Early Lopinavir/ritonavir does not reduce mortality in COVID-19 patients: Results of a large multicenter study
Authors: Jaime Lora-Tamayo, Guillermo Maestro, Antonio Lalueza, Manuel Rubio-Rivas, Gracia Villarreal Paul, Francisco Arnalich Fernández, José Luis Beato Pérez, Juan Antonio Vargas Núñez, Mónica Llorente Barrio, Carlos Lumbreras Bermejo
Journal: Journal of Infection (2021)

•This is the largest study assessing the efficacy of LPV/r against SARS-CoV-2.•The overall use of LPV/r was not associated with lower mortality in CoVID19 patients.•The early use of LPV/r (median 5 days) showed no benefit either. The COVID-19 pandemic, an unprecedented event for current generations of physicians, has stricken hard on society.1Anderson Roy M. Heesterbeek Hans Klinkenberg Don Hollingsworth T.Déirdre How will country-based mitigation measures influence the course of the COVID-19 epidemic?.Lancet. 2020; : 931-934https://doi.org/10.1016/S0140-6736(20)30567-5Abstract Full Text Full Text PDF PubMed Scopus (2265) Google Scholar There is a significant lack of effective drugs for stopping viral replication. Lopinavir/ritonavir (LPV/r) is a well-known combination used in patients with HIV which was included in the arsenal against SARS-CoV-2 early in the pandemic.2Sarkar Chandan Mondal Milon Torequl Islam Muhammad Martorell Miquel Docea Anca Oana Maroyi Alfred et al.Potential therapeutic options for COVID-19: current status, challenges, and future perspectives.Front Pharmacol. 2020; https://doi.org/10.3389/fphar.2020.572870Crossref PubMed Scopus (77) Google Scholar Its use in COVID-19 was based on inconsistent results from experimental and clinical research that was mostly done while investigating other β-coronaviruses (SARS and MERS). A number of randomized clinical trials have observed no benefit of LPV/r beyond the standard of care.3Horby Peter W. Mafham Marion Bell Jennifer L. Linsell Louise Staplin Natalie Emberson Jonathan et al.Lopinavir–ritonavir in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial.Lancet. 2020; 396: 1345-1352https://doi.org/10.1016/S0140-6736(20)32013-4Abstract Full Text Full Text PDF PubMed Scopus (478) Google Scholar, 4Cao B. Wang Y. Wen D. Liu W. Wang Jingli Fan G. et al.A trial of lopinavir-ritonavir in adults hospitalized with severe covid-19.N Engl J Med. 2020; 382: 1787-1799https://doi.org/10.1056/NEJMoa2001282Crossref PubMed Scopus (3823) Google Scholar, 5Pan Hongchao Peto Richard Henao-Restrepo Ana-Maria Preziosi Marie-Pierre Sathiyamoorthy Vasee et al.WHO Solidarity Trial ConsortiumRepurposed antiviral drugs for Covid-19 - interim WHO solidarity trial results.N Engl J Med. 2020; https://doi.org/10.1056/NEJMoa2023184Crossref Scopus (1641) Google Scholar However, voices have been raised against interpreting these results as grounds from definitively ruling out LPV/r since some of these studies lacked statistical power, reported encouraging outcomes in secondary endpoints, and included patients with a prolonged period of symptoms before initiation of treatment.6Carmona-Bayonas A. Jimenez-Fonseca P. Castañón E. A trial of Lopinavir–Ritonavir in Covid-19.N Engl J Med. 2020; 382: e68https://doi.org/10.1056/nejmc2008043Crossref PubMed Google Scholar,7Kunz Kurt M. A trial of Lopinavir–Ritonavir in Covid-19.N Engl J Med. 2020; 382: e.68https://doi.org/10.1056/NEJMc2008043Crossref Scopus (49) Google Scholar Indeed, there may be a subpopulation of COVID-19 patients – notably those early in the course of the infection – for whom LPV/r may improve their prognosis. In a recent report, Klement-Frutos et al. describe a favorable outcome of patient with COVID-19 after beginning of LPV/r on day 9 of symptoms.8Klement-Frutos Elise Burrel Sonia Peytavin Gilles Marot Stéphane Lê Minh P. Godefroy Nagisa et al.Early administration of ritonavir-boosted lopinavir could prevent severe COVID-19.J Infect. 