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.

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 patient's compliance in the clinical setting.

Short-term risk for AIDS-indicator diseases predicted by plasma HIV-1 RNA and CD4+ lymphocytes.

The objective of this study was to assess the value of quantitative HIV-1 RNA as a predictor for the short-term risk of developing AIDS-defining events in comparison with CD4 cell counts. A total of 1,028 samples from 324 patients were analysed. Median initial CD4 cell counts and HIV-1 RNA were 249 x 10(6)/l (range 0-1400 x 10(6)/l) and 4.5 log copies/ml (range: 2.3-6.4 log copies/ml). CD4 cell counts and viral load (VL) values obtained the year before a single AIDS-indicator disease were selected to define the risk of developing that event. Cox regression models with CD4 cell counts and VL values treated as time-dependent covariates were performed to analyse the risk for developing certain events. Receiver operating characteristic (ROC) curves were used to compare CD4 cell counts and VL values as predictive markers for progression. During a median follow-up of 870 d (range 30-1381 d), 132 patients developed AIDS. Median log VL values during the year before the event were 3.6 for non-progressors and 5.2 for those who developed AIDS (p < 0.0001). Minimum log VL threshold values for developing diseases were 2.3 for tuberculosis, 3.8 for Candida esophagitis, 4.4 for wasting syndrome, 4.5 for CMV disease and 4.7 for PCP. VL values were not, however, a better predictive marker for developing specific events than were CD4 cell counts. Although we have identified VL thresholds for the risk of developing certain AIDS-indicator diseases, the indication for starting prophylactic regimens may still be based on CD4 cell counts.

Efficacy of low-dose subcutaneous interleukin-2 to treat advanced human immunodeficiency virus type 1 in persons with

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 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.

High-dose saquinavir plus ritonavir: long-term efficacy in HIV-positive protease inhibitor-experienced patients and predictors of virologic response.

The year-long antiviral efficacy of a high-dose salvage regimen consisting of saquinavir (800 mg twice daily) plus ritonavir (400 mg twice daily) was evaluated in 58 HIV-positive patients who had seen no improvement under first-line protease inhibitor-containing regimens, nor in baseline predictors of virologic response. The efficacy of therapy was determined by CD4+/CD8+ and HIV-1 RNA values. The primary endpoint of our study was the percentage of patients with HIV-1 RNA levels <200 copies/ml (virologic success) at 6 and 12 months of of follow-up. Secondary endpoints were log10 reduction in HIV-1 RNA levels and CD4+ increases through follow-up. Surrogate markers related with a lower HIV-1 RNA area under the curve were identified at baseline. Kaplan-Meier analysis and Cox proportional hazards models were applied to identify baseline predictors of achieving viral suppression at <200 copies/ml. All analyses were intention to treat-last observation carried forward. Patients achieved a median HIV-1 RNA level reduction of >0.5 log through 1 year (-0.59 log10 at 12 months), as well as CD4+ counts increased significantly (89 cells/mm3 at 12 months). Overall, 53% of patients were likely to achieve HIV-1 RNA levels <200 copies/ml at 6 months. Seventy-six percent of patients who started therapy at HIV-1 RNA levels <5000 copies/ml but only 42% with baseline viral load of 5000 to 30,000 copies/ml and 18.7% with baseline viral load >30,000 copies/ml were likely to achieve viral suppression at 6 months (p < .001, log-rank test). Patients with baseline HIV-1 RNA levels between 5000 and 30,000 copies/ml (relative hazard [RH], 0.39; 95% confidence interval [CI], 0.01 to 0.98; p = .0396) and patients with baseline HIV-1 RNA levels >30,000 copies/ml (RH, 0.20; 95% CI, 0.07-0.61; p = .0040) were less likely to reach undetectable HIV-1 RNA levels than those with baseline HIV-1 RNA levels <5000 copies/ml. Salvage highly active antiretroviral therapy (HAART) strategies including saquinavir (SQV) at high doses plus ritonavir (RTV) exert a significant long-term efficacy in more than half of PI-experienced patients without significant additional toxicity. This therapeutic efficacy is strongly implemented by a switch at the lower HIV-1 RNA levels.

Benefit of switching from a protease inhibitor (PI) to nevirapine in PI-experienced patients suffering acquired HIV-related lipodystrophy syndrome (AHL): interim analysis at 3 months of follow-up.

