Conventional wisdom has held that adherence with the therapeutic regimen is associated with an improved outcome in patients with chronic medical conditions. While this would also appear to be intuitively true in HIV-infected patients treated with the protease-inhibitor agents, the precise impact of suboptimal adherence on virologic and clinical outcome in these patients had not been defined. We showed that adherence was a key determinant of successful virologic and immunologic response, and defined the optimal level of adherence with protease-inhibitor therapy that was necessary to achieve these outcomes. The paper has become widely cited because of the immediate relevance of these findings in the management of HIV infected patients. Indeed, the reviewer for the Annals of Internal Medicine had predicted that "this important study will have significant implications for HIV medical practice."

Conventionally, consumption of greater than 80% of the prescribed doses has been considered an acceptable level of adherence to therapy in chronic illnesses. This breakpoint, however, was largely derived from studies of antihypertensive and diabetic medications. We documented a linear association between the degree of adherence and the risk of virologic failure, and showed that adherence with protease-inhibitors had to reach 95% or greater to optimize virologic outcome.

Our approach to research, in general, has been to identify unresolved problems that we encounter in our patients and then seek solutions or devise strategies to resolve them. As HIV care providers, we recognized the critical importance of suboptimal adherence on limiting the efficacy of therapy in our patients. We believed that interventions to enhance adherence must first document how adherence affected outcome, and then what modifiable conditions could improve nonadherence. Given the implications for our patients, we conducted this study even though there was no source of funding or support for it.

Patients with HIV infection who took 95% or greater of the prescribed doses of protease-inhibitor therapy were much less likely to have detectable HIV in their blood. Therefore, this is the level of adherence with medication that patients and care providers should strive to achieve. We also showed that patients with > 95% adherence to their protease-inhibitor medication had significantly greater increase in CD4 lymphocytes and fewer days of hospitalization during the study period. Finally, we showed that active psychiatric illness was an independent risk factor that undermined adherence, and therefore efforts to diagnose and treat psychiatric problems may be a means to improve adherence, and perhaps outcome in patients with HIV infection.