Virologic and Regimen Termination Surrogate End Points in AIDS Clinical Trials

Abstract

Suppression of plasma human immunodeficiency virus (HIV) RNA levels has been widely accepted as an appropriate surrogate end point for HIV disease progression, and it is currently used as the primary end point to determine efficacy in many antiretroviral trials. However, this end point does not always measure other important effects of treatment, such as inducement of multidrug resistance, which depletes future therapy options, and toxic effects. An alternative that directly factors in these treatment costs is a composite regimen termination end point, defined as a protocol-determined change in regimen due to either virologic failure or treatment-related toxic effects. Pros and cons for using purely virologic vs various composite primary end points are discussed. Conclusions include (1) a trial's clinical objective guides the choice of primary end point, (2) a purely virologic end point is often preferable, (3) it may be important to analyze both end point types in interpreting study results, and (4) long-term clinical outcome studies are needed for identifying the most predictive surrogate end points.

Hematocrit was not validated as a surrogate end point for survival among epoetin-treated hemodialysis patients

“…Low serum albumin levels and poor dialysis adequacy have been found to be associated with mortality [32][33][34][35]. Finally, other researchers have noted that drug resistance represents an important effect not fully measured by various surrogates [36]. Properly adjusting for shared causes, through randomization, for instance, is necessary to draw accurate conclusions about the use of hematocrit as a surrogate based on variations in mortality rates for patients with similar measures of hematocrit.…”

Early Treatment in HIV Patients: A Cost–Utility Analysis from the Italian Perspective

“…In fact, often the effectiveness is expressed in terms of viral load within clinical trials. However, from the data of controlled studies in treatment-naïve patients and observational studies, it may be assumed that this indicator is strictly linked to the loss of CD4 levels and the clinical progression of the disease [34][35][36][37][38]. Bearing this limitation in mind, a deterministic sensitivity analysis was performed for extreme values capable of demonstrating high levels of cost effectiveness even as this parameter changes.…”

Thérapeutiques antirétrovirales : principes du traitement de l’infection par le VIH

“…l'efficacité immunologique qui s'é value par la remonté e des lymphocytes T CD4+ sous traitement ; la tolé rance clinique et biologique qui s'é value par la surveillance clinique et biologique par les tests de routine et de fac¸on plus ré cente par les mesures morphomé triques radiologiques permettant de rechercher des signes d'anomalies infracliniques de la ré partition des graisses ; la dynamique de survenue de ré sistance pour les patients en é chappement et l'impact é ventuel de ces ré sistances sur les traitements futurs [62].…”