Guadalupe Gómez

Long-term neuropsychiatric disorders on efavirenz-based approaches : Quality of life, psychologic issues, and adherence

Background:Efavirenz has been associated with neuropsychiatric disorders, although little is known about its long-term toxicity. Objective:To assess neuropsychiatric disorders and their relation to efavirenz plasma levels as well as quality of life, psychologic status, and adherence in HIV-infected patients on long-term efavirenz-based antiretroviral therapy. Methods:Cross-sectional study comparing 60 patients on an efavirenz-based approach (EFV group) and 60 patients on a protease inhibitor-containing regimen (PI group) for at least 1 year. Adverse events, efavirenz plasma levels, quality of life, psychologic status, and adherence were assessed. Results:The mean time on treatment was 91.1 ± 39.5 weeks in the EFV group and 119.9 ± 67.4 weeks in the PI group. Mild dizziness, sadness, mood changes, irritability, lightheadedness, nervousness, impaired concentration, abnormal dreams, and somnolence were reported more frequently in the EFV group than in the PI group (P < 0.05). Forty-nine of 60 patients presented with therapeutic efavirenz plasma levels (range: 1.0-4.0 mg/L). Efavirenz plasma levels were similar in subjects with and without neuropsychiatric disorders. No significant differences were found between the EFV group and the PI group regarding quality of life and psychologic status. Sixty percent of patients in the EFV group and 55% in the PI group reported adherence ≥95%. Conclusions:Mild and clinically tolerable neuropsychiatric disorders may persist in patients after a mean of 2 years using an efavirenz-based approach. Quality of life and psychologic status remained good in both study groups. Interventions to enhance long-term adherence should be applied in clinical practice.

High prevalence of and progression to low bone mineral density in HIV-infected patients: a longitudinal cohort study

Background:Low bone mineral density (BMD) is an emerging metabolic condition in HIV-infected patients; however, data on progression of this disease are scarce. Methods:We studied 671 patients with at least one dual-energy X-ray absorptiometry scan (391 of them ≥2 scans) to determine the prevalence and progression of BMD and establish related factors. Linear regression and logistic polytomic regression were used for the cross-sectional study and mixed effects and generalized estimating equations were used for the longitudinal study. Results:Osteopenia and osteoporosis were diagnosed in 47.5 and 23%, respectively. Progression to bone demineralization was observed in 28% of the patients over a median of 2.5 years (12.5% progressed to osteopenia and 15.6% to osteoporosis). In the 105 patients with at least 5 years of follow-up, progression was 47% (18% to osteopenia; 29% to osteoporosis). Factors associated with bone loss and progression were age [odds ratio (OR) 1.07; 95% confidence interval (CI) 1.05–1.08; P < 0.0001], male sex (OR 2.23; 95% CI 1.77–2.8; P < 0.0001), low body mass index (OR 1.14; 95% CI 1.11–1.17; P < 0.0001), time on protease inhibitor (OR 1.18; 95% CI 1.12–1.24; P < 0.0001), time on tenofovir (OR 1.08; 95% CI 1.03–1.14; P < 0.0019), and current use of protease inhibitors (OR 1.64; 95% CI 1.35–2.04; P < 0.0001). Conclusions:Our results show a high prevalence of and considerable progression to osteopenia/osteoporosis in our cohort. Our findings support the importance of applying adequate strategies to prevent bone demineralization and of close monitoring of BMD in HIV-infected patients, specifically in at-risk patients who are taking antiretrovirals that affect bone mineralization.

Antiretroviral therapy interruption guided by CD4 cell counts and plasma HIV-1 RNA levels in chronically HIV-1-infected patients.

