Risks of metabolic syndrome in the ADVANCE and NAMSAL trials.

Introduction: The ADVANCE and NAMSAL trials evaluating antiretroviral drugs have both reported substantial levels of clinical obesity in participants. As one of the main risk factors for metabolic syndrome, growing rates of obesity may drive metabolic syndrome development. This study aims to evaluate the risk of metabolic syndrome in the ADVANCE and NAMSAL trials. Methods: The number of participants with metabolic syndrome was calculated at baseline and week 192 as central obesity and any of the following two factors: raised triglycerides, reduced HDL-cholesterol, raised blood pressure and raised fasting glucose. Differences between the treatment arms were calculated using the χ2 test. Results: Across all visits to week 192, treatment-emergent metabolic syndrome was 15% (TAF/FTC + DTG), 10% (TDF/FTC + DTG) and 7% (TDF/FTC/EFV) in ADVANCE. The results were significantly higher in the TAF/FTC + DTG arm compared to the TDF/FTC/EFV arm (p < 0.001), and the TDF/FTC + DTG vs. the TDF/FTC/EFV arms (p < 0.05) in all patients, and in females. In NAMSAL, the incidence of treatment-emergent metabolic syndrome at any time point was 14% (TDF/3TC + DTG) and 5% (TDF/3TC + EFV) (p < 0.001). This incidence was significantly greater in the TDF/3TC/DTG arm compared to the TDF/3TC/EFV arm in all patients (p < 0.001), and in males (p < 0.001). Conclusion: In this analysis, we highlight treatment-emergent metabolic syndrome associated with dolutegravir, likely driven by obesity. Clinicians initiating or monitoring patients on INSTI-based ART must counsel for lifestyle optimisation to prevent these effects.

Evaluation of publication bias for 12 clinical trials of molnupiravir to treat SARS-CoV-2 infection in 13 694 patients with meta-analysis.

In response to the COVID-19 pandemic, Merck Sharp & Dohme (MSD) acquired the global licensing rights for the antiviral molnupiravir, promising affordable access via licensing deals. Numerous Indian pharmaceutical companies subsequently conducted trials of the drug. Registered trials of molnupiravir were searched on the Clinical Trials Registry-India (CTRI) and efforts made to detect resulting public data. Per the CTRI, 12 randomized trials of molnupiravir were conducted in 13 694 Indian patients, from mid-2021. By August 2022, only a preprint and medical conference presentation had resulted. Additionally, two trials were mentioned in press releases suggesting failure of treatment. The available data contain unexplained results that differ significantly from both the PANORAMIC and MSD MOVe-OUT trials. Approximately one-third of the global data on molnupiravir remain unpublished. We conducted a meta-analysis with four studies that provided results and observed that molnupiravir does not have a significant benefit for hospitalizations.

Weight and Metabolic Changes After Switching From Tenofovir Alafenamide/Emtricitabine (FTC)+Dolutegravir (DTG), Tenofovir Disoproxil Fumarate (TDF)/FTC + DTG, and TDF/FTC/Efavirenz to TDF/Lamivudine/DTG.

Participants randomized to first-line tenofovir alafenamide (TAF)/emtricitabine (FTC)+dolutegravir (DTG), tenofovir disoproxil fumarate (TDF)/FTC + DTG, or TDF/FTC/efavirenz (EFV) for 192 weeks were then switched to TDF/lamivudine (3TC)/DTG for 52 weeks. Participants switching either TAF/FTC + DTG or TDF/FTC/EFV to TDF/3TC/DTG showed statistically significant reductions in weight, low-density lipoprotein, triglycerides, glucose and glycated hemoglobin.

The dangers of non-randomized, observational studies: experience from the COVID-19 epidemic.

