title: Estimating and comparing reduction in HIV-1 RNA in clinical trials using methods for interval censored data.
abstract: The magnitude of reduction in HIV-1 RNA levels provides an important complement to the end point based on the percentage of patients achieving HIV-1 RNA levels below a threshold value. Analyses and interpretation of this end point, however, is difficult due to the lower limit of quantification. Crude methods of analyzing HIV-1 RNA data provide biased estimates of the HIV-1 RNA reduction. Censored methods that take into account the censoring of HIV-1 RNA measurements by the limit of quantification greatly improve the analysis of HIV-1 RNA reduction end points. It was shown, however, that when there is a high percentage of censoring, those methods can overestimate HIV-1 RNA reduction. We suggest going a step further, considering that HIV-1 RNA reduction is left-censored by the limit of quantification and right-bounded by the HIV-1 RNA levels at baseline. We then suggest using nonparametric and parametric methods introduced for interval-censored data to analyze such data. A convenient feature of the methodology is the ability to easily handle missing HIV-1 RNA data, although some assumptions are required. For instance, the HIV-1 RNA reduction can be estimated using the so-called "missing = failure" scenario. Graphic procedures to check the validity of using parametric methods are described. The methods are discussed and illustrated with data of 2 recent clinical trials. Surprisingly, it was found that the log10 transformation of the HIV-1 RNA reduction was not appropriate in our data.
authors.affiliation: INSERM Unité 472, Hôpital Paul Brousse, Villejuif, France. flandre@vjf.inserm.fr
authors.forename: Philippe
authors.initials: P
authors.lastname: Flandre
authors.forename: Alexandre
authors.initials: A
authors.lastname: Alcais
authors.forename: Diane
authors.initials: D
authors.lastname: Descamps
authors.forename: Laurence
authors.initials: L
authors.lastname: Morand-Joubert
authors.forename: Véronique
authors.initials: V
authors.lastname: Joly
mesh_terms: D002986:Clinical Trials as Topic; D015658:HIV Infections / Q000097:blood / Q000188:drug therapy*; D015497:HIV-1 / Q000302:isolation & purification*; D006801:Humans; D015233:Models, Statistical; D012367:RNA, Viral / Q000097:blood* / Q000302:isolation & purification; D015203:Reproducibility of Results; D018401:Sample Size
chemical_list: D012367:RNA, Viral