Objective:We evaluated the safety of CD4 cell count and plasma HIV-1 RNA (pVL)-guided treatment interruptions (GTI) and determined predictors of duration of treatment interruption. Methods:Chronically HIV-1-infected adults with sustained CD4 cell counts > 500 cells/μl and pVL < 50 copies/ml were randomly assigned to either continue with standard antiretroviral therapy (control group, n = 101) or to interrupt therapy aimed at maintaining CD4 cell counts > 350 cells/μl and pVL < 100 000 copies/ml (GTI group, n = 100). Both groups were followed for 2 years. Results:There were no AIDS-defining illnesses or deaths in either group. Compared to controls, subjects interrupting therapy reduced treatment exposure by 67%, but suffered significantly more adverse events related to the intake of medication or to therapy interruption [relative hazard, 2.71; 95% confidence interval (CI), 1.64–4.49; P < 0.001), mainly due to an excess in mononucleosis-like symptoms. While GTI subjects demonstrated improvements in the psychosocial spheres of quality of life and pain reporting, GTI had no effect on the physical aspects of quality of life. Although both groups had a similar hazard for developing CD4 cell count < 200 cells/μl; at least 10% of subjects on GTI had CD4 cell counts < 350 cells/μl at every time point. Drug resistance mutations were detected in 36% of subjects but were selected de novo only in subjects interrupting non-nucleoside reverse transcriptase inhibitor therapy. Lower CD4 cell count nadir, higher set-point pVL and prior exposure to suboptimal regimens were all independent predictors of the need to reinitiate treatment. Conclusions:Overall, GTI were not as safe as continuing therapy. Despite achieving some improvements in quality of life, GTI did not reduce the overall rate of management-related adverse events.

Nadir CD4 cell count predicts neurocognitive impairment in HIV-infected patients.

Though antiretroviral therapy attenuates neurocognitive disruption, impairment is still observed. We studied the nadir CD4 cell count as a predictor of neurocognitive changes. This cross-sectional study assessed 64 HIV-infected patients in two groups: G1 (n = 26, nadir CD4 < or =200 cells/ml) and G2 (n = 38, nadir CD4 >200 cells/ml). Percentages of patients showing neurocognitive impairment were compared according to different nadir CD4 cutoffs (200, 250, 300, and 350 cells/ml). From G2, we also took the subgroup of patients receiving treatment (G3) and compared this group with G1, in which all patients were being treated. Demographic and clinical variables were evaluated, as were differences in neurocognitive function. Neurocognitive impairment tended to be more prevalent in G1 [19 patients (73.1%)] than in G2 [20 (52.6%), p = 0.123]. When nadir CD4 cutoffs were compared, there was a trend toward more impaired subjects as the CD4 nadir decreased. Significantly different functioning was found in attention/working memory (digit span backward, p = 0.032) and executive functions (trail making test, part B, p = 0.020), with better performance in G2. Comparison between G1 and G3 confirmed those findings. We found differences in neurocognitive functioning in relation to nadir CD4 count in HIV-infected patients. Attention should be given to this value in the management of neurocognitive protection in HIV infection.

Tutorial on methods for interval-censored data and their implementation in R

Interval censoring is encountered in many practical situations when the event of interest cannot be observed and it is only known to have occurred within a time window. The theory for the analysis of interval-censored data has been developed over the past three decades and several reviews have been written. However, it is still a common practice in medical and reliability studies to simplify the interval censoring structure of the data into a more standard right censoring situation by, for instance, imputing the midpoint of the censoring interval. The availability of software for right censoring might well be the main reason for this simplifying practice. In contrast, several methods have been developed to deal with interval-censored data and the corresponding algorithms to make the procedures feasible are scattered across the statistical software or remain behind the personal computers of many researchers. The purpose of this tutorial is to present, in a pedagogical and unified manner, the methodology and the available software for analyzing interval-censored data. The paper covers frequentist non-parametric, parametric and semiparametric estimating approaches, non-parametric tests for comparing survival curves and a section on simulation of interval-censored data. The methods and the software are described using the data from a dental study.

Estimation of the infection time and latency distribution of AIDS with doubly censored data

We consider the nonparametric estimation of the time to infection with HIV and the latency period between infection and the onset of AIDS in data where both the events of infection and AIDS are not directly observed. The methods use self-consistency equations that are more easily and quickly solvable than the nonparametric estimators proposed by De Gruttola and Lagakos (1989, Biometrics 45, 1-11). The techniques are illustrated with data on hemophiliacs who became infected through contamination of the blood factor they were given to control their hemophilia.

Frequentist and Bayesian approaches for interval-censored data

Interval censoring appears when the event of interest is only known to have occurred within a random time interval. Estimation and hypothesis testing procedures for interval-censored data are surveyed. We distinguish between frequentist and Bayesian approaches. Computational aspects for every proposed method are described and solutions with S-Plus, whenever are feasible, are mentioned. Three real data sets are analyzed.

