Background In this study, we aimed to evaluate the effects of tocilizumab in adult patients admitted to hospital with COVID-19 with both hypoxia and systemic inflammation. Methods This randomised, controlled, open-label, platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing several possible treatments in patients hospitalised with COVID-19 in the UK. Those trial participants with hypoxia (oxygen saturation <92% on air or requiring oxygen therapy) and evidence of systemic inflammation (C-reactive protein ≥75 mg/L) were eligible for random assignment in a 1:1 ratio to usual standard of care alone versus usual standard of care plus tocilizumab at a dose of 400 mg–800 mg (depending on weight) given intravenously. A second dose could be given 12–24 h later if the patient's condition had not improved. The primary outcome was 28-day mortality, assessed in the intention-to-treat population. The trial is registered with ISRCTN (50189673) and ClinicalTrials.gov ( NCT04381936 ). Findings Between April 23, 2020, and Jan 24, 2021, 4116 adults of 21 550 patients enrolled into the RECOVERY trial were included in the assessment of tocilizumab, including 3385 (82%) patients receiving systemic corticosteroids. Overall, 621 (31%) of the 2022 patients allocated tocilizumab and 729 (35%) of the 2094 patients allocated to usual care died within 28 days (rate ratio 0·85; 95% CI 0·76–0·94; p=0·0028). Consistent results were seen in all prespecified subgroups of patients, including those receiving systemic corticosteroids. Patients allocated to tocilizumab were more likely to be discharged from hospital within 28 days (57% vs 50%; rate ratio 1·22; 1·12–1·33; p<0·0001). Among those not receiving invasive mechanical ventilation at baseline, patients allocated tocilizumab were less likely to reach the composite endpoint of invasive mechanical ventilation or death (35% vs 42%; risk ratio 0·84; 95% CI 0·77–0·92; p<0·0001). Interpretation In hospitalised COVID-19 patients with hypoxia and systemic inflammation, tocilizumab improved survival and other clinical outcomes. These benefits were seen regardless of the amount of respiratory support and were additional to the benefits of systemic corticosteroids. Funding UK Research and Innovation (Medical Research Council) and National Institute of Health Research.

BACKGROUNDEarly clinical data from studies of the NVX-CoV2373 vaccine (Novavax), a recombinant nanoparticle vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that contains the full-length spike glycoprotein of the prototype strain plus Matrix-M adjuvant, showed that the vaccine was safe and associated with a robust immune response in healthy adult participants. Additional data were needed regarding the efficacy, immunogenicity, and safety of this vaccine in a larger population. METHODSIn this phase 3, randomized, observer-blinded, placebo-controlled trial conducted at 33 sites in the United Kingdom, we assigned adults between the ages of 18 and 84 years in a 1:1 ratio to receive two intramuscular 5-μg doses of NVX-CoV2373 or placebo administered 21 days apart. The primary efficacy end point was virologically confirmed mild, moderate, or severe SARS-CoV-2 infection with an onset at least 7 days after the second injection in participants who were serologically negative at baseline. RESULTSA total of 15,187 participants underwent randomization, and 14,039 were included in the per-protocol efficacy population. Of the participants, 27.9% were 65 years of age or older, and 44.6% had coexisting illnesses. Infections were reported in 10 participants in the vaccine group and in 96 in the placebo group, with a symptom onset of at least 7 days after the second injection, for a vaccine efficacy of 89.7% (95% confidence interval [CI], 80.2 to 94.6). No hospitalizations or deaths were reported among the 10 cases in the vaccine group. Five cases of severe infection were reported, all of which were in the placebo group. A post hoc analysis showed an efficacy of 86.3% (95% CI, 71.3 to 93.5) against the B.1.1.7 (or alpha) variant and 96.4% (95% CI, 73.8 to 99.5) against non-B.1.1.7 variants. Reactogenicity was generally mild and transient. The incidence of serious adverse events was low and similar in the two groups. CONCLUSIONSA two-dose regimen of the NVX-CoV2373 vaccine administered to adult participants conferred 89.7% protection against SARS-CoV-2 infection and showed high efficacy against the B.1.1.7 variant.

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Risk if ART is deferred is taken from [328]. The predicted 6-month risk if ART is initiated is based on the assumption that the rate with immediate therapy initiation is one-third the rate without therapy initiation. This (probably conservative) value is based on considering evidence from multiple sources, including references [32,[329][330][331][332][333].BHIVA treatment guidelines 569 r 2008 British HIV Association HIV Medicine (2008) 9, 563-608 but high CD4 percentages, but also may support a decision to start therapy earlier in patients with absolute CD4 counts 4350 cells/mL but with low CD4 percentages {e.g. o14%, where Pneumocystis carinii pneumonia (PCP) prophylaxis is indicated [35]; some studies have indicated increased risk of disease progression in patients with CD4 percentages o15-17% [36]}. Patients with a CD4 count 4350 cells/mLAs detailed above, at CD4 counts 4350 cells/mL, multiple cohort studies have suggested that there might be benefits to ART. This is supported by data from the substudy of patients not on therapy at entry to the SMART study [32]. Some of the previous concerns about earlier initiation of therapy have been reduced because of the availability of simpler, less toxic and better tolerated antiretroviral regimens, improved pharmacokinetic profiles and increasing options after virological failure. For the majority of patients, the absolute risk of deferring therapy until the CD4 count is o350 cells/mL is likely to be low, but in a subgroup at particularly high risk of clinical events that may be preventable by ART, this is not the case. For all these reasons, in a small number of patients, treatment may be started or considered before the CD4 count is below 350 cells/mL, including the following: AIDS diagnosis (e.g. Kaposi's sarcoma); any HIV-related comorbidity; hepatitis B infection, where treatment of hepatitis B is indicated (see hepatitis guidelines); hepatitis C infection in some cases, where treatment for hepatitis is deferred; low CD4 percentage (e.g. o14%, where PCP prophylaxis would be indicated); established CVD or a very high risk of cardiovascular events (e.g. Framingham risk of CVD 420% over 10 years).Additionally, it is likely that successful antiretroviral treatment, by reducing viral load, reduces infectivity irrespective of the current CD4 cell count, and this may be taken into account in deciding on the timing of starting treatment, particularly in discordant couples where the infected partner has a high viral load. This is likely to be an issue in a very small number of patients, and it must be stressed that antiretroviral treatment in this context would be an adjunct rather than an alternative to safer sex.In patients who do not have an AIDS diagnosis or coinfection with hepatitis B or C virus, and whose CD4 counts are above 500 cells/mL, the benefits of starting therapy remain unclear, the risk of deferring therapy is low, and we recommend that they consider enrolment in the START study, where this is an option. ComorbiditiesWhilst it has been clearly shown that...