In regulatory evaluations, high-quality randomized controlled trials (RCTs) are considered the gold standard for assessing the efficacy of medical interventions. However, during the COVID-19 pandemic, the urgent need for treatment options led to regulatory approvals being made based on evidence from non-randomized, observational studies. In this study we contrast results from observational studies and RCTs of six drugs to treat COVID-19 infection. Across a range of studies evaluating hydroxychloroquine, remdesivir, ivermectin, aspirin, molnupiravir and tenofovir for COVID-19, there was statistically significant evidence of benefit from non-randomized observational studies, which was then not seen in RCTs. We propose that all observational studies need to be labelled as 'non-randomized' in the title. This should indicate that they are not as reliable for evaluating the efficacy of a drug and should not be used independently for regulatory approval decisions.

Comparing Prospective Incident Severe Acute Respiratory Syndrome Coronavirus 2 Infection Rates During Successive Waves of Delta and Omicron in Johannesburg, South Africa.

In high-risk individuals in Johannesburg, during the Delta coronavirus disease 2019 wave, 22% (125/561) were positive, with 33% symptomatic (2 hospitalizations; 1 death). During Omicron, 56% (232/411) were infected, with 24% symptomatic (no hospitalizations or deaths). The remarkable speed of infection of Omicron over Delta poses challenges to conventional severe acute respiratory syndrome coronavirus 2 control measures.

Efficacy of Approved Versus Unapproved Vaccines for Severe Acute Respiratory Syndrome Coronavirus 2 Infection in Randomized Blinded Clinical Trials.

Background: Five severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines are approved in North America and/or Europe: Pfizer/BioNTech, Moderna, Janssen, Oxford-AstraZeneca, and Novavax. Other vaccines have been developed, including Sinopharm, SinoVac, QazVac, Covaxin, Soberana, Zifivax, Medicago, Clover, and Cansino, but they are not approved in high-income countries. This meta-analysis compared the efficacy of US Food and Drug Administration (FDA)/European Medicines Agency (EMA)-approved and -unapproved vaccines in randomized clinical trials (RCTs). Methods: A systematic review of trial registries identified RCTs of SARS-CoV-2 vaccines. Risk of bias was assessed using the Cochrane tool (RoB 2). In the meta-analysis, relative risks of symptomatic infection and severe disease were compared for each vaccine versus placebo, using Cochrane-Mantel Haenszel Tests (random effects method). Results: Twenty-two RCTs were identified and 1 was excluded for high-risk of bias. Ten RCTs evaluated 5 approved vaccines and 11 RCTs evaluated 9 unapproved vaccines. In the meta-analysis, prevention of symptomatic infection was 84% (95% confidence interval [CI], 68%-92%) for approved vaccines versus 72% (95% CI, 66%-77%) for unapproved vaccines, with no significant difference between vaccine types (P = .12). Prevention of severe SARS-CoV-2 infection was 94% (95% CI, 75%-98%) for approved vaccines versus 86% (95% CI, 76%-92%) for unapproved vaccines (P = .33). The risk of serious adverse events was similar between vaccine types (P = .12). Conclusions: This meta-analysis of 21 RCTs in 390 459 participants showed no significant difference in efficacy between the FDA/EMA-approved and -unapproved vaccines for symptomatic or severe infection. Differences in study design, endpoint definitions, variants, and infection prevalence may have influenced results. New patent-free vaccines could lower costs of worldwide SARS-CoV-2 vaccination campaigns significantly.

Non-effectiveness of Ivermectin on Inpatients and Outpatients With COVID-19; Results of Two Randomized, Double-Blinded, Placebo-Controlled Clinical Trials.

