COVID-19 Convalescent Plasma Outpatient Therapy to Prevent Outpatient Hospitalization: A Meta-analysis of Individual Participant Data From Five Randomized Trials.

Background: Monoclonal antibody and antiviral treatments for COVID-19 disease remain largely unavailable worldwide, and existing monoclonal antibodies may be less active against circulating omicron variants. Although treatment with COVID-19 convalescent plasma (CCP) is promising, randomized clinical trials (RCTs) among outpatients have shown mixed results. Methods: We conducted an individual participant data meta-analysis from all outpatient CCP RCTs to assess the overall risk reduction for all-cause hospitalizations by day 28 in all participants who had transfusion initiated. Relevant trials were identified by searching MEDLINE, Embase, MedRxiv, WHO, Cochrane Library, and Web of Science from January 2020 to September 2022. Results: Five included studies from four countries enrolled and transfused 2,620 adult patients. Comorbidities were present in 1,795 (69%). The anti-Spike or virus neutralizing antibody titer range across all trials was broad. 160 (12.2%) of 1315 control patients were hospitalized, versus 111 (8.5%) of 1305 CCP-treated patients, yielding a 3.7% (95%CI: 1.3%-6.0%; p=.001) ARR and 30.1% RRR for all-cause hospitalization. The effect size was greatest in those with both early transfusion and high titer with a 7.6% ARR (95%CI: 4.0%-11.1%; p=.0001) accompanied by at 51.4% RRR. No significant reduction in hospitalization was seen with treatment > 5 days after symptom onset or in those receiving CCP with antibody titers below the median titer. Conclusions: Among outpatients with COVID-19, treatment with CCP reduced the rate of all-cause hospitalization. CCP may be most effective when given within 5 days of symptom onset and when antibody titer is higher. Key Points: While the outpatient COVID-19 randomized controlled trial meta-analysis indicated heterogeneity in participant risk factors and convalescent plasma, the combined CCP efficacy for reducing hospitalization was significant, improving with transfusion within 5 days of symptom onset and high antibody neutralization levels.

More virological failure with lamivudine than emtricitabine in efavirenz and nevirapine regimens in the Dutch nationwide HIV Cohort.

INTRODUCTION: Lamivudine (3TC) and emtricitabine (FTC) are considered interchangeable by HIV-1 guidelines in first-line tenofovir/efavirenz (TDF/EFV) and TDF/nevirapine (NVP) combination antiretroviral therapy (cART). Data from trials on equivalence of 3TC and FTC are inconsistent. We examined the effectiveness of 3TC and FTC in the national HIV cohort in the Netherlands. MATERIAL AND METHODS: Observational cohort study on cART naïve HIV-1 patients. Therapy was initiated as 3TC or FTC with TDF/EFV or TDF/NVP between 2002 and 2012. Patients with baseline resistance or prior cART experience were excluded. Main outcomes were Week 48 virological failure (VF) by on treatment analysis, time to HIV-RNA <400 copies/mL within 48 weeks and VF within 240 weeks after at least one HIV-RNA <400 copies/mL. Acquired resistance to reverse transcriptase was evaluated. Analyses were done by logistic regression and Cox proportional hazard models. Propensity score adjusted models and intention to treat evaluations were included as sensitivity analysis. RESULTS: A total of 4836 patients initiated 3TC/TDF/EFV (n=546), FTC/TDF/EFV (n=3391), 3TC/TDF/NVP (n=207) or FTC/TDF/NVP (n=692). Ninety-six patients were excluded for baseline resistance or prior cART experience. By Week 48, VF proportions were higher for 3TC/TDF/EFV (10.8%) compared to FTC/TDF/EFV (3.6%) and for 3TC/TDF/NVP (27.0%) compared to FTC/TDF/NVP (11.0%). The multivariable adjusted odds ratio (OR) on VF was 1.78 (95% CI 1.11-2.84; p=0.016) with 3TC/TDF/EFV compared to FTC/TDF/EFV and 2.09 (95% CI 1.25-3.52; p=0.005) with 3TC/TDF/NVP compared to FTC/TDF/NVP. Propensity score adjusted models and intention to treat analyses showed comparable results. The time to virological suppression within 48 weeks was not influenced by using 3TC or FTC in cART. If HIV-RNA <400 copies/mL was achieved on initial cART first, no differences in VF within 240 weeks were observed between 3TC and FTC with TDF/EFV (p=0.090) or TDF/NVP (P=0.255). Patients failing 3TC-containing cART had higher median HIV-RNA at VF compared to FTC containing cART (p<0.001) and 89.8% had acquired resistance on 3TC compared to 81.2% on FTC. CONCLUSIONS: Including FTC in cART is associated with better virological responses compared to 3TC. As cost constraints may call for the use of generic 3TC, a well-powered randomized trial to confirm the presumed equivalence of 3TC and FTC is needed.

