice daily; RBV, Ribavarin; SARS, Severe acute respiratory syndrome; SFJDC, ShuFengJieDu capsule; TDF, tenofovir.
Additional information provided by the authors.
3.2. SARS
Two observational studies and one case report among patients with SARS [2, 17, 18] reported outcomes of patients who were given antiretrovirals. A study from China reported a reduction in mortality in patients receiving LPV/r of 2.3% (95% CI 0% to 6.8%) compared to matched controls (15.6%, 9.8% to 22.8%) [2]. A second study from China reported that none of the 41 patients given LPV/r died compared with seven of 111 patients in the control group [18]. The third study, also from China, was a case report of a 30‐year‐old HIV‐positive man who recovered; he was receiving abacavir, efavirenz, tenofovir and LPV/r as antiretroviral therapy [17]. All patients also received ribavirin and steroids of varying dose and duration.
3.3. MERS
Six observational studies, including two retrospective observational studies [3, 21] and four case reports [16, 19, 20, 22] – one was from Greece, one from Austria, two from Saudi Arabia and two from the Republic of Korea – provided data on patients diagnosed with MERS. There were 42 deaths among 165 patients who were given LPV/r together with other interventions including ribavirin and pegylated interferon.
3.4. COVID‐19
One randomized, controlled open‐label study reported on the efficacy and safety of LPV/r for treating hospitalized adults with severe COVID‐19 [23]. In this trial 99 patients received LPV/r (400/100 mg twice a day; median time between symptom onset and randomization 13 days) and 100 patients received standard care for 14 days. LPV/r was not associated with a statistically significant difference in time to clinical improvement; 28 day mortality was numerically lower in the LPV/r group (14/99) compared to the control group (25/100), but this difference was not statistically significant in the intention‐to‐treat analysis. Accelerated clinical recovery and reduced mortality were observed in those treated within 12 days of symptom onset, but not in those treated later. Almost half of patients in the LPV/r group (46 patients, 48.4%) and control group (49 patients, 46.7%) reported one or more adverse events: gastrointestinal‐related complaints including nausea, vomiting and diarrhoea were more common in the lopinavir/ritonavir group. A second randomized trial assessed patients admitted to hospital with mild/moderate COVID‐19, and compared outcomes of 21 patients given LPV/r (200mg/50mg twice a day) with 16 patients given ardibol and 7 patients who were not given any antiviral therapy [24]. In this trial, LPV/r did not show any benefit in terms of time to viral clearance (PCR negativity) or progression to severe disease. For both trials, certainty of the evidence was low due to risk of bias (investigators not blinded to the intervention, and imprecision.
In the observational studies, three case reports [25, 26, 27]. three case series [28, 29, 30], and six observational studies [31, 32, 33, 34, 35, 36] reported outcomes of patients with COVID‐19 who received LPV/r; nine studies were from China, one was from Singapore and two from the Republic of Korea. Among the 361 patients in the nine studies where outcomes could be associated with receipt of LPV/r, three patients died. One study reported that 53 of 56 patients received LPV/r and three patients died; however, it was unclear how many of the patients who died had received LPV/r [31].
LPV/r is recommended by WHO as part of second‐line antiretroviral therapy [37]. Among people living with HIV receiving LPV/r diarrhoea, nausea and vomiting are commonly reported side effects at start of treatment [22]. These side effects were reported by four out of five individuals who received LPV/r for the treatment of COVID‐19 in Singapore, and only one individual completed the 14‐day treatment course as a result of adverse events [29].
The certainty of the evidence for outcomes across these three diseases is very low. The sample size was small and only two studies provided comparative outcomes (one using historical controls) and none used a randomized design to be able to assess the comparative effectiveness of different interventions. Timing, duration and dose of treatment varied, and in the majority of studies patients were provided with other interventions which may have contributed to the reported outcomes. GRADE Tables are provided in Appendix S2.