This multicentre, randomized, open-label, prospective trial is evaluating the effects of switching treatment from a protease inhibitor (PI)-containing regimen to one containing the non-nucleoside reverse transcriptase (RT) inhibitor nevirapine in human immunodeficiency virus (HIV)-infected patients with durable viral suppression but suffering from lipodystrophy. Objectives of this ongoing study are to evaluate the effects of this switch on changes in body shape and metabolic abnormalities associated with acquired HIV-related lipodystrophy syndrome (AHL), as well as on maintenance of viral suppression and immunological and psychological effects. Preliminary data involving 57 patients with 3 months of follow-up show an initial improvement of AHL in two regions, the face and arms. There is also a tendency toward improved cholesterol and triglyceride levels and improved quality of life among patients receiving the nevirapine-containing regimen. Maintenance of viral suppression was equivalent in both treatment groups. Additional data with longer follow-up are needed to confirm these results.

Efficacy of adding indinavir to previous reverse transcriptase nucleoside analogues in relation to genotypic and phenotypic resistance development in advanced HIV-1-infected patients.

We assessed the efficacy of adding indinavir in patients with advanced HIV-1 infection, who were previously exposed to different reverse transcriptase (RT) nucleoside analogues. Twenty-five patients with an initial median CD4 cell count of 20 cells/mm3 (range, 0-80 cells/mm3) were treated with indinavir (800 mg three times per day) for 24 weeks. The median initial viral load was 5.4 log (range, 3.6-6.7 log). Of these patients, 56% (14 of 25) had an initial decrease in viral load of >1 log and sustained response of >0.5 log of HIV-1 RNA from baseline. Twelve of these 14 responder patients (85%) showed a sustained RNA response undetectable by NASBA assay, and no genotypic changes in protease were detected at week 24. In those with a temporary or absent response to indinavir, either resistant viruses or lack of compliance was observed. In compliant patients (15 of 16), relatively small increases in 50% inhibitory concentration (IC50) to indinavir and only two to three amino acid changes were sufficient to produce treatment failure. Phenotypic drug-resistant assays at 24 weeks revealed cross-resistance to ritonavir in all the patient isolates and to saquinavir in one third of the isolates. We observed an initial and persistent response to the addition of indinavir in patients with advanced disease and prolonged antiretroviral treatment. Therapy failure, as defined by increases in viral RNA, was associated with either lack of compliance or the development of low level indinavir-resistant virus. Clinical studies need to be designed to determine to what extent these viruses may respond to other protease inhibitors.

[Value of HIV-1 viral load and CD4 lymphocyte count as determinants of progression to AIDS and survival]. / Valor de la carga viral del VIH-1 y de los linfocitos CD4+ como determinantes de la progresión a sida y de la supervivencia.

BACKGROUND: HIV-1 viral load is regarded as a better surrogate marker for progression and death than CD4+ cell counts. Both markers are analysed in a cohort of patients with unknown seroconversion date and advanced HIV infection. PATIENTS AND METHODS: Retrospective cohort analysis of 421 patients, most on antiretroviral therapy, with a median initial CD4+ cell count of 209 x 10(6)/l and a median initial viral load of 4.7 log copies/ml. One thousand two hundred and eighty-six samples were analysed. Univariate and bivariate analysis were performed with initial and sequential CD4+ cell counts and viral load values to estimate the risk of progression and death by Cox regression models. RESULTS: After a median follow up of 763 days, 124 patients developed AIDS and 117 died. Relative risks of progression related to the group that maintained viral load values always < 35,000 copies/ml were: 5-fold (95% CI: 1.4-17.0; p < 0.05) for patients with any viral load value > 35,000 copies/ml but always < 200,000 copies/ml; and 13.6 fold (95% CI: 5.4-34.2; p < 0.0001) for patients who could not maintain viral load < 200.000 copies/ml. CD4+ counts = 100 x 10(6)/l and viral load = 220,000 copies/ml were the threshold values that best fitted to estimate the probability of survival by a bivariate analysis. CONCLUSIONS: The maintenance of sequential viral load values < 35.000 copies/ml is associated with a lower risk of progression. The maintenance of sequential viral load values < 150,000 copies/ml is associated with higher short-term survival rates.

Impact on the immune system of undetectable plasma HIV-1 RNA for more than 2 years.