2021; 82: 159-198https://doi.org/10.1016/j.jinf.2020.05.039Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar Therefore, we aimed to assess the efficacy of LPV/r in a large, multicenter cohort of patients, with special interest in those who received treatment soon after the onset of symptoms. This work belongs to the SEMI-COVID-19 Registry, which is an ongoing, nationwide, retrospective, anonymized cohort of consecutive adult patients hospitalized in Spain for microbiologically confirmed COVID-19.9Casas-Rojo J.M. Antón-Santos J.M. Millán-Núñez-Cortés J. Lumbreras-Bermejo C. Ramos-Rincón J.M. Roy-Vallejo E. et al.Clinical characteristics of patients hospitalized with COVID-19 in Spain: results from the SEMI-COVID-19 registry.Rev Clin Esp. 2020; https://doi.org/10.1016/j.rce.2020.07.003Crossref PubMed Scopus (220) Google Scholar The Registry was approved by the Ethics Committees of the participating centers, and included data on over 300 variables. The primary endpoint was raw-in hospital mortality at 30 days from admission. Patients were considered to have been treated with LPV/r if they had received at least one dose of the drug. Common dosage of LPV/r was 400/100 mg bid. In order to mitigate the effects of possible confounding variables in a non-randomized assessment of treatment with LPV/r, propensity score (PS) was performed. The propensity of receiving LPV/r was estimated using a logistic regression model that included confounding variables which could have affected treatment choice or outcomes as independent variables. The nearest neighbor method with a caliper of 0.1 as used in PS matching and standardized mean differences (SMD) were calculated to evaluate adequacy of propensity matching. Both conditional logit and mixed effects logistic regressions were performed. Furthermore, univariate and multivariate logistic regression models were fitted in order to estimate the treatment effect using all data, as a sensitivity analysis. Multiple imputation was used to handle missing data and model estimates and standard errors were calculated using Rubin's rules.10Rubin Donald B. Multiple Imputation for Nonresponse in Surveys. John Wiley & Sons, Inc., Hoboken, NJ, USA1987Crossref Google Scholar Statistical analyses were performed using R software (v.3.6.2). As of June 1, 2020, the Registry included 9,594 cases, of which 8,553 met the inclusion criteria (Suppl. Fig. 1). Fifty-seven percent were men, median age was 69 years (IQR 56–79), and half of subjects (50.2%) had high blood pressure. Patients were admitted after a median time since symptoms onset of 7 days (IQR 4–9), with median SaO2/FiO2 ratio of 376 (IQR 300–452), C-reactive protein of 58 mg/L (IQR 19–123), and lymphocytes of 940 cells/µL. LPV/r was administered to 5,396 patients (63%) after a median of 0 days since admission (IQR 0–1). Table 1 shows that LPV/r was more likely to be prescribed to patients who presented with more severe clinical condition, including presence of fever, cough, radiological infiltrates (91.7% vs 80.4% p<0.001) and a lower SaO2/FiO2 ratio. On the other hand, LPV/r was less frequent among