3.5. Antiretroviral drugs as post‐exposure prophylaxis
Three studies reported a possible protective effect of LPV/r against coronavirus infection [38, 39, 40]. The first, a retrospective observational study from China, noted that 0 out of 19 patients hospitalized on same floor as SARS patients contracted the disease. Of the 19 patients, 11 were on differing regimens of antiretroviral therapy; none received LPV/r [38]. The second study, from South Korea, retrospectively enrolled health care workers considered at high risk of MERS infection. Of 22 healthcare workers given post‐exposure prophylaxis (PEP) comprising ribavirin and LPV/r, none were infected; this compared to 9 of 21 healthcare workers not given PEP who became infected [39]. The third study, from China, compared characteristics of 8 HIV‐positive individuals on different antiretroviral regimens who had contracted COVID‐19 infection with 1166 patients who had not been infected [40]. No statistically significant relationship was found between type of antiretroviral regimen and infection status. The certainty of the evidence across outcomes was again very low due to uncertainty due to limited sample size, lack of uniformity of regimens being used to treat patients, and lack of information regarding intensity of exposure (Appendix S2).
3.6. Registered clinical trials
Of 85 titles screened, 25 registered trials were identified that plan to assess the safety and efficacy of antiretrovirals – 20 assessing LPV/r (including 1 for the treatment of MERS and one for SARS, the rest for COVID‐19), two ritonavir, two darunavir and cobicistat and one tenofovir alafenamide fumarate. Estimated completion dates are from March 2020 to January 2022 (Appendix S3).
4. CONCLUSIONS
This systematic review identified two randomized trials and 21 observational studies provided clinical outcome data on the use of LPV/r for the treatment of COVID‐19, SARS and MERS. The randomized trials showed no clinical benefit, the observational studies were inconclusive, and the certainty of the body of evidence across all important outcomes was low or very low. Based on available evidence it is uncertain whether LPV/r and other antiretrovirals improve clinical outcomes in severe symptomatic disease or prevent infection among patients at high risk of acquiring COVID‐19. Any differences in potential therapeutic effect of LPV/r between SARS, MERS and COVID‐19 may partly be due to different clinical presentations; many of the patients had complicated courses including stays in intensive care units and were on multiple concurrent, unproven treatments.
Several randomized trials are planned to assess the safety and efficacy of antiretroviral drugs, including LPV/r, for the treatment of COVID‐19, MERS‐CoV and SARS‐CoV. While the conduct of such trials is challenging [41], high quality evidence is needed to improve clinical and programmatic decisions to use antiretroviral drugs for current and future coronavirus outbreaks.
The procurement and use of LPV/r or other antiretroviral drugs to treat or prevent COVID‐19 infection should take into consideration the need to ensure continued availability for people living with HIV who need LPV/r as part of their antiretroviral therapy. Overuse of LPV/r for COVID‐19 in the current epidemic runs a risk of shortage of a drug that is currently used as a second line treatment for people living with HIV.
WHO plans to update this review at least monthly throughout 2020, and longer as needed, to update the evidence as new studies are completed.
Competing interests
The authors have no conflict of interest to declare.
Authors’ contributions
NF and SN conceived the review. NF undertook all reviews and extracted the data, which was verified by AR. NF, AC, SN, AR, MV and MD interpreted the data. All authors contributed to the writing of the manuscript and approved the final version.
Funding
This work was partly supported by a grant to the Bill & Melinda Gates Foundation.
Disclaimer
The authors alone are responsible for the views expressed in this article and they do not necessarily represent the views of the organization.
Supporting information
Appendix S1. Search terms.
Appendix S2. Grade assessment.
Appendix S3. Planned clinical trials of antiretroviral drugs.
Acknowledgement
We thank Tomas Allen for advice on the search strategy. We also thank Drs Alhumaid and Zhang for providing additional information on their studies.
