Joan Romeu

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.

HIV dynamics and T-cell immunity after three structured treatment interruptions in chronic HIV-1 infection.

ObjectiveTo evaluate whether controlled re-exposures to autologous HIV-1 could boost HIV-specific immunity and limit virus replication in patients with chronic HIV-1 infection. Patients and designSubjects with at least 2 years virus suppression during antiretroviral therapy and a CD4 : CD8 ratio > 1 were randomly assigned to interrupt highly active antiretroviral treatment (HAART) three times (n = 12) or to continue their previous HAART (n = 14). ResultsIn 10/12 interrupter patients a rebound of HIV-1 RNA was detected in all three structured treatment interruptions (STI). Plasma virus doubling time was shorter during the first STI than in the second and third STI, corresponding to an average 13% reduction in viral basic reproductive rate. However, the mean time before plasma viral load rose to > 50 copies/ml was significantly shorter in the second and third STI. The average frequency of HIV-specific CD8 T cells in the interrupter patients at the end of the third STI cycle was significantly higher compared with the baseline and the end of the first STI. A substantial increase in HIV-specific CD8 T cell frequencies was found in four interrupter patients, whereas there were no changes in all 14 non-interrupter individuals. A weak p24-specific T helper response developed in 5/12 interrupter patients compared with no response in non-interruptors, but these responses were transient and disappeared rapidly. ConclusionThe increase in the control of viral replication, and positive effects of STI on immune responses in this population should encourage the further development of HIV-specific immune-based therapeutic strategies.

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.

Efficacy of Low-Dose Subcutaneous Interleukin-2 to Treat Advanced Human Immunodeficiency Virus Type 1 in Persons with ⩽250/μL CD4 T Cells and Undetectable Plasma Virus Load

The immunologic efficacy of low-dose recombinant interleukin-2 (rIL-2) administered subcutaneously (sc) once a day in combination with highly active antiretroviral therapy (HAART) was assessed in a pilot study in patients with advanced human immunodeficiency virus (HIV) disease. Twenty-five persons with </=250 CD4 cells/microL and plasma HIV-1 RNA levels </=500 copies/mL for >24 weeks were randomly assigned to receive sc rIL-2 (3 x 10(6) IU once a day) with their previous antiretroviral regimen (n=13) or to continue with the same treatment (n=12). The level of CD4 T cells was significantly higher in the IL-2 group at week 24 (105+/-65/microL; P<.05) but not in the control group (30+/-78/microL). Memory T cells initially contributed to the CD4 T cell increase at week 4 (P<.05). Naive T cell increases (99+/-58/microL) in the IL-2 group became statistically significant at week 24 compared with the control group (28+/-27/microL; P<.05). Subcutaneous rIL-2 once a day in combination with HAART was well tolerated and improved immunologic surface markers in patients with advanced HIV infection.

Influence of highly active anti‐retroviral therapy on response to treatment and survival in patients with acquired immunodeficiency syndrome‐related non‐Hodgkin's lymphoma treated with cyclophosphamide, hydroxydoxorubicin, vincristine and prednisone

Combined highly active anti‐retroviral therapy (HAART) with protease and reverse transcriptase inhibitors has modified the natural history of opportunistic infections and neoplasms in human immunodeficiency virus (HIV)‐infected patients. We analysed the influence of HAART on the response to treatment and survival in a series of 58 patients with acquired immune deficiency syndrome (AIDS)‐related non‐Hodgkins lymphoma (NHL) treated with CHOP (cyclophosphamide, hydroxydoxorubicin, vincristine and prednisone). Two groups of patients were included: (i) forty‐one patients diagnosed with NHL between 1988 and 1996 who were not treated with HAART; (ii) seventeen patients diagnosed since 1996, who were receiving or commenced HAART when NHL was diagnosed. The response rate to CHOP was higher in group 2 (13 out of 17 cases; 75%) than in group 1 (14 out of 41 cases; 34%) (P = 0·003). The 2‐year probability of event‐free survival (EFS) [95% confidence interval (CI)] for group 1 was 0·5 (0·24–0·74), whereas for group 2 it was 0·85 (0·61–0·90) (P = 0·024). The lymphoma‐free survival (LFS) was also significantly different for both groups (2‐year LFS probability 0·53 vs. 1·0, P = 0·04). The median (95% CI) overall survival (OS) for group 1 was 7 months (range, 3–10·8 months), whereas it was not reached in group 2 (P = 0·0015). In the multivariate analysis for remission attainment, the only variables with a higher probability to achieve complete remission (CR) were HAART (P = 0·01) and International Prognostic Index score 1 (P = 0·02). The only statistically significant variable in the multivariate analysis for EFS was HAART (P = 0·049) and the variables with prognostic value for OS in the multivariate analysis were B symptoms (P = 0·01) and HAART (P = 0·003). Patients with AIDS‐related NHL treated with CHOP and HAART had a higher CR rate than those treated only with CHOP. In this study, HAART was an independent prognostic factor for CR, OS and EFS in patients with AIDS‐related NHL.

A Therapeutic Dendritic Cell-Based Vaccine for HIV-1 Infection

A double-blinded, controlled study of vaccination of untreated patients with chronic human immunodeficiency virus type 1 (HIV-1) infection with 3 doses of autologous monocyte-derived dendritic cells (MD-DCs) pulsed with heat inactivated autologous HIV-1 was performed. Therapeutic vaccinations were feasible, safe, and well tolerated. At week 24 after first vaccination (primary end point), a modest significant decrease in plasma viral load was observed in vaccine recipients, compared with control subjects (P = .03). In addition, the change in plasma viral load after vaccination tended to be inversely associated with the increase in HIV-specific T cell responses in vaccinated patients but tended to be directly correlated with HIV-specific T cell responses in control subjects.

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.