at-risk subjects in whom toxicity may be more likely: elderly patients presenting with altered mental status, dementia, or other debilitating baseline conditions, as well as patients on immunosuppressive drugs and pregnant women.Table 1– Baseline characteristics and clinical presentation of all patients according to the administration of LPV/r.Unmatched data (n = 8,553)Matched data (n = 5,068)No LPV/r (n = 3,157)LPV/r (n = 5,396)pNo LPV/r (n = 2,534)LPV/r (n = 2,534)pBaseline features Age (years)†Continuous variables expressed as median and [interquartile range]. LPV/r: lopinavir/ritonavir.74.9 [60.4;85.2]66.2 [54.3;75.8]<0.00170.8 [57.2;81.5]69.5 [56.6;78.7]<0.001 Sex (female)1511 (47.9%)2155 (39.9%)<0.0011124 (44.4%)1083 (42.7%)0.257 Pregnancy22 (0.70%)15 (0.28%)0.00818 (0.71%)13 (0.51%)0.471 Race (Caucasian)2850 (91.2%)4647 (87.9%)<0.0012268 (89.5%)2279 (89.9%)0.644 Charlson Comorbidity Index1.00 [0.00;2.00]0.00 [0.00;1.00]<0.0011.00 [0.00;2.00]1 [0.00;2.00]0.626 High blood pressure1817 (57.7%)2480 (46.1%)<0.0011357 (53.6%)1288 (50.8%)0.056 Immunosuppressive therapy257 (8.14%)291 (5.39%)<0.001205 (8.09%)186 (7.34%)0.040 Dementia628 (20.0%)199 (3.70%)<0.001171 (6.75%)179 (7.06%)0.009Clinical presentation Duration of symptoms (days) †Continuous variables expressed as median and [interquartile range]. LPV/r: lopinavir/ritonavir.6.00 [3.00;9.00]7.00 [4.00;9.00]<0.0016.00 [3.00;9.00]7.00 [4.00;9.00]0.337 Cough2170 (69.2%)4281 (79.6%)<0.0011892 (74.7%)1918 (75.7%)0.678 Dyspnea1787 (56.9%)3108 (57.9%)0.3701439 (56.8%)1440 (56.8%)1.000 Altered mental status574 (18.4%)351 (6.58%)<0.001262 (10.3%)249 (9.83%)0.576 Temperature36.9 [36.3;37.6]37.1 [36.4;37.9]<0.00136.9 [36.3;37.7]37.0 [36.4;37.8]0.013 Heart rate (beats/min) †Continuous variables expressed as median and [interquartile range]. LPV/r: lopinavir/ritonavir.86.0 [75.0;98.0]88.0 [77.0;100]<0.00186.5 [76.0;99.0]87.0 [76.0;99.0]0.816 Respiratory rate > 20 breaths/min958 (31.2%)1558 (29.7%)0.155728 (28.7%)735 (29.0%)0.852Laboratory SaO2/FiO2 †Continuous variables expressed as median and [interquartile range]. LPV/r: lopinavir/ritonavir.387 [304;452]372 [297;452]<0.001392 [307;457]381 [304;452]0.008 Lymphocytes (cells/µL) †Continuous variables expressed as median and [interquartile range]. LPV/r: lopinavir/ritonavir.990 [700;1330]910 [700;1260]0.0801000 [700;1320]940 [700;1300]0.042 C-reactive protein (mg/L) †Continuous variables expressed as median and [interquartile range]. LPV/r: lopinavir/ritonavir.55.0 [17.0;120]59.9 [19.8;125]0.00255.7 [17.1;120]55.9 [18.0;119]0.391 Creatinine (mg/dL) †Continuous variables expressed as median and [interquartile range]. LPV/r: lopinavir/ritonavir.0.93 [0.75;1.23]0.89 [0.73;1.10]<0.0010.90 [0.74;1.17]0.90 [0.74;1.14]0.718Other treatments Interferon-β52 (1.65%)1073 (20.1%)<0.00152 (2.05%)78 (3.08%)0.049 Hydroxychloroquine2299 (72.8%)4893 (90.7%)<0.0012084 (82.2%)2133 (84.2%)0.071 Remdesivir17 (0.54%)26 (0.48%)0.84212 (0.47%)12 (0.47%)1.000Mortality688 (22.8%)821 (15.7%)<0.001431 (17.0%)406 (16.0%)0.364† Continuous variables expressed as median and [interquartile range]. LPV/r: lopinavir/ritonavir. Open table in a new tab Overall, 1,509 patients died (17.6%). The univariate parameters predicting mortality is shown in Table 2. A PS allowed for comparing two cohorts with similar values on the parameters associated with the prescription of LPV/r (Table 1). Most parameters were adequately matched according to SMD, although some variables had SMD values >0.02 (Suppl. Table 1): In this matched cohort, the adjusted odds ratio (aOR) for mortality for the use of LPV/r was 0.932 (95CI 0.799–1.087; p>0.05) according to both conditional and mixed effects logistic models.Table 2– Univariate analysis of mortality in all patients and those with duration of symptoms of less than 8 days.All (n = 8,553)Early cohort (n = 6,099)OR (95CI)POR (95CI)pSex (female)0.783 (0.698–0.879)<0.0010.775 (0.681–0.882)<0.001Age (per year)1.090 (1.084–1.096)<0.0011.082 (1.076–1.089)<0.001Race (Caucasian)3.267 (2.499–4.272)<0.0013.715 (2.734–5.047)<0.001High blood pressure2.833 (2.509–3.200)<0.0012.700 (2.354–3.097)<0.001Dementia4.323 (3.715–5.031)<0.0013.704 (3.137–4.374)<0.001Immunosuppressive treatment1.747 (1.431–2.134)<0.0011.656 (1.328–2.066)<0.001Charlson Comorbidity Index (per point)1.334 (1.296–1.373)<0.0011.307 (1.265–1.349)<0.001Duration of symptoms (per day)0.930 (0.918–0.943)<0.0010.907 (0.886–0.928)<0.001Cough0.652 (0.576–0738)<0.0010.703 (0.612–0.806)<0.001Temperature (per °C)1.088 (1.026–1.154)0.0051.069 (1.000–1.141)0.049Dyspnea1.865 (1.653–2.104)<0.0011.828 (1.597–2.091)<0.001Confusion5.341 (4.620–6.174)<0.0014.433 (3.774–5.208)<0.001Respiratory rate > 20 breaths/min3.396 (3.020–3.819)<0.0013.239 (2.838–3.696)<0.001SaO2/FiO2 (per unit)0.993 (0.992–0.993)<0.0010.993 (0.992–0.993)<0.001Lymphocytes (per cells x 103/µL)1.000 (1.000–1.000)0.4241.000 (1.000–1.000)0.470C-reactive protein (per mg/L)1.005 (1.005–1.006)<0.0011.006 (1.005–1.006)<0.001Creatinine (per mg/dL)1.789 (1.651–1.938)<0.0011.647 (1.515–1.792)<0.001Treatment with Hydroxychloroquine0.447 (0.391–0.512)<0.0010.483 (0.416–0.562)<0.001Treatment with Interferon-β2.094 (1.813–2.420)<0.0012.098 (1.787–2.463)<0.001Treatment with Remdesivir1.096 (0.507–2.366)0.8160.871 (0.360–2.109)0.760Treatment with LPV/r0.651 (0.581–0.729)<0.0010.705 (0.620–0.801)<0.001LPV/r: lopinavir/ritonavir. OR: odds ratio. 95CI: 95% confidence interval. Open table in a new tab LPV/r: lopinavir/ritonavir. OR: odds ratio. 95CI: 95% confidence interval. Of the 6,099 patients who were admitted to hospital within 8 days since onset of symptoms (median time to admission since onset of symptoms 5 days [IQR 3–7]), LPV/r was prescribed to 3,377 (55%). Variables associated with the use of LPV/r were similar to those observed in the cohort as a whole (Suppl. Table 2). In a propensity score matching carried out on this subset of patients, early use of LPV/r was not associated with a lower mortality (conditional logistic regression: aOR 1.110 (95CI 0.944–1.300; p = 0.245); mixed effects logistic regression: aOR 1.105 (95CI 0.944–1.300; p = 0.272)). Consistent with previous studies, our analysis found no overall benefit to the use of LPV/r.3Horby Peter W. Mafham Marion Bell Jennifer L. Linsell Louise Staplin Natalie Emberson Jonathan et al.Lopinavir–ritonavir in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial.Lancet. 2020; 396: 1345-1352https://doi.org/10.1016/S0140-6736(20)32013-4Abstract Full Text Full Text PDF PubMed Scopus (478) Google Scholar, 4Cao B. Wang Y. Wen D. Liu W. Wang Jingli Fan G. et al.A trial of lopinavir-ritonavir in adults hospitalized with severe covid-19.N Engl J Med. 2020; 382: 1787-1799https://doi.org/10.1056/NEJMoa2001282Crossref PubMed Scopus (3823) Google Scholar, 5Pan Hongchao Peto Richard Henao-Restrepo Ana-Maria Preziosi Marie-Pierre Sathiyamoorthy Vasee et al.WHO Solidarity Trial ConsortiumRepurposed antiviral drugs for Covid-19 - interim WHO solidarity trial