Eugenia Negredo

Prospective randomized two-arm controlled study to determine the efficacy of a specific intervention to improve long-term adherence to highly active antiretroviral therapy.

Background: Nearly perfect compliance seems to be indispensable to obtain the maximum benefit from highly active antiretroviral therapy (HAART). Interventions to ensure a high level of adherence during a relatively long‐term period of therapy are necessary. Methods: This is a prospective, randomized, two‐arm controlled study including patients starting their first‐ or second‐line HAART who were randomized to receive psychoeducative intervention to implement adherence (experimental group [EG]) or a usual medical follow‐up (control group [CG]). We aimed to study the efficacy of a psychoeducative intervention to ensure long‐term adherence to HAART, its relation with the virologic efficacy of treatment, and to determine the variables related to long‐term adherence. Visits were made at weeks 0, 4, 24, and 48 for data collection. Self‐reported adherence was registered at each visit and its veracity was tested by randomized blood analyses performed without previous warning to 40% of patients. Appropriate adherence was defined as the consumption of ≥95% of medication prescribed. Statistical analyses were performed both by the as treated (AT) and the intention to treat missing = failure (ITT) methods. Results: In all, 116 patients were included. At week 48, 94% of patients in the EG versus 69% controls achieved adherence ≥95% (p = .008); 89% of patients in the EG versus 66% controls had HIV‐1 RNA levels <400 copies/ml (p = .026). Overall, 85% of patients with adherence ≥95% but only 45% of those with adherence <95% had viral load (VL) <400 copies/ml (p = .008). In multivariate analysis, variables significantly related to adherence were having received a psychoeducative intervention (odds ratio [OR], 6.58; p = .04), poor effort to take medication (OR, 5.38; p = .03), and high self‐perceived capacity to follow the regimen (OR, 13.76; p = .04). Self‐reported adherence and drug plasma levels coincided in 93% of cases. However, differences in adherence did not reach statistical significance in the ITT analysis although a clear tendency toward benefit was observed in EG. Conclusions: Specific and maintained psychoeducative interventions based on excellence on clinical practice are useful to keep high levels of adherence as well as high levels of viral suppression. There is a clear relation between high adherence levels and virologic success. Assessment of certain specific variables related to adherence may be helpful to monitor patients compliance in the clinical setting.

antiretroviral Treatment Simplification With Nevirapine in Protease Inhibitor-experienced Patients With Hiv-associated Lipodystrophy : 1-year Prospective Follow-up of a Multicenter, Randomized, Controlled Study

Background: Simpler and less toxic antiretroviral strategies are needed to maximize treatment compliance without sacrificing potency, at least for drug‐experienced HIV‐infected patients currently on regimens containing protease inhibitors (PIs). Small nonrandomized studies have suggested a beneficial role of PI‐sparing regimens on lipodystrophy. Objectives: To assess the virologic, immunologic, and clinical benefit of switching the PI to nevirapine in patients with HIV‐associated lipodystrophy and sustained viral suppression before entry in the study. Design: Open‐labeled, prospective, randomized, multicenter study. Setting: Seven reference inpatient centers for HIV/AIDS in Spain. Patients: One hundred six HIV‐infected adults with clinically evident lipodystrophy who sustained HIV‐RNA suppression for at least 6 months with PI‐containing antiretroviral combinations. Intervention: Replacement of the PI with nevirapine during 48 weeks (Group A) versus continuing the prior PI (Group B). Measurements: Several virologic and immunologic analyses, standard and specific biochemical tests, and anthropometric and dual X‐ray absorptiometry measurements. Results: At week 48, an HIV‐1 RNA level <400 copies/ml was maintained in 79% and 77% of patients in Groups A and B, respectively, whereas 74% and 72% of patients had viral load levels <50 copies/ml. Absolute CD4+ counts significantly increased in both groups compared with baseline values, and a significant decrease in CD38+CD8+ cells was observed in Group A (p < .01) but not in group B. Overall, no significant changes in anthropometric or body shape measurements were found after 48 weeks. Fasting total cholesterol and triglyceride levels decreased in Group A (but not in Group B) compared with baseline values (p < .05), although no significant differences were seen between groups at the end of the study. Subjects in Group A reported a better quality of life (QOL) index than controls (p < .001), with the main reason reported being the greater simplicity of the new drug regimen. Conclusions: Protease inhibitor‐sparing regimens, including nevirapine, seem to be an effective alternative for PI‐experienced patients. Nevirapine‐based triple therapies allow maintained control of HIV‐1 RNA levels and improve the immunologic response at 48 weeks of follow‐up in patients with prior sustained virologic suppression. The switch to nevirapine significantly improved the lipidic profile in Group A, although there were no differences between groups at the end of the study. Additionally, no significant changes were seen in terms of lipodystrophy‐related body shape changes 1 year after the PI substitution. Finally, nevirapine‐containing regimens have a simpler dosing schedule, and this facilitates high adherence and improves QOL.