Sustained antiretroviral treatment adherence in survivors of the pre-HAART era: attitudes and beliefs

Abstract The objective of this study was to assess adherence of HIV-1-infected patients who started treatment in the pre-HAART era and to determine variables associated with better adherence, including relevant attitudes and beliefs. This is a cross-sectional study enrolling patients who had received antiretroviral therapy for ≥10 years. Adherence was evaluated through self-reporting and plasma drug concentrations. Treatment variables, attitudes and beliefs were collected during structured interviews. The results show that for 87 patients the median (interquartile range) time on therapy was 13 (10–19) years; 80 were on therapy at the time of analysis. Adherence was ≥95% in 54 patients (67.5%), 90–94% in 22 (27.5%) and <90% in 4 (5%). Drug concentrations were below the lower limit of detection in five patients. Younger age (p=0.014), female gender (p=0.005), current substance abuse (p=0.004) and hepatitis C virus co-infection (p<0.001) were related to lower adherence. Adherence did not differ in relation to different drug families or once- or twice-daily regimens. Patients with adherence <95% were more likely to have interrupted treatment without doctors recommendation (p=0.009). Adherent patients exhibited a higher perception of risk of developing the illness and of benefits of therapy, higher self-efficacy and intention to adhere and were more influenced by events that motivate medication intake. To conclude, adherence was >90% in most patients on antiretroviral therapy for ≥10 years. Adherence was more related to beliefs about health and illness than to the characteristics of medication or level of knowledge about treatment. Care adherence interventions should include assessment of health beliefs.

Influence of the type of pegylated interferon on the onset of depressive and neuropsychiatric symptoms in HIV-HCV coinfected patients

Abstract This is a prospective observational comparative 48-week study to assess the impact of the different types of Peg-IFN on depressive and neuropsychiatric symptoms during treatment in HIV-HCV coinfected patients. Thirty-one patients treated with Peg-IFN α-2b 1.5µg/kg/w plus ribavirine (RBV) (Peg-IFN α-2b Group) and 32 patients receiving Peg-IFN α-2a 180µg/w plus RBV (Peg-IFN α-2a Group) were included. Depressive and neuropsychiatric symptoms, quality of life and adherence were assessed. Fifteen subjects (23%) discontinued therapy (p = 0.3, between groups). Overall, 37 patients presented mild to moderate depressive symptoms, 9 moderate to severe and 3 severe, without differences between groups. Patients in Peg-IFN α-2b reported higher fatigue and dizziness at weeks 12 (p < 0.05) and 24 (p < 0.05), and irritability and memory loss at week 24 (p < 0.05) with respect to Peg-IFN α-2a Group. At week 12, role functioning, general health perception, vitality, emotional role, mental health and the summary areas of physical health and mental health were lower in Peg-IFN α-2b Group (p < 0.05). The same was observed in physical functioning (p = 0.05) and role functioning, general health perception, emotional role and mental health (p < 0.001) at week 24. Three months after finishing treatment, no patient had depressive or neuropsychiatric symptoms, and quality of life improved. Antiretroviral adherence was low but adherence to anti-HCV therapy remained high in both groups. According to our data, Peg-IFN α-2a and Peg-IFN α-2b exert a similar impact on the overall rate of depressive symptoms, although patients treated with Peg-IFN α-2a experience less fatigue and fewer neuropsychiatric symptoms and a lower impairment in their physical and mental quality of life.

Statistical considerations when using a composite endpoint for comparing treatment groups

When comparing two treatment groups in a time-to-event analysis, it is common to use a composite event consisting of two or more distinct outcomes. The goal of this paper is to develop a statistical methodology to derive efficiency guidelines for deciding whether to expand a study primary endpoint from E1 (for example, non-fatal myocardial infarction and cardiovascular death) to the composite of E1 and E2 (for example, non-fatal myocardial infarction, cardiovascular death or revascularisation). We investigate this problem by considering the asymptotic relative efficiency of a log-rank test for comparing treatment groups with respect to a primary relevant endpoint E1 versus the composite primary endpoint, say E, of E1 and E2, where E2 is some additional endpoint.