results.N Engl J Med. 2020; https://doi.org/10.1056/NEJMoa2023184Crossref Scopus (1641) Google Scholar We have focused on patients who received the antiviral at an earlier stage in the hope of finding greater activity. Indeed, in other viral diseases, the administration of antiviral drugs must be done as soon as possible in order to have a clinically significant activity.11Aoki Fred Y. Hayden Frederick G. Dolin Raphael Principles and practice of infectious diseases.in: Mandell Gerald l. Bennett John E. Dolin Raphael Princ. Pract. Infect. Dis.7th Ed. Churchill Livingstone Inc., Philadelphia2010Google Scholar Of note, patients included in Rao's clinical trial had a median duration of symptoms of 13 days (IQR 11–16) 4Cao B. Wang Y. Wen D. Liu W. Wang Jingli Fan G. et al.A trial of lopinavir-ritonavir in adults hospitalized with severe covid-19.N Engl J Med. 2020; 382: 1787-1799https://doi.org/10.1056/NEJMoa2001282Crossref PubMed Scopus (3823) Google Scholar, and those recruited in the RECOVERY trial presented after 8 days of disease (IQR 4–12).3Horby Peter W. Mafham Marion Bell Jennifer L. Linsell Louise Staplin Natalie Emberson Jonathan et al.Lopinavir–ritonavir in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial.Lancet. 2020; 396: 1345-1352https://doi.org/10.1016/S0140-6736(20)32013-4Abstract Full Text Full Text PDF PubMed Scopus (478) Google Scholar In our sub-analysis, the median duration was 5 days (IQR 3–7), thus allowing us to perform a evaluation on patients who were indeed at a very early stage of disease. However, results were again disappointing, and add another nail in the coffin of LPV/r when considering its use for COVID-19. Our study has some limitations. First, it has the biases inherent to retrospective observational studies. Also, despite the fact that the number of patients included allowed us to perform PS matching, which may have reasonably controlled for many of these biases, the balance of some parameters was not perfect according to SMD values. Still, as a multicenter study involving a large number of hospitals, it has the strength of being rooted in real-life practice, far from strict inclusion and exclusion criteria of clinical trials. Second, we have used mortality as a primary endpoint, as others have done, but we cannot rule out any benefits of LPV/r that would have emerged had we analyzed softer outcomes, such as time to improvement or disease duration, as suggested by the report of Klement-Frutos et al.8Klement-Frutos Elise Burrel Sonia Peytavin Gilles Marot Stéphane Lê Minh P. Godefroy Nagisa et al.Early administration of ritonavir-boosted lopinavir could prevent severe COVID-19.J Infect. 2021; 82: 159-198https://doi.org/10.1016/j.jinf.2020.05.039Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar Finally, our analysis has used data from COVID-19 first wave in Spain, when efficacy of corticosteroids or other drugs was not yet proved. Thus, our analysis is not adjusted for these treatments. However, these therapies, at least during the first wave of the pandemic, have usually been reserved for severe patients, and thus may be surrogate predictors of unfavorable progress. In conclusion, we have analyzed a large, multicenter cohort of patients with COVID-19 and have not found any benefits to administering LPV/r, even when it was administered within the first 8 days of symptoms. Our results discourage its use in SARS-CoV-2 infection. This work was supported by the Spanish Society of Internal Medicine (SEMI).