Virological, Immunological, and Clinical Impact of Switching from Protease Inhibitors to Nevirapine or to Efavirenz in Patients with Human Immunodeficiency Virus Infection and Long-Lasting Viral Suppression

Seventy-seven subjects infected with human immunodeficiency virus were randomized to switch from protease inhibitor (PI) therapy to nevirapine therapy (group A; n=26) or to efavirenz therapy (group B; n=25) or to continue PI therapy (group C; n=26). At month 12, viral suppression had been maintained in 96% of patients in group A, 92% of patients in group B, and 92% of patients in group C. A significant increase in the CD4(+) level was observed in all 3 groups. In group A, lipid profiles improved, whereas levels of gamma-glutamiltransferase and alanine aminotransferase significantly increased; 1 subject interrupted treatment because of hepatotoxicity. In group B, an increase in gamma-glutamiltransferase levels was also observed, and 3 patients interrupted treatment because of central nervous system symptoms. Two patients in group C withdrew therapy. Quality of life significantly improved for groups A and B. In patients receiving effective PI-based therapy, the replacement of the PI with either nevirapine or efavirenz is safe and virologically effective.

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.

Quality of life, emotional status, and adherence of HIV-1-infected patients treated with efavirenz versus protease inhibitor-containing regimens.

&NA; We assessed the impact of an efavirenz‐containing regimen versus a protease inhibitor‐containing regimen on quality of life, emotional status, and adherence of HIV‐1‐infected patients. In addition, we sought to define the adverse events associated with these treatments, with a special focus on central nervous system disorders in the efavirenz treatment group. This prospective, randomized, two‐arm, controlled study included 100 patients for whom initial treatment with a protease inhibitorcontaining regimen failed. Patients were randomized to start treatment with two nucleoside retrotranscriptase inhibitors plus efavirenz (group 1; 51 patients) or two nucleoside retrotranscriptase inhibitors plus one or more new protease inhibitors (group 2; 49 patients). Quality of life was assessed by a five‐point item adapted from the HIV questionnaire of the Medical Outcomes Study, emotional status was evaluated by the Profile of Mood State questionnaire, and patients self‐reported adherence. Data were analyzed by both an as‐treated method and an intention‐to‐treat‐last observation carried forward method. Patients in group 1 reported the following findings at week 4: dizziness (66%), abnormal dreaming (48%), light‐headedness (37%), and difficulty sleeping (35%). At week 24, dizziness (13%; p < .001), abnormal dreaming (18%; p = .002), light‐headedness (13%; p = .01), difficulty sleeping (7%; p = .001), and nervousness (13%; p = .01) decreased in these patients. Irritability, abnormal dreaming, and nervousness persisted at week 48 in 13%, 10%, and 8% of group 1 patients, respectively. Patients in group 2 reported the following findings at week 4: lightheadedness (8%), dizziness (5%), difficulty sleeping (4%), nervousness (4%), and headaches (3%). Patients in group 2 reported the following findings at week 48: difficulty sleeping (4%), nervousness (3%), headaches (3%), and light‐headedness (2%). In group 1, quality of life (p < .001) and emotional status (week 48; p = .004) improved, both of which were better than those in group 2 (p = .001). Both groups maintained high levels of medication adherence, and no significant differences in the number of patients who had viral loads of <200 copies/mL at week 48 were found (78% of group 1 patients vs. 85% of group 2 patients; p = not significant). At week 48, the mean CD4 cell count ± SD was 497 ± 224/mm3 in group 1 and 539 ± 298/mm3 in group 2 (p = not significant). Despite similar immunologic and virologic outcomes, a second‐line efavirenz‐containing regimen improved quality of life of HIV‐1‐infected patients compared with a second‐line protease inhibitor‐containing regimen. However, close follow‐up of patients receiving treatment with efavirenz‐based regimens is recommended, especially for those with previous emotional disturbances due to central nervous system disorders in the short term and those with persistence of a low percentage of these disorders in the long term.

