Anna Bonjoch

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.

Long-Lasting Remission of Cytomegalovirus Retinitis without Maintenance Therapy in Human Immunodeficiency Virus-Infected Patients

Seven AIDS patients who were receiving suppressive therapy for previously diagnosed cytomegalovirus (CMV) retinitis were offered treatment with protease inhibitors (PIs). Secondary prophylaxis for CMV was discontinued after 3 months of therapy with PIs if patients had >150 CD4 cells/mm3 and a human immunodeficiency virus (HIV) load of <200 copies/mL and if they were negative for CMV as determined by qualitative CMV polymerase chain reaction (PCR). Ophthalmologic exams were done periodically. After a median follow-up of 9 months (range, 9-12), no new episodes of CMV retinitis were observed. CD4 cell counts were >150 cells/mm3 in all cases, HIV loads were <200 copies/mL, and results for qualitative CMV PCRs remained negative. These observations suggest that for selected patients with healed CMV retinitis who have immunologic and virologic evidence of a clinical response to potent combination antiretroviral therapy, temporary discontinuation of a chronic anti-CMV suppressive therapy may not result in further retinal necrosis. However, the long-term immunologic benefit of PIs and hence the safety of prolonged withdrawal of anti-CMV therapy is unknown.

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.

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.

Role of Structured Treatment Interruption before a 5-Drug Salvage Antiretroviral Regimen: The Retrogene Study

We evaluated the efficacy of a 5-drug salvage regimen, preceded by a 12-week, structured treatment interruption (STI), in 46 multidrug-treated, human immunodeficiency virus type 1-infected patients with detectable viremia. Patients were randomly assigned to receive a 5-drug salvage regimen immediately (noninterruption [NI] group; n=24 patients) or after 12 weeks of STI (interruption [I] group; n=22 patients). At week 48, 45% of patients in the I group and 46% of patients in the NI group had virus loads <50 HIV-1 RNA copies/mL (P=.619). No differences in CD4 cell counts were seen between groups at week 48 (P=.734). A complete reversion to wild-type genotype was detected in 35% of patients in the I group, but this phenomenon did not affect the virological response. The only overall baseline factor associated with ensuing virus suppression was a lower number of nucleoside reverse-transcriptase inhibitor-resistant mutations (relative risk, 0.66; 95% confidence interval, 0.47-0.93; P=.021). A prior STI seems to confer no additional benefit to subsequent virological or immunological outcomes of a salvage regimen.

Genetic evolution of gp41 reveals a highly exclusive relationship between codons 36, 38 and 43 in gp41 under long-term enfuvirtide-containing salvage regimen.

Objective:To analyse the genetic changes in the gp41 protein in HIV-infected patients with detectable plasma viraemia receiving a long-term salvage enfuvirtide regimen. Methods:We studied 13 heavily antiretroviral-experienced patients receiving a salvage regimen containing enfuvirtide. Substitutions in gp41 were analysed by population-based sequencing at baseline and longitudinally after the initiation of enfuvirtide treatment. To investigate sequence evolution we also analysed multiple gp41 clones from four selected patients. A Fishers two-tailed test was used to assess the distribution of resistance-associated mutations in the clonal sequences. Results:Mutations at positions 36 and 38 in gp41 (HR1) emerged rapidly (median emerging time 10 weeks), but disappeared at subsequent timepoints in most of the patients. Amino acid changes did not accumulate over time, with no patient having more than two mutations in HR1 after 6 months of treatment. The mutation N43D was not observed together with changes at positions 36 or 38 in any patient. Clonal analysis showed that the three main gp41 resistance mutations were highly mutually exclusive (P < 0.001), being present in individual clones and constituting independent populations. Conclusion:Substitutions at positions 36 and 38 are rapidly selected but disappear thereafter in HIV-1-infected patients failing an enfuvirtide-containing salvage therapy. We found a highly exclusive relationship between the three main enfuvirtide resistance-associated mutations (amino acids 36, 38 and 43), suggesting that the genetic evolution of HIV-1 gp41 protein is a dynamic and much more complex process than previously though.

Improvement of Mitochondrial Toxicity in Patients receiving a Nucleoside Reverse-Transcriptase Inhibitor-Sparing Strategy: Results from the Multicenter Study with Nevirapine and Kaletra (MULTINEKA)

BACKGROUND Nucleoside reverse-transcriptase inhibitor (NRTI)-related mitochondrial toxicity has been suggested as a key factor in the induction of antiretroviral-related lipoatrophy. This study aimed to evaluate in vivo the effects of NRTI withdrawal on mitochondrial parameters and body fat distribution. METHODS A multicenter, prospective, randomized trial assessed the efficacy and tolerability of switching to lopinavir-ritonavir plus nevirapine (nevirapine group; n = 34), compared with lopinavir-ritonavir plus 2 NRTIs (control group; n = 33) in a group of human immunodeficiency virus-infected adults with virological suppression. A subset of 35 individuals (20 from the nevirapine group and 15 from the control group) were evaluated for changes in the mitochondrial DNA (mtDNA) to nuclear DNA ratio and cytochrome c oxidase (COX) activity after NRTI withdrawal. Dual-energy X-ray absorptiometry (DEXA) scans were used to objectively quantify fat redistribution over time. RESULTS The nevirapine group experienced a progressive increase in mtDNA content (a 40% increase at week 48; P = .039 for comparison between groups) and in the COX activity (26% and 32% at weeks 24 and 48, respectively; P = .01 and P = .09 for comparison between groups, respectively). There were no statistically significant between-group differences in DEXA scans at week 48, although a higher fat increase in extremities was observed in the nevirapine group. No virologic failures occurred in either treatment arm. CONCLUSIONS Switching to a nucleoside-sparing regimen of nevirapine and lopinavir-ritonavir maintained full antiviral efficacy and led to an improvement in mitochondrial parameters, which suggests a reversion of nucleoside-associated mitochondrial toxicity. Although DEXA scans performed during the study only revealed slight changes in fat redistribution, a longer follow-up period may show a positive correlation between reduced mitochondrial toxicity and a clinical improvement of lipodystrophy.