Abstract

In an effort to evaluate factors associated with the development of antiretroviral (ARV) resistance, we assessed the prevalence of toxicity-related regimen changes and modeled its association to the subsequent development of ARV resistance in a cohort of treatment-naive individuals initiating ARV therapy (ART). A retrospective analysis of patients initiating ART was conducted at the UAB 1917 Clinic from 1 January 2000 to 30 September 2007. Cox proportional hazards models were fit to identify factors associated with the development of resistance to ≥1 ARV drug class. Among 462 eligible participants, 14% (n=64) developed ARV resistance. Individuals with ≥1 toxicity-related regimen change (HR=3.94, 95% CI=1.09–14.21), initiating ART containing ddI or d4T (4.12, 1.19–14.26), and from a minority race (2.91, 1.16–7.28) had increased risk of developing resistance. Achieving virologic suppression within 12 months of ART initiation (0.10, 0.05–0.20) and higher pretreatment CD4 count (0.85 per 50 cells/mm3, 0.75–0.96) were associated with decreased hazards of resistance. Changes in ART due to drug intolerance were associated with the subsequent development of ARV resistance. Understanding the role of ARV drug selection and other factors associated with the emergence of ARV resistance will help inform interventions to improve patient care and ensure long-term treatment success.

Abstract

Several new antiretroviral (ARV) agents for treatment experienced HIV-infected patients have been approved since June 2006, including darunavir (DRV) and raltegravir (RAL). While efficacious in clinical trials, the effectiveness, durability, and tolerability of these new ARVs remains understudied in the context of routine clinical care. The Darunavir Outcomes Study is a prospective cohort study of three-class ARV-experienced patients changing regimens at the 1917 Clinic after 1/7/2006. All treatment decisions were at the discretion of primary providers. Multivariate (MV) logistic regression for 48 week VL <400c/ml and Cox models for regimen durability were completed. Propensity score methods controlled for sociodemographics. Among 108 patients, mean age of 46, 48% were white, 80% male, with prior exposure to a mean 10.5 ARVs. Overall, 64% of patients achieved 48-week VL <400 c/ml. In MV modeling DRV/rll (OR = 5.77;95%CI = 1.62–20.58) and RAL (OR = 3.84;95%CI = 1.23–11.95) use increased odds of 48-week suppression. Use of these agents exhibited a trend towards prolonged regimen durability in Cox models. Among those highly ARV-experienced, regimens containing DRV/r and/or RAL were more likely to achieve 48-week VL <400 c/ml and exhibited a trend towards prolonged durability. New agents have transformed the treatment landscape for ARV-experienced patients, with effectiveness in routine clinical care mirroring efficacy in clinical trials.

Abstract

The durability of HAART regimens is often limited by antiretroviral toxicity and nonadherence, which lead to virologic failure. We sought to determine sociodemographic and psychosocial patient factors predictive of short-term discontinuation of HAART regimens overall and stratified by the reason for discontinuation. A retrospective cohort study of the UAB 1917 Clinic Cohort evaluated short-term HAART regimen discontinuation (within 12 months of regimen initiation) between 1/1995 and 8/2004 classified as (1) gastrointestinal (GI) toxicity, (2) non-GI toxicity, (3) virologic failure or nonadherence (VF/NA), (4) loss to follow-up, and (5) other. Multivariable multinomial logistic regression models accounting for dependent observations were fit to assess the relationship between patient factors and type-specific regimen discontinuation. Among the 738 study participants, 1026 of 1852 HAART regimens (55%) were discontinued within 12 months of initiation. In multivariable analysis, discontinuation for GI toxicity was more common in patients lacking private health insurance and those with a history of intravenous (IV) drug use, whereas non-GI toxicity was more common in younger patients and females. African-American patients and those with a history of IV drug use were more likely to stop a regimen due to VF/NA. Loss to follow-up was more common in younger patients, individuals who were uninsured, and those with a history of IV drug use. Short-term discontinuation of HAART regimens is more common in vulnerable populations that bear a disproportionate burden of the U.S. HIV/AIDS epidemic. More vigilant monitoring of patient populations at higher risk of toxicity and virologic failure may allow for improved HAART regimen durability.

We evaluated the association between two antiretroviral therapy (ART) adherence measurements—the medication possession ratio (MPR) and patient self-report—and detectable HIV viremia in the setting of rapid service scale-up in Lusaka, Zambia. Drug adherence and outcomes were assessed in a subset of patients suspected of treatment failure based on discordant clinical and immunologic responses to ART. A total of 913 patients were included in this analysis, with a median time of 744 days (Q1, Q3: 511, 919 days) from ART initiation to viral load (VL) measurement. On aggregate over the period of follow-up, 531 (58%) had optimal adherence (MPR ≥95%), 306 (34%) had suboptimal adherence (MPR 80–94%), and 76 (8%) had poor adherence (MPR <80%). Of the 913 patients, 238 (26%) had VL ≥400 copies/ml when tested. When compared to individuals with optimal adherence, there was increasing risk for virologic failure in those with suboptimal adherence [adjusted relative risk (ARR): 1.3; 95% confidence interval (CI): 1.0, 1.6] and those with poor adherence (ARR: 1.7; 95% CI: 1.3, 2.4) based on MPR. During the antiretroviral treatment course, 676 patients (74%) reported no missed doses. The proportion of patients with virologic failure did not differ significantly among those reporting any missed dose from those reporting perfect adherence (26% vs. 26%, p = 0.97). Among patients with suspected treatment failure, a lower MPR was associated with higher rates of detectable viremia. However, the suboptimal sensitivity and specificity of MPR limit its utility as a sole predictor of virologic failure.

Abstract

We evaluated the association between two antiretroviral therapy (ART) adherence measurements—the medication possession ratio (MPR) and patient self-report—and detectable HIV viremia in the setting of rapid service scale-up in Lusaka, Zambia. Drug adherence and outcomes were assessed in a subset of patients suspected of treatment failure based on discordant clinical and immunologic responses to ART. A total of 913 patients were included in this analysis, with a median time of 744 days (Q1, Q3: 511, 919 days) from ART initiation to viral load (VL) measurement. On aggregate over the period of follow-up, 531 (58%) had optimal adherence (MPR ≥95%), 306 (34%) had suboptimal adherence (MPR 80–94%), and 76 (8%) had poor adherence (MPR <80%). Of the 913 patients, 238 (26%) had VL ≥400 copies/ml when tested. When compared to individuals with optimal adherence, there was increasing risk for virologic failure in those with suboptimal adherence [adjusted relative risk (ARR): 1.3; 95% confidence interval (CI): 1.0, 1.6] and those with poor adherence (ARR: 1.7; 95% CI: 1.3, 2.4) based on MPR. During the antiretroviral treatment course, 676 patients (74%) reported no missed doses. The proportion of patients with virologic failure did not differ significantly among those reporting any missed dose from those reporting perfect adherence (26% vs. 26%, p = 0.97). Among patients with suspected treatment failure, a lower MPR was associated with higher rates of detectable viremia. However, the suboptimal sensitivity and specificity of MPR limit its utility as a sole predictor of virologic failure.