Cohorts, Trials, and Evidence: Expanding Our Confidence in Guidelines for Antiretroviral Resistance Testing

Practice sometimes gets ahead of the evidence. Physicians frequently base decisions on evidence with less strength than the "gold standard" of prospective randomized trials with clinical end points. Care guidelines may advocate such decisions on the basis of preliminary research, expert opinion, and data derived from clinical cohorts. Reliance on imperfect evidence is not necessarily a problem, particularly if the intervention is plausible given the current understanding of disease pathogenesis (face validity). Recommendations based on such evidence are more likely when treatments or diagnostic technology advance so rapidly and become so widely accepted that the equipoise needed for randomized trials is lost. In this case, trials simply are not feasible. In this issue, Palella and colleagues (1) address an example of this problem.
HIV can become drug resistant when it is allowed to replicate in the presence of antiretroviral agents (2). Drug resistance can limit treatment benefit and often requires a change in the prescribed regimen (3). Drug-resistant retroviruses can also be transmitted (4), potentially compromising the host's response to drugs to which HIV is already resistant. Awareness of these facts emerged shortly after antiretroviral drugs were developed and the technology for detecting drug resistance became widely available (5). The 2 types of HIV drug resistance assays are genotyping and phenotyping. Genotyping, the faster and less expensive method, reports genetic mutations known to be associated with resistance, whereas phenotyping tests the ability of the virus to grow in the presence of specific antiretroviral drugs (6). These tests rapidly penetrated the marketplace of HIV care. They were accurate; their conceptual foundation closely resembled bacterial resistance testing, which was already widely accepted; and testing was plausible within the framework of the biology of HIV infection. Whether routine testing for drug resistance improved mortality, however, was never rigorously tested in randomized trials. Despite this shortcoming, many guidelines recognize HIV drug resistance testing to be a cost-effective standard of care (7, 8) at baseline in untreated persons to detect transmitted drug resistance and in cases of recurring viremia after initial suppression of chronic infection (9–11).