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Although many methods for assessing adherence have been developed, most are not feasible for busy clinical settings. Using patients from the Adherence and Efficacy of Protease inhibitor Therapy (ADEPT) study (1998-2000), we systematically evaluated the relationship between psychosocial, environmental, clinical, and other factors with adherence to create composite variables (CVs) that are efficient with high sensitivity for detecting nonadherence and great potential for busy clinics. Eligible patients were protease inhibitor naive or started a regimen within 3 months from baseline. Of the 128 patients who responded to survey at baseline, weeks 8, 24, and/or 48, mean (standard deviation [SD]) age was 39.3 (8.2) years with 81% male. About half of the patients were Latino, followed by 28% African American and 14% Caucasian. Sixteen percent reported injection drug use, and 40% had male-male sex. Mean CD4 count was 184.8 cells/[mm.sup.3] with a range from 1 to 1130 cells/[mm.sup.3]. Thirty-two variables had a significant association with adherence at one or two time points and 9 were significantly associated with adherence over time. Among these significant factors, 8 also had a relationship with a clearly monotonic trend, by which 219 CVs were formed. Among these CVs, 8 were significantly associated with adherence and had a relationship with monotonic trend. Compared to traditional self-reported adherence, CVs had much higher sensitivities (p < 0.001) for detecting nonadherence. We conclude that CVs consisting of a combination of psychological, behavior, and adherence questions may be reasonable substitutes for direct adherence questions, which are limited by problems with recall and social biases. Trust in physicians, having a child, history of substance use, CD4 count, and belief that antiretrovirals can help living longer or improve quality of life can efficiently predict nonadherence. Because these variables are readily obtainable in clinical settings, these selected questions may provide a clinically useful means of screening patients for antiretroviral medication nonadherence.

Acquired resistance to antiretroviral agents is an established sequela of HIV pharmacotherapy. Viral mutations can confer reduced susceptibility to antiretroviral medications, resulting in virologic and clinical failure in more than half of treated patients. Cross-resistance that can develop within each drug class leads to the progressive loss of future therapeutic options for individual patients. Although protease inhibitors (PIs) are a potent class of antiretrovirals, resistance can still develop rapidly, and multiple-PI resistance has become a serious, growing clinical problem. Development of rational treatment strategies that recognize specific patterns of cross-resistance among PIs are needed to help clinicians choose the most appropriate PI. Rational sequencing of PI use should be based on genotypic and phenotypic resistance testing. Maintaining higher drug plasma levels or using specific PI combinations may also diminish PI cross-resistance. New agents that are less likely to induce or be susceptible to cross-resistance will be of value in HIV treatment. This article reviews the acquisition of resistance to currently available PIs, discussing the drug-specific mutational patterns and evidence of clinical cross-resistance. The resistance profiles of two newer PIs, atazanavir and tipranavir, are also presented.

The objective of this pilot study was to examine attitudes toward protease inhibitors (PIs) among HIV-infected individuals and to assess the relationship between PI attitudes and adherence to PIs. Respondents were recruited from four AIDS service organizations in New York City; the total sample consisted of 97 HIV-infected individuals who were taking a PI. The sample consisted largely of African Americans and Latinos from inner city areas, and most had a low level of education. Adherence was suboptimal, with more than 50% of respondents failing to take their PI medications exactly as prescribed within the previous month. Individuals who had recently used illegal drugs within the past 6 months were more likely to be nonadherent to PIs. Those who were not adherent to PI medications reported greater concern about the side effects of PIs and were more likely to believe that it was acceptable to skip doses of PIs.

For several years, protease inhibitor (PI)-containing antiretroviral treatment (ART) regimens have demonstrated long-term virologic and immunologic benefits and good durability of response. However, first-generation PIs have been associated with high pill burdens, gastrointestinal side effects, perturbation of lipid levels and glucose metabolism, and, in some cases, food and hydration requirements. Coadministration of low-dose ritonavir with PIs has enhanced their pharmacokinetic profile (lower doses, fewer pills, less frequent dosing schedules) and pharmacodynamics (increased potency, especially against resistant viruses) but has also been associated with increases in lipid levels. Two new PIs, atazanavir and 908 (fosamprenavir), may offer salvageable PI treatment options and may also address issues of potency, tolerability, and convenience by requiring fewer pills and causing fewer lipid and glucose perturbations than current PI options. The availability of these novel PIs may improve long-term treatment options for many patients.

In order to establish the role of the protease inhibitor nelfinavir in current clinical practice, a prospective 18-month open-label comparison of efficacy and tolerability of nelfinavir was performed among HIV-infected patients who either incorporated nelfinavir in their first-line highly active antiretroviral therapy (HAART) regimen (group A, 57 patients), or who added nelfinavir to a rescue antiretroviral regimen (following at least two attempts with protease inhibitor-based HAART) (group B, 67 patients). All evaluable data were analyzed according to the prior and concurrent antiretroviral therapy, including genotypic resistance assays for patients undergoing salvage therapy. A significantly better virologic outcome (as expressed by a > 2 [log.sub.10] drop of plasma viremia versus baseline or attainment of undetectable levels), was shown among patients belonging to group A versus group B, where a number of genotypic mutations possibly elicited by previous anti-HIV treatment strongly impaired a potent and sustained nelfinavir activity. On the whole, the immunologic response (as expressed by the mean [CD4.sup.+] lymphocyte count versus baseline), substantially paralleled the virologic one in all analyzed subgroups, but a tendency toward a maintained immunologic competence was also observed in the majority of patients experiencing virologic failure. Nelfinavir introduction was sufficiently safe, because a limited percentage of patients suffered from mild-to moderate, novel, or continuing adverse events, which proved significantly more frequent in the salvage group but did not affect adherence to HAART.