Background: Ivermectin which was widely considered as a potential treatment for COVID-19, showed uncertain clinical benefit in many clinical trials. Performing large-scale clinical trials to evaluate the effectiveness of this drug in the midst of the pandemic, while difficult, has been urgently needed. Methods: We performed two large multicenter randomized, double-blind, placebo-controlled clinical trials evaluating the effectiveness of ivermectin in treating inpatients and outpatients with COVID-19 infection. The intervention group received ivermectin, 0.4mg/kg of body weight per day for 3 days. In the control group, placebo tablets were used for 3 days. Results: Data for 609 inpatients and 549 outpatients were analyzed. In hospitalized patients, complete recovery was significantly higher in the ivermectin group (37%) compared to placebo group (28%; RR, 1.32 [95% CI, 1.04-1.66]; p-value = 0.02). On the other hand, the length of hospital stay was significantly longer in the ivermectin group with a mean of 7.98 ± 4.4 days compared to the placebo receiving group with a mean of 7.16 ± 3.2 days (RR, 0.80 [95% CI, 0.15-1.45]; p-value = 0.02). In outpatients, the mean duration of fever was significantly shorter (2.02 ± 0.11 days) in the ivermectin group versus (2.41 ± 0.13 days) placebo group with p value = 0.020. On the day seventh of treatment, fever (p-value = 0.040), cough (p-value = 0.019), and weakness (p-value = 0.002) were significantly higher in the placebo group compared to the ivermectin group. Among all outpatients, 7% in ivermectin group and 5% in placebo group needed to be hospitalized (RR, 1.36 [95% CI, 0.65-2.84]; p-value = 0.41). Also, the result of RT-PCR on day five after treatment was negative for 26% of patients in the ivermectin group versus 32% in the placebo group (RR, 0.81 [95% CI, 0.60-1.09]; p-value = 0.16). Conclusion: Our data showed, ivermectin, compared with placebo, did not have a significant potential effect on clinical improvement, reduced admission in ICU, need for invasive ventilation, and death in hospitalized patients; likewise, no evidence was found to support the prescription of ivermectin on recovery, reduced hospitalization and increased negative RT-PCR assay for SARS-CoV-2 5 days after treatment in outpatients. Our findings do not support the use of ivermectin to treat mild to severe forms of COVID-19. Clinical Trial Registration: www.irct.ir IRCT20111224008507N5 and IRCT20111224008507N4.

Ivermectin for the prevention of COVID-19: addressing potential bias and medical fraud.

BACKGROUND: Ivermectin is an antiparasitic drug being investigated in clinical trials for the prevention of COVID-19. However, there are concerns about the quality of some of these trials. OBJECTIVES: To conduct a meta-analysis with randomized controlled trials of ivermectin for the prevention of COVID-19, while controlling for the quality of data. The primary outcome was RT-PCR-confirmed COVID-19 infection. The secondary outcome was rate of symptomatic COVID-19 infection. METHODS: We conducted a subgroup analysis based on the quality of randomized controlled trials evaluating ivermectin for the prevention of COVID-19. Quality was assessed using the Cochrane risk of bias measures (RoB 2) and additional checks on raw data, where possible. RESULTS: Four studies were included in the meta-analysis. One was rated as being potentially fraudulent, two as having a high risk of bias and one as having some concerns for bias. Ivermectin did not have a significant effect on preventing RT-PCR-confirmed COVID-19 infection. Ivermectin had a significant effect on preventing symptomatic COVID-19 infection in one trial with some concerns of bias, but this result was based on post hoc analysis of a multi-arm study. CONCLUSIONS: In this meta-analysis, the use of ivermectin was not associated with the prevention of RT-PCR-confirmed or symptomatic COVID-19. The currently available randomized trials evaluating ivermectin for the prevention of COVID-19 are insufficient and of poor quality.

Ivermectin for COVID-19: Addressing Potential Bias and Medical Fraud.

Ivermectin has become a controversial potential medicine for coronavirus disease 2019. Some early studies suggested clinical benefits in treatment of infection. However, the body of evidence includes studies of varying quality. Furthermore, some trials have now been identified as potentially fraudulent. We present a subgroup meta-analysis to assess the effects of stratifying by trial quality on the overall results. The stratification is based on the Cochrane Risk of Bias measures and raw data analysis where possible. The results suggest that the significant effect of ivermectin on survival was dependent on largely poor-quality studies. According to the potentially fraudulent study (risk ratio [RR], 0.08; 95% CI, 0.02-0.35), ivermectin improved survival ~12 times more in comparison with low-risk studies (RR, 0.96; 95% CI, 0.56-1.66). This highlights the need for rigorous quality assessments, for authors to share patient-level data, and for efforts to avoid publication bias for registered studies. These steps are vital to facilitate accurate conclusions on clinical treatments.