Ford, N. , Vitoria, M. , Rangaraj, A. , Norris, S. L. , Calmy, A. and Doherty, M. Systematic review of the efficacy and safety of antiretroviral drugs against SARS, MERS or COVID‐19: initial assessment. J Int AIDS Soc. 2020; 23(4):e25489
Contributor Information
Nathan Ford, Email: fordn@who.int.
Marco Vitoria, Email: vitoriam@who.int.
Ajay Rangaraj, Email: rangaraja@who.int.
Susan L Norris, Email: norriss@who.int.
Alexandra Calmy, Email: alexandra.calmy@hcuge.ch.
Meg Doherty, Email: dohertym@who.int.
REFERENCES
- 1. Zhou Y, Vedantham P, Lu K, Agudelo J, Carrion R Jr, Nunneley JW, et al. Protease inhibitors targeting coronavirus and filovirus entry. Antiviral Res. 2015;116:76–84. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2. Chan KS, Lai ST, Chu CM, Tsui E, Tam CY, Wong MM, et al. Treatment of severe acute respiratory syndrome with lopinavir/ritonavir: a multicentre retrospective matched cohort study. Hong Kong Med J. 2003;9:399–406. [PubMed] [Google Scholar]
- 3. Choi WS, Kang CI, Kim Y, Choi JP, Joh JS, Shin HS, et al. Clinical presentation and outcomes of middle east respiratory syndrome in the Republic of Korea. Infect Chemother. 2016;48:118–26. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4. de Wilde AH, Jochmans D, Posthuma CC, Zevenhoven‐Dobbe JC, van Nieuwkoop S, Bestebroer TM, et al. Screening of an FDA‐approved compound library identifies four small‐molecule inhibitors of Middle East respiratory syndrome coronavirus replication in cell culture. Antimicrob Agents Chemother. 2014;58:4875–84. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5. Chan JF, Yao Y, Yeung ML, Deng W, Bao L, Jia L, et al. Treatment with lopinavir/ritonavir or interferon‐beta1b improves outcome of MERS‐CoV infection in a nonhuman primate model of common marmoset. J Infect Dis. 2015;212:1904–13. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6. Jin YH, Cai L, Cheng ZS, Cheng H, Deng T, Fan YP, et al. A rapid advice guideline for the diagnosis and treatment of 2019 novel coronavirus (2019‐nCoV) infected pneumonia (standard version). Mil Med Res. 2020;7:4. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7. Tan EL, Ooi EE, Lin CY, Tan HC, Ling AE, Lim B, et al. Inhibition of SARS coronavirus infection in vitro with clinically approved antiviral drugs. Emerg Infect Dis. 2004;10:581–6. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8. Morra ME, Van Thanh L, Kamel MG, Ghazy AA, Altibi AMA, Dat LM, et al. Clinical outcomes of current medical approaches for Middle East respiratory syndrome: a systematic review and meta‐analysis. Rev Med Virol. 2018;28:e1977. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9. Momattin H, Al‐Ali AY, Al‐Tawfiq JA. A Systematic Review of therapeutic agents for the treatment of the Middle East Respiratory Syndrome Coronavirus (MERS‐CoV). Travel Med Infect Dis. 2019;30:9–18. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10. Beck B, Shin B, Choi Y, Park S, Kang K. Predicting commercially available antiviral drugs that may act on the novel coronavirus (2019‐nCoV), Wuhan, China through a drug‐target interaction deep learning model. bioRxiv. 2020. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11. Dayer M, Taleb‐Gassabi S, Dayer M. Lopinavir; A potent drug against coronavirus infection: insight from molecular docking study. Archiv Clin Infect Dis. 2017;12:e13823. [Google Scholar]
