In these trials, passive administration of VRC01, a broadly neutralizing antibody against human immunodeficiency virus that targets the HIV CD4-binding site, had some anti-HIV effect in 24 persons ...with chronic HIV infection.
Therapeutic administration of monoclonal antibodies has revolutionized treatment options in oncology, rheumatology, endocrinology, gastroenterology, neurology, and the field of infectious diseases.
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The use of broadly neutralizing antibodies (bNAbs) against human immunodeficiency virus (HIV) is a potential approach to the prevention of HIV infection and its therapy and cure.
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VRC01 is a bNAb that targets the CD4-binding site of the HIV envelope glycoprotein. VRC01 has been shown to neutralize approximately 90% of a broad panel of 190 group M HIV envelope pseudotyped viruses with a mean 50% inhibitory concentration (IC
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Passive administration . . .
Benkeser et al. present a very informative paper evaluating the efficiency gains of covariate adjustment in settings with binary, ordinal, and time‐to‐event outcomes. The adjustment method focuses on ...estimating the marginal treatment effect averaged over the covariate distribution in both arms combined. The authors show that covariate adjustment can achieve power gains that could find answers more quickly. The suggested approach is an important weapon in the armamentarium against epidemics like COVID‐19. I recommend evaluating the procedure against more traditional approaches for conditional analyses (e.g., logistic regression) and against blinded methods of building prediction models followed by randomization‐based inference.
As randomization methods use more information in more complex ways to assign patients to treatments, analysis of the resulting data becomes challenging. The treatment assignment vector and outcome ...vector become correlated whenever randomization probabilities depend on data correlated with outcomes. One straightforward analysis method is a re‐randomization test that fixes outcome data and creates a reference distribution for the test statistic by repeatedly re‐randomizing according to the same randomization method used in the trial. This article reviews re‐randomization tests, especially in nonstandard settings like covariate‐adaptive and response‐adaptive randomization. We show that re‐randomization tests provide valid inference in a wide range of settings. Nonetheless, there are simple examples demonstrating limitations.
The first table in many articles reporting results of a randomized clinical trial compares baseline factors across arms. Results that appear inconsistent with chance trigger suspicion, and in one ...case, accusation and confirmation of data falsification. We confirm theoretically results of simulation analyses showing that inconsistency with chance is extremely difficult to prove in the absence of any information about correlations between baseline covariates. We offer a reasonable diagnostic to trigger further investigation.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Human immunodeficiency virus (HIV) disease leads to impaired B cell and antibody responses through mechanisms that remain poorly defined. A unique memory B cell subpopulation ...(CD20(hi)/CD27(lo)/CD21(lo)) in human tonsillar tissues was recently defined by the expression of the inhibitory receptor Fc-receptor-like-4 (FCRL4). In this study, we describe a similar B cell subpopulation in the blood of HIV-viremic individuals. FCRL4 expression was increased on B cells of HIV-viremic compared with HIV-aviremic and HIV-negative individuals. It was enriched on B cells with a tissuelike memory phenotype (CD20(hi)/CD27(-)/CD21(lo)) when compared with B cells with a classical memory (CD27(+)) or naive (CD27(-)/CD21(hi)) B cell phenotype. Tissuelike memory B cells expressed patterns of homing and inhibitory receptors similar to those described for antigen-specific T cell exhaustion. The tissuelike memory B cells proliferated poorly in response to B cell stimuli, which is consistent with high-level expression of multiple inhibitory receptors. Immunoglobulin diversities and replication histories were lower in tissuelike, compared with classical, memory B cells, which is consistent with premature exhaustion. Strikingly, HIV-specific responses were enriched in these exhausted tissuelike memory B cells, whereas total immunoglobulin and influenza-specific responses were enriched in classical memory B cells. These data suggest that HIV-associated premature exhaustion of B cells may contribute to poor antibody responses against HIV in infected individuals.
Antiretroviral therapy is highly effective in suppressing human immunodeficiency virus (HIV)
. However, eradication of the virus in individuals with HIV has not been possible to date
. Given that HIV ...suppression requires life-long antiretroviral therapy, predominantly on a daily basis, there is a need to develop clinically effective alternatives that use long-acting antiviral agents to inhibit viral replication
. Here we report the results of a two-component clinical trial involving the passive transfer of two HIV-specific broadly neutralizing monoclonal antibodies, 3BNC117 and 10-1074. The first component was a randomized, double-blind, placebo-controlled trial that enrolled participants who initiated antiretroviral therapy during the acute/early phase of HIV infection. The second component was an open-label single-arm trial that enrolled individuals with viraemic control who were naive to antiretroviral therapy. Up to 8 infusions of 3BNC117 and 10-1074, administered over a period of 24 weeks, were well tolerated without any serious adverse events related to the infusions. Compared with the placebo, the combination broadly neutralizing monoclonal antibodies maintained complete suppression of plasma viraemia (for up to 43 weeks) after analytical treatment interruption, provided that no antibody-resistant HIV was detected at the baseline in the study participants. Similarly, potent HIV suppression was seen in the antiretroviral-therapy-naive study participants with viraemia carrying sensitive virus at the baseline. Our data demonstrate that combination therapy with broadly neutralizing monoclonal antibodies can provide long-term virological suppression without antiretroviral therapy in individuals with HIV, and our experience offers guidance for future clinical trials involving next-generation antibodies with long half-lives.
In a mathematical approach to hypothesis tests, we start with a clearly defined set of hypotheses and choose the test with the best properties for those hypotheses. In practice, we often start with ...less precise hypotheses. For example, often a researcher wants to know which of two groups generally has the larger responses, and either a t-test or a Wilcoxon-Mann-Whitney (WMW) test could be acceptable. Although both t-tests and WMW tests are usually associated with quite different hypotheses, the decision rule and p-value from either test could be associated with many different sets of assumptions, which we call perspectives. It is useful to have many of the different perspectives to which a decision rule may be applied collected in one place, since each perspective allows a different interpretation of the associated p-value. Here we collect many such perspectives for the two-sample t-test, the WMW test and other related tests. We discuss validity and consistency under each perspective and discuss recommendations between the tests in light of these many different perspectives. Finally, we briefly discuss a decision rule for testing genetic neutrality where knowledge of the many perspectives is vital to the proper interpretation of the decision rule.
Hung et al. (2007) considered the problem of controlling the type I error rate for a primary and secondary endpoint in a clinical trial using a gatekeeping approach in which the secondary endpoint is ...tested only if the primary endpoint crosses its monitoring boundary. They considered a two‐look trial and showed by simulation that the naive method of testing the secondary endpoint at full level α at the time the primary endpoint reaches statistical significance does not control the familywise error rate at level α. Tamhane et al. (2010) derived analytic expressions for familywise error rate and power and confirmed the inflated error rate of the naive approach. Nonetheless, many people mistakenly believe that the closure principle can be used to prove that the naive procedure controls the familywise error rate. The purpose of this note is to explain in greater detail why there is a problem with the naive approach and show that the degree of alpha inflation can be as high as that of unadjusted monitoring of a single endpoint.
Adaptive clinical trials are becoming very popular because of their flexibility in allowing mid‐stream changes of sample size, endpoints, populations, etc. At the same time, they have been regarded ...with mistrust because they can produce bizarre results in very extreme settings. Understanding the advantages and disadvantages of these rapidly developing methods is a must. This paper reviews flexible methods for sample size re‐estimation when the outcome is continuous.
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