Outcome of a second-line protease inhibitor-containing regimen in patients failing or intolerant of a first highly active antiretroviral therapy.
ABSTRACT The outcome of second-line protease inhibitor (PI)-containing highly active antiretroviral therapy (HAART) was investigated in 263 patients who were failed by (n = 148) or intolerant of (n = 115) a first HAART regimen. The endpoints were virologic failure (decline in HIV RNA < 1 log10 copies/ml after > or = 2 months) and discontinuation due to intolerance/toxicity. During a median follow-up of 483 days (33-1087 days), 154 patients (59%) discontinued the second regimen, 86 (33%) because of intolerance/toxicity; another 135 patients (51.3%) showed virologic failure. Independent factors associated with virologic failure (Cox's model) were 7 to 12 months of first HAART (hazard ratio [HR] 1.70 versus < or = 6 months: 95% confidence interval [CI], 1.08-2.70) and gender (HR 1.58 males versus females: 95% CI, 1.04-2.30); the negatively associated factors were advanced age (HR 0.61 > 34 years versus < or = 34 years: 95% CI, 0.42-0.88), a saquinavir-containing first HAART (HR 0.57 versus indinavir: 95% CI, 0.34-0.93) and change due to intolerance/toxicity (HR 0.58 versus failure: 95% CI, 0.35-0.98). The independent variables predictive of discontinuation due to intolerance/toxicity were the reason for switching (HR 1.79 intolerance versus failure: 95% CI, 1.02-3.16) and the first protease inhibitor (PI) regimen (HR 0.42 ritonavir versus indinavir: 95% CI, 0.22-0.80). Given that patients who are failed by a first regimen are at high risk of having rescue therapy fail as well, second-line regimens including therapies directed by testing of drug resistance patterns of clinical viral isolates are warranted. Patients experiencing toxicity due to a first PI-containing regimen are at risk of toxicity to other PIs and should be addressed to PI-sparing HAART.
- SourceAvailable from: Elizabeth T Golub[show abstract] [hide abstract]
ABSTRACT: Sustained use of antiretroviral therapy has been consistently shown to be one of the primary predictors of long-term effectiveness. Switching and discontinuation reflect patient and provider decisions that may limit future treatment options. In this study, we utilize data reported at semi-annual study visits from three prospective cohort studies, the AIDS Link to IntraVenous Exposure (ALIVE), the Women's Interagency HIV Study (WIHS), and the Multicenter AIDS Cohort Study (MACS), to investigate determinants of HAART modification with a particular focus on reported injection drug use (IDU). Longitudinal data collected between 1996 and 2004 contributed from 2,266 participants (37% with a reported history of IDU) who reported initiating their first HAART regimen during follow-up were utilized. Separate proportional-hazards models were used to identify factors measured prior to HAART-initiation associated with the time to first HAART discontinuation and first switch of components of HAART among continuous HAART users. The use of PI- vs. NNRTI-based regimens among HAART users with and without any history of IDU was similar over follow-up. The median time to a first report of discontinuation of HAART was 1.1 years for individuals with a history of IDU but 2.5 years for those without a history of IDU and multivariate analyses confirmed overall that individuals with a history of IDU were at greater risk for HAART discontinuation (adj RH = 1.24, 95% CI: 1.03-1.48). However, when restricting to data contributed after 1999, there was no longer any significant increased risk (adj RH = 1.05, 95% CI: 0.81-1.36). After adjusting for pre-HAART health status and prior ARV exposure, individuals who were ethnic/racial minorities, reported an annual income < $10,000/year, and were not employed were at significantly greater risk for HAART discontinuation. The median time to a first change in HAART regimen was approximately 1.5 years after first HAART report and was not elevated among those with a history of IDU (adj RH = 1.09, 95% CI: 0.89-1.34). Our analyses demonstrate that injection drug use by itself does not appear to be an independent risk factor for HAART switching or discontinuation in more recent years. However, as continued HAART use is of paramount importance for long-term control of HIV infection, efforts to improve maintenance to therapy among disadvantaged and minority populations remain greatly needed.AIDS Research and Therapy 01/2007; 4:12. · 2.54 Impact Factor
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ABSTRACT: Although the importance of the initial regimen in highly active antiretroviral therapy (HAART) has been emphasized, the effect on clinical outcome of early modification of the initial HAART regimen has not been well-defined. The analysis included antiretroviral-naive HIV patients who started HAART between 1999 and 2005 at a university hospital. Early modification was defined as any drug change within 2 months of starting HAART. The effect of early regimen modification on the occurrence of new AIDS-defining illness or death was assessed using Kaplan-Meier survival estimates, and hazard ratios were estimated using Cox's proportional hazards regression model. Of 398 patients beginning HAART, 21% experienced early modification of their regimen, the most common reason being gastrointestinal toxicity (49%). After adjusting for risk factors for occurrence of a new AIDS event or death, identified by univariate analysis, the hazards ratio contrasting early modification with maintenance of initial HAART regimen was 3.06 (95% confidence interval, 1.36-6.90; p = 0.007). There were significant differences between the AIDS event-free survival curves of patients in clinical categories B or C with or without early modification of initial HAART regimen (p = 0.0002), but no significant difference in patients in clinical category A (p = 0.706). A considerable proportion of patients who started HAART changed treatment regimen mainly due to intolerance early after start of HAART. Early modification of an initial HAART regimen was associated with poor clinical outcome in HIV patients in the advanced clinical categories.AIDS Research and Human Retroviruses 07/2007; 23(6):794-800. · 2.71 Impact Factor
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ABSTRACT: A competing risk framework occurs when individuals have the potential to experience only one of the several mutually exclusive outcomes. Standard survival methods often overestimate the cumulative incidence of events when competing events are censored. Mixture distributions have been previously applied to the competing risk framework to obtain inferences regarding the subdistribution of an event of interest. Often the competing event is treated as a nuisance, but it may be of interest to compare adverse events against the beneficial outcome when dealing with an intervention. In this paper, methods for using a mixture model to estimate an adverse-benefit ratio curve (ratio of the cumulative incidence curves for the two competing events) and the ratio of the subhazards for the two competing events are presented. A parametric approach is described with some remarks for extending the model to include uncertainty in the event type that occurred, left truncation in order to allow for time-dependent analyses, and uncertainty in the timing of the event resulting in interval censoring. The methods are illustrated with data from an HIV clinical cohort examining whether individuals initiating effective antiretroviral therapy have a greater risk of antiretroviral discontinuation or switching compared with HIV RNA suppression.Statistics in Medicine 05/2008; 27(21):4313-27. · 2.04 Impact Factor