- 12. Guyatt GH, Oxman AD, Vist GE, Kunz R, Falck‐Ytter Y, Alonso‐Coello P, et al. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. BMJ. 2008;336(7650):924–6. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13. Macconnachie AA, Collins TC, Seaton RA, Kennedy DH. Three men, a paint brush and a coronavirus. Int J STD AIDS. 2007;18:132–3. [DOI] [PubMed] [Google Scholar]
- 14. Wang XF, Yuan J, Zheng YJ, Chen J, Bao YM, Wang YR, et al. Retracted: clinical and epidemiological characteristics of 34 children with 2019 novel coronavirus infection in Shenzhen. Zhonghua Er Ke Za Zhi. 2020;58:E008. [DOI] [PubMed] [Google Scholar]
- 15. Peiris JS, Chu CM, Cheng VC, Chan KS, Hung IF, Poon LL, et al. Clinical progression and viral load in a community outbreak of coronavirus‐associated SARS pneumonia: a prospective study. Lancet. 2003;361:1767–72. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16. Shalhoub S, AlZahrani A, Simhairi R, Mushtaq A. Successful recovery of MERS CoV pneumonia in a patient with acquired immunodeficiency syndrome: a case report. J Clin Virol. 2015;62:69–71. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17. Wong AT, Tsang OT, Wong MY, Lim WL, Zheng BJ, Lee SS, et al. Coronavirus infection in an AIDS patient. AIDS. 2004;18:829–30. [DOI] [PubMed] [Google Scholar]
- 18. Chu CM, Cheng VC, Hung IF, Wong MM, Chan KH, Chan KS, et al. Role of lopinavir/ritonavir in the treatment of SARS: initial virological and clinical findings. Thorax. 2004;59:252–6. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19. Spanakis N, Tsiodras S, Haagmans BL, Raj VS, Pontikis K, Koutsoukou A, et al. Virological and serological analysis of a recent Middle East respiratory syndrome coronavirus infection case on a triple combination antiviral regimen. Int J Antimicrob Agents. 2014;44:528–32. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20. Meyer B, Basra A, Aberle S, Aberle J, Robibaro B, Wenisch C, et al. MERS‐COV disease associated ARDS – a case report. Crit Care Med. 2015;43(12):308.25318386 [Google Scholar]
- 21. Alhumaid S, Tobaiqy M, Albagshi M, Alrubaya A, Algharib F, Aldera A, et al. MERS‐CoV transmitted from animal‐to‐human vs MERSCoV transmitted from human‐to‐human: comparison of virulence and therapeutic outcomes in a Saudi hospital. Trop J Pharmaceut Res. 2018;17(6):1155–64. [Google Scholar]
- 22. Kim UJ, Won EJ, Kee SJ, Jung SI, Jang HC. Combination therapy with lopinavir/ritonavir, ribavirin and interferon‐alpha for Middle East respiratory syndrome. Antivir Ther. 2016;21:455–9. [DOI] [PubMed] [Google Scholar]
- 23. Cao B, Wang Y, Wen D, Liu W, Wang J, Fan G, et al. A randomized, controlled, open‐label study to evaluate the efficacy and safety of oral lopinavir/ritonavir. NEJM. 2020. [Epub ahead of print]. [Google Scholar]
- 24. Li Y, Xie Z, Lin W, Cai W, Wen C, Guan Y, et al. An exploratory randomized, controlled study on the efficacy and safety of lopinavir/ritonavir or arbidol treating adult patients hospitalized with mild/moderate COVID‐19 (ELACOI). medRxiv preprint. 10.1101/2020.03.19.20038984 [DOI] [Google Scholar]
- 25. Lim J, Jeon S, Shin HY, Kim MJ, Seong YM, Lee WJ, et al. Case of the index patient who caused tertiary transmission of COVID‐19 infection in Korea: the application of lopinavir/ritonavir for the treatment of COVID‐19 infected pneumonia monitored by quantitative RT‐PCR. J Korean Med Sci. 2020;35:e79. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26. Han W, Quan B, Guo Y, Zhang J, Lu Y, Feng G, et al. The course of clinical diagnosis and treatment of a case infected with coronavirus disease 2019. J Med Virol. 2020;92(5):461–3. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27. Kim JY, Choe PG, Oh Y, Oh KJ, Kim J, Park SJ, et al. The first case of 2019 novel coronavirus pneumonia imported into Korea from Wuhan, China: implication for infection prevention and control measures. J Korean Med Sci. 2020;35:e61. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28. Wang Z, Chen X, Lu Y, Chen F, Zhang W. Clinical characteristics and therapeutic procedure for four cases with 2019 novel coronavirus pneumonia receiving combined Chinese and Western medicine treatment. BioSci Trends. 2020;14(1):64–8. [DOI] [PubMed] [Google Scholar]
- 29. Young BE, Ong SWX, Kalimuddin S, Low JG, Tan SY, Loh J, et al. Epidemiologic features and clinical course of patients infected with SARS‐CoV‐2 in Singapore. JAMA. 2020. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 30. Liu F, Xu A, Zhang Y, Xuan W, Yan T, Pan K, et al. Patients of COVID‐19 may benefit from sustained lopinavir‐combined regimen and the increase of eosinophil may predict the outcome of COVID‐19 progression. Int J Infect Dis. 2020:1–28. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 31. Chen N, Zhou M, Dong X, Qu J, Gong F, Han Y, et al. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet. 2020;395:507–13. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 32. Jun C, Yun L, Xiuhung X, Ping L, Feng L, Tao L, et al. Efficacy of lopinavir, ritonavir and abidol for the treatment of new coronavirus pneumonia. Chinese. J Infect Dis. 2020;38. [Google Scholar]
- 33. Deng L, Li C, Zeng Q, Liu X, Li X, Zhang H, et al. Arbidol combined with LPV/r versus LPV/r alone against Corona Virus Disease 2019: a retrospective cohort study. J Infect. 2020. [Epub ahead of print]. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 34. Liu K, Chen Y, Lin R, Han K. Clinical feature of COVID‐19 in elderly patients: a comparison with young and middle‐aged patients. J Infect. 2020:1–12. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 35. Wan S, Xiang Y, Fang W, Zheng Y, Li B, Hu Y, et al. Clinical features and treatment of COVID‐19 patients in Northeast Chongqing. J Med Virol. 2020. [Epub ahead of print]. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 36. Cai Q, Yang M, Liu D, Chen J, Shu D, Xia J, et al. Experimental treatment with favipiravir for COVID‐19: an open‐label control study. Engineering. 2020:1–13. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 37. WHO . Update of recommendations on first‐ and second‐line antiretroviral regimens. Geneva: World Health Organization; 2019. [Google Scholar]
- 38. Chen XP, Li GH, Tang XP, Xiong Y, Chen XJ, Cao Y. Lack of severe acute respiratory syndrome in 19 AIDS patients hospitalized together. J Acquir Immune Defic Syndr. 2003;34:242–3. [DOI] [PubMed] [Google Scholar]
- 39. Park SY, Lee JS, Son JS, Ko JH, Peck KR, Jung Y, et al. Post‐exposure prophylaxis for Middle East respiratory syndrome in healthcare workers. J Hosp Infect. 2019;101:42–6. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 40. Guo W, Ming F, Dong Y, Zhang Q, Zhang X, Mo P, et al. A survey for COVID‐19 among HIV/AIDS patients in two Districts of Wuhan, China. Lancet. 2020. [cited 2020 Apr 1]. Preprint. Available from: https://ssrn.com/abstract=3550029 [Google Scholar]
- 41. Muller MP, McGeer A, Straus SE, Hawryluck L, Gold WL. Clinical trials and novel pathogens: lessons learned from SARS. Emerg Infect Dis. 2004;10:389–94. [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Appendix S1. Search terms.
Appendix S2. Grade assessment.
Appendix S3. Planned clinical trials of antiretroviral drugs.