Núria Pérez-Álvarez

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.

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.

CD4 T-cell hyperactivation and susceptibility to cell death determine poor CD4 T-cell recovery during suppressive HAART.

Background:The failure to increase CD4 T-cell counts in some HAART-treated HIV-infected patients with satisfactory virological responses has been related to low CD4 T-cell production, high turnover and death. However, the relative contribution of these factors is still unclear, strongly limiting the definition of appropriate therapeutic strategies for these patients. Methods:A cross-sectional study was designed to evaluate the contribution of thymic activity, microbial translocation, cellular activation and death to CD4 T-cell recovery. We included 230 HIV-infected individuals on suppressive HAART (>2 years); 95 of them were considered ‘discordant’ (CD4 T-cell count <350 cells/μl) and 135 were considered ‘concordant’. Comparative and logistic regression analyses were performed. Results:Discordant patients showed higher levels of activated [human leukocyte antigen (HLA)-DR+CD95+ and CD38+CD45RA−] cells in both the CD8 and CD4 T-cell compartments. Notably, the most significant differences were observed in CD4 T cells. Discordant patients showed lower naive CD4 T-cell production (CD45RA+CD31+ cells), higher spontaneous ex-vivo CD4 T-cell death and higher plasma levels of soluble CD14. Multivariate analysis showed that activation and death of CD4 T cells, along with nadir CD4 T-cell counts, were the only predictive factors for poor immune recovery. Moreover, the low correlations found between CD4 T-cell activation or death with thymic output and bacterial translocation suggest that additional factors modulate cellular activation and death and, in turn, CD4 T-cell recovery. Conclusion:CD4 T-cell repopulation during HAART is determined by CD4 T-cell activation and death. Therefore, strategies aimed to reduce these parameters should be envisaged to treat discordant patients.

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.

Raltegravir intensification shows differing effects on CD8 and CD4 T cells in HIV-infected HAART-suppressed individuals with poor CD4 T-cell recovery.

Background:Immunodiscordant HIV-infected patients show viral suppression during antiretroviral therapy but fail to recover CD4 T cells. Immunodiscordance is characterized by partial CD4 T-cell immunodeficiency and increased inflammation, activation and immunosenescence in both CD4 and CD8 T cells. Methods:A randomized, controlled, 48-week intensification study to assess the effect of raltegravir on immunological parameters in immunodiscordant patients (CD4 cell counts <350 cells/&mgr;l; viral load <50 copies/ml for >2 years). Patients were randomized (2 : 1) to intensify therapy with raltegravir (intensified arm, n = 30) or continue with the same therapy (control arm, n = 14). Results:Both groups showed similar immunological baseline characteristics. CD4 T-cell counts increased faster in the intensified arm (P = 0.01, week 12). However, no differences between groups were observed at week 48. Additionally, no changes in thymic output (CD45RA+CD31+ cells), activation (HLA-DR+CD95+ cells) or ex-vivo cell death were observed in CD4 T cells at any time point intergroups or intragroups. Conversely, intensified arm showed significant decreases in the expression of the CD8 T-cell activation marker CD38 at weeks 24–48, which were more evident in memory cells. Despite this, the levels of HLA-DR expression in CD8 T cells and plasma soluble CD14 remained stable in both arms overtime. Conclusion:Long-term (48-week) raltegravir intensification failed to counterbalance CD4 T-cell deficiency and its associated features: hyperactivation and death of CD4 T cells. However, raltegravir induced a specific reduction of CD38 expression in CD8 T cells, suggesting a beneficial effect on CD8 T-cell hyperactivation, which has been linked with HIV-associated comorbidities.

HIV-1 Infection in Subjects Older than 70: A Multicenter Cross-Sectional Assessment in Catalonia, Spain

We designed a multicenter cross-sectional study to describe the epidemiological characteristics of the HIV-1-infected population aged 70 years or more in our setting. 179 individuals from eight university hospitals in Barcelona, Spain, were included, representing 1.5% of HIV-1 infected subjects followed during 2008. Most subjects were male (76%) and had acquired HIV infection through sexual intercourse (87%); 69% had been diagnosed with HIV-1 after their sixties. The CD4 cell counts at HIV-1 diagnosis were < 200 cells/mm(3) in 52% of individuals, whereas this was only seen in 34% of subjects from a published cohort including younger HIV- infected adults from the same setting [1]. Most of our patients were on HAART, had undetectable HIV-1 viremia and the most recent median CD4 cell counts were >or= 350 cells/mm(3). 154 subjects had at least one comorbid condition, including dyslipidemia (54%), hypertension (36%), hyperglycemia or diabetes (30%), cardiovascular disease (23%), chronic renal failure (18%), history of neoplasia (17%) and cognitive impairment (11%). Lipodystrophy was reported in 58% of individuals. Rates of hypercholesterolemia, diabetes and cancer were higher than those reported in unselected local population (28%, 17% and 7%, respectively). The study participants were taking an average of 2.97 drugs (range 1-10) other than antiretrovirals. In conclusion, the elder population infected with HIV-1 is likely being diagnosed late and at lower CD4+ counts and is frequently affected by comorbidities and co-medication. Based on our findings, we suggest some recommendations regarding the management of this growing population.

The effect of atorvastatin treatment on HIV-1-infected patients interrupting antiretroviral therapy.

We conducted a pilot study to assess the effect of atorvastatin on HIV replication. Patients with stable HAART-controlled infection interrupted therapy and were randomly assigned to a control group or to start atorvastatin 40 or 80 mg/day. Statin groups showed lower serum cholesterol but similar viral loads and CD4 T-cell counts to the control group at weeks 4 and 12. Paradoxically, baseline serum cholesterol, but not atorvastatin, influenced viral rebound at week 4.

Early but limited effects of raltegravir intensification on CD4 T cell reconstitution in HIV-infected patients with an immunodiscordant response to antiretroviral therapy

BACKGROUND Immune hyperactivation in immunodiscordant patients can induce residual HIV replication and limit CD4 T cell recovery. We assessed the impact of raltegravir intensification on CD4 T cell recovery and viral persistence. METHODS We performed a randomized, controlled, pilot trial. Patients with CD4 T cell counts <350 cells/mm(3) despite suppressive antiretroviral therapy were randomized (2 : 1) to intensify with raltegravir (intensified arm, n = 30) or to continue with the same regimen (control arm, n = 14) for 48 weeks. Then, the control individuals intensified their treatment for 24 weeks (delayed-intensification arm). We analysed changes in CD4 T cell counts, total and episomal HIV DNA in peripheral blood mononuclear cells and predictive factors for response. RESULTS Raltegravir intensification induced a rapid increase in CD4 T cell counts (week 12) (P = 0.007), although this was not sustained over time. Control patients maintained constant but slow increases in CD4 T cell counts (present in the pre-study period), reaching CD4 T cell counts similar to those of patients in the intensification arm at week 48. This effect was confirmed by the analysis of the delayed-intensification arm. Proviral DNA levels remained stable in both arms over time; episomal DNA forms and ultrasensitive plasma viral load were barely detected during the study. Increases in CD4 T cell counts were associated with low baseline CD95 expression in CD4 and CD8 T cells (P = 0.020). CONCLUSIONS Raltegravir intensification modestly impacts viral dynamics and induces a rapid but limited gain in CD4 T cell counts in immunodiscordant patients. Residual viral replication does not seem to be the main cause of unsatisfactory CD4 T cell recovery in these patients.