Ezetimibe, a promising lipid-lowering agent for the treatment of dyslipidaemia in HIV-infected patients with poor response to statins.

Objective:To assess the efficacy, safety, and pharmacokinetic interactions of ezetimibe in HIV-infected patients with poorly controlled antiretroviral-associated dyslipidaemia while taking pravastatin alone. Design:A prospective, open-label, one-arm study of 24 weeks duration. Patients and setting:Nineteen patients (18 on stable HAART), with low density lipoprotein (LDL)-cholesterol values of ≥ 130 mg/dl despite the use of pravastatin. Methods:Ezetimibe, 10 mg/day, was added to pravastatin 20 mg/day, while patients maintained the same antiretroviral regimen. Determinations of total, LDL-, and high density lipoprotein (HDL)-cholesterol, triglycerides, apoproteins, and inflammatory factors (homocystein and C-reactive protein) were performed at baseline, and at weeks 6, 12, and 24. Liver enzymes and creatinine phosphokinase were also assessed. Protease inhibitor (PI) or non-nucleoside reverse transcriptase inhibitor (NNRTI) Cmin was determined just before and 12 weeks after ezetimibe introduction. Results:At week 24, 61.5% of patients achieved the endpoint of the study (LDL-cholesterol < 130 mg/dl). Significant declines in mean total and LDL-cholesterol levels were observed between baseline and weeks 6, 12, and 24, irrespective of antiretroviral type (PI or NNRTI). Mean HDL-cholesterol and apoprotein A increased significantly. No patients discontinued therapy due to intolerance or presented toxicity of grade 2 or more. No differences were observed in lopinavir or nevirapine Cmin measured just before and 12 weeks after ezetimibe introduction. Conclusion:The addition of ezetimibe to ongoing pravastatin seems to be an effective and safe option for HIV-infected patients not achieving the NCEP ATPIII LDL-cholesterol goals while receiving a statin alone. Its high tolerability and the lack of interactions with the cytochrome CYP3A4 indicate that ezetimibe will not increase the risk of toxicity or pharmacokinetic interactions with antiretrovirals.

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.

Unexpected CD4 cell count decline in patients receiving didanosine and tenofovir-based regimens despite undetectable viral load.

Background: We recently observed a significant CD4 cell count decline in patients receiving didanosine (ddI) 400 mg, tenofovir (TDF) and nevirapine (NVP), despite virological suppression. Methods: We identified from our computerized patient database subjects who initiated combinations containing ddI and/or TDF for reasons other than virological failure, including simplification or intolerance. Changes in total, CD4+ and CD8+ lymphocyte counts since the initiation of therapy were analysed retrospectively. Plasma concentration of ddI was prospectively determined in eight of these patients receiving ddI 400 mg + TDF + NVP and 3 weeks after a ddI dosage reduction. Results: A total of 302 patients were studied. A significant decrease in CD4 and CD8 and in total lymphocyte counts was only seen in subjects receiving ddI standard dose + TDF-containing regimens, despite the maintenance of viral suppression. More than 50% of these patients showed a decline of more than 100 CD4 cells at 48 weeks. In contrast, subjects not receiving ddI + TDF together experienced the expected progressive increase in CD4 T-cell counts. Plasma levels of ddI were elevated in all patients receiving the standard ddI dose + TDF. DdI plasma levels significantly decreased when patients weighting > 60 kg reduced ddI dose to 250 mg, achieving similar levels to those generated by ddI 400 mg without TDF. Conclusions: Co-administration of ddI at standard doses plus TDF appears to exert a deleterious effect on CD4 and CD8 counts. Although lymphocyte toxicity related to excessive ddI plasma levels could explain our findings, other mechanisms cannot be excluded. Pharmacokinetic data suggest ddI dose reduction when coadministered with TDF.