The efficacy, pharmacokinetics, safety and cardiovascular risks of switching nevirapine to rilpivirine in HIV-1 patients: the RPV switch study.

INTRODUCTION: Nevirapine (NVP) induces cytochrome P450 3A4 by which rilpivirine (RPV) is metabolized. Switching NVP to RPV could result in decreased RPV exposure with subsequent virological failure and dyslipidemia because NVP is regarded as the least dyslipidemic, non-nucleoside, reverse transcriptase inhibitor. This trial evaluated the efficacy, pharmacokinetics, safety and cardiovascular risks of switching NVP to RPV. MATERIALS AND METHODS: Prospective open label controlled trial. HIV-1 patients with HIV-1 RNA <50 copies/mL on once daily NVP, emtricitabine/tenofovir (FTC/TDF) switched to single tablet RPV/FTC/TDF. Eligible patients on NVP, FTC/TDF were controls. Primary endpoint was week 12 HIV-1 RNA <50 copies/mL by intention to treat analysis. Secondary endpoints were week 24 HIV-1 RNA <50 copies/mL, NVP and RPV pharmacokinetics, safety and fasting lipids, Framingham risk scores (FRS) and Adult Treatment Panel III (ATP-III) lipid goals. RESULTS: Of 189 eligible patients, we included 50 RPV switchers and 139 NVP controls. Week 12 HIV-RNA was <50 copies/mL in 46/50 switchers (92.0%) which was not different from the hypothesized 90% week 12 suppression rate (p=.431). Forty-four of 50 switchers had week 24 HIV-1 RNA <50 copies/mL compared to 126/139 controls (difference: 2.6%, 95% CI -7.6% to 12.8%, p=.593). NVP plasma concentrations were below detection level in all at week 3. Mean week 1 RPV trough concentration was 0.083 mg/L and comparable to phase III trial data (p=0.747). Adverse events occurred in 36 switchers, the majority (82.0%) were grade one. Two switchers discontinued RPV for side effects. Significant changes over 24 weeks (p<0.001) were observed in switchers on total cholesterol (TC, -0.67 mmol/L, 95% CI -0.50 to 0.83), low density lipoprotein (LDL)-C (-0.36, 95% CI -0.21 to -0.51) and high density lipoprotein (HDL)-C (-0.28, 95% CI -0.20 to -0.35). The TC/HDL-C ratio increased 0.20 (95% CI 0.02 to 0.37; p=.029) and systolic blood pressure decreased 6.0 mmHg (95% CI -1.7 to -10.3; p=.007). The median FRS did not change over 24 weeks (8.4% vs. 7.7%; p=.119). More patients achieved LDL-C (+15%; p=.016) and TC (+25%; p<0.001) ATP-III treatment goals at week 24 on RPV. CONCLUSIONS: A NVP to RPV switch does not influence RPV exposure and results in adequate ongoing HIV-1 suppression. RPV could be an option for patients at risk for cardiovascular diseases.