Reversal of atherogenic lipoprotein profile in HIV-1 infected patients with lipodystrophy after replacing protease inhibitors by nevirapine

BackgroundThe widespread use of protease inhibitors (PI) has been associated with abnormalities in the lipid profile of HIV-1-infected patients. Treatment simplification approaches in which PI are replaced by nevirapine (NVP) have been shown to improve PI-related toxicity. ObjectiveTo assess the impact on plasma lipids of replacing the PI by NVP in HIV-1 infected patients with lipodystrophy. MethodsWe studied 34 patients with lipodystrophy who had been the first to be enrolled in a prospective, randomized trial of continuing current treatment, or replacing PI with NVP. Sixteen patients replaced their PI with NVP and 18 continued their current PI-containing treatment. Total, low density lipoprotein (LDL), very low density lipoprotein (VLDL), intermediate density lipoprotein and high density lipoprotein (HDL) cholesterol and triglyceride levels, the size and particle number of LDL were determined at baseline and after 24 weeks, by nucleic magnetic resonance spectroscopy. FindingsAfter 24 weeks of replacing the PI with NVP, we observed a reduction of total cholesterol (P = 0.028), LDL-cholesterol (P = 0.001), the number of circulating LDL particles (P = 0.003) and the VLDL-1 triglyceride level (P = 0.032). A concomitant significant increase was observed in both HDL-cholesterol level (P = 0.002) and HDL particle size (P < 0.001). No significant changes were observed in the group that continued taking the PI. ConclusionsThe replacement of PI by NVP improved the lipid profile both by reducing the number and lipid content of atherogenic LDL particles, and increasing the protective HDL fraction. Although total triglyceride levels remained unchanged, a reduction in the VLDL-1 fraction contributes to the reduction of LDL particles. These changes are expected to reduce the risk of cardiovascular disease in HIV-1-infected patients on highly active antiretroviral therapy.

Measurement of Intracellular Didanosine and Tenofovir Phosphorylated Metabolites and Possible Interaction of the Two Drugs in Human Immunodeficiency Virus-Infected Patients

ABSTRACT Recent work has demonstrated the existence of a systemic interaction between didanosine (ddI) and tenofovir disoproxyl fumarate (TDF) that leads to a significant increase in plasma ddI levels when coadministered with TDF (40 to 50% increase). These two drugs are, respectively, nucleoside and nucleotide analogues of adenosine and efficiently inhibit the human immunodeficiency virus (HIV) reverse transcriptase when transformed to their triphosphate moieties in the intracellular (IC) medium (ddA-TP and TFV-DP, respectively). Since ddI and TDF partly share the same IC metabolic pathway leading to the active triphosphates, we investigated a putative IC interaction. We used high-performance liquid chromatography-tandem mass spectrometry techniques to determine ddA-TP and TFV-DP IC levels in HIV-infected patients cotreated with both drugs, in comparison with patients treated with just one of the two drugs. These measurements revealed no significant differences in IC levels of the corresponding triphosphates when ddI (250 mg, once a day [QD]) was coadministered with TDF (300 mg, QD) compared to ddI 400 mg (QD) administered without TDF, thus supporting the dose adaptation proposed for this combination. However, we observed that both ddA-TP and TFV-DP have very long IC half-lives, resulting in unusual IC pharmacokinetic profiles with no significant changes in triphosphate concentrations between two dosings. In the case of TFV-DP, this t1/2 of elimination was roughly estimated to be 180 h (7.5 days). This characteristic is certainly interesting in terms of efficacy but could have some drawbacks in terms of virus resistance for patients discontinuing these drugs.