OBJECTIVE: To investigate the impact of prolonged HIV suppression on the immune system by analysing the expression of several lymphocyte surface markers in a group of HIV-1-infected patients who maintained undetectable HIV-1 RNA levels for more than 24 months. PATIENTS AND METHODS: The study included a highly selected group of nine HIV-1-infected asymptomatic subjects and seven HIV-1-seronegative controls. The inclusion criteria of HIV-1-infected patients was to have plasma HIV-1 RNA levels below 20 (1.3 log10) copies/ml for at least 24 months while under antiretroviral treatment with nucleoside analogues. The patient population was retrospectively taken from a cohort of 1418 treated subjects. Mean initial absolute CD4+ T-cell count and percentage were 468+/-234 x 10(6)/l (range, 202-935 x 10(6)/l) and 25+/-6% (range, 16-33%), respectively. Plasma HIV-1 RNA quantification was determined using a standard and ultrasensitive reverse transcriptase polymerase chain reaction assay. Median HIV-1 RNA plasma level before antiretroviral treatment was 3.14 log10 copies/ml (range, 1.74-3.73 log10 copies/ml). Two or three-colour immunophenotyping was performed on whole blood and frozen peripheral blood mononuclear cells by flow cytometry. RESULTS: A significant increase was noted in CD4+ lymphocyte counts at the end of the study in HIV-1-positive patients. In addition, the CD4: CD8 ratio rose significantly with respect to baseline, although it remained lower than in the controls. CD45RA+ and CD45RO+ population percentages did not differ between groups. A significant rise in CD45RA+ T cells was observed. Analysis of T-cell activation measuring the expression of human leukocyte antigen-DR and CD25 did not differ between groups. The proportion of CD8+ lymphocytes that were CD28+ was similar in both groups at the end of the follow-up. T-cell receptor Vbeta subfamily analysis showed that an expansion of the T-cell receptor repertoire might occur in these patients. CONCLUSION: Patients who maintain undetectable viral load for prolonged periods of time with antiretroviral therapy may achieve a partial immune restoration of the immune system. Our results suggest that treatment of patients at early stages of HIV infection is warranted.

Efficacy of triple combination therapy with zidovudine (ZDV) plus zalcitabine (ddC) plus lamivudine (3TC) versus double (ZDV+3TC) combination therapy in patients previously treated with ZDV+ddC.

OBJECTIVE: To evaluate the immunological and virological efficacy of triple combination therapy with zidovudine (ZDV) plus zalcitabine (ddC) plus lamivudine (3TC) and a double (ZDV+3TC) combination therapy in patients previously treated with ZDV plus ddC. DESIGN: A 6-month follow-up open-label randomized study was undertaken in 46 HIV-1-infected patients previously treated for at least 6 months with ZDV plus ddC, who were allocated to receive either ZDV/ddC/3TC (n = 15) or ZDV/3TC (n = 15) or to continue with the ZDV/ddC regimen (control group; n = 16). METHODS: Changes in CD4+ cell counts and plasma viral load (VL) were analysed with analysis of variance. Sequencing of the reverse transcriptase gene was performed in a subset of 3TC-treated patients. RESULTS: Mean CD4+ cell counts increased significantly above baseline in both 3TC regimens whereas counts decreased in the control group. Significant plasma VL reduction was achieved in both 3TC combination therapy groups at weeks 4 and 24 compared with the control group. Coexistence of mutations conferring resistance to ZDV and 3TC were found in patients from both 3TC treatment groups. CONCLUSIONS: Both therapy strategies, switching ddC to 3TC or adding 3TC, significantly improved the virological and immunological efficacy compared with continuing ZDV/ddC. Our results support the use of 3TC in patients previously treated with the ZDV/ddC combination.

Quantitative HIV-1 RNA as a marker of clinical stability and survival in a cohort of 302 patients with a mean CD4 cell count of 300 x 10(6)/l.

OBJECTIVE: To analyse plasma HIV-1 RNA levels as a marker of clinical stability and survival in a cohort of HIV-infected patients whose time of seroconversion is unknown. DESIGN: Retrospective cohort study. SETTING: Retrovirology laboratory and AIDS Unit in a teaching hospital. PATIENTS: A total of 916 samples from 302 patients, most on antiretroviral therapy, were analysed. Mean initial CD4 cell counts and HIV-1 RNA were 299 x 10(6)/l (range: 0-1600) and 134,261 copies/ml (range: < 200-4,300,000), respectively. Sixty-six cases had been diagnosed previously with AIDS. METHODS: Analysis of progression to AIDS and survival, according to initial and longitudinal viral load (VL) and CD4 cell count measurements was performed by Kaplan-Meier test. Relative risks were calculated by Cox's proportional hazards model. RESULTS: During a mean follow-up of 444 +/- 309 days, 29 patients developed AIDS and 21 died. Relative risk (RR) of progression related to the group with VL < 35,000 was: 10.4 when CD4 > or = 250 x 10(6)/l and VL > or = 35,000 (P = 0.001); and 45.3 when CD4 < 250 x 10(6)/l and VL > or = 35,000 (P < 0.0001). Cumulative probability of progression was: 0%, 0% and 12.3%, at the first, second and third year respectively, for patients with all their sequential VL determinations < 60,000; and 13.3%, 34.7% and 79.3% for patients who did not maintain VL values always < 60,000 (RR = 23; P < 0.0001). The minimum value of VL that reached statistical significance for the survival analysis was 100,000 copies/ml (P < 0.0001). CONCLUSIONS: VL > or = or < 35,000 is a better discriminant for progression than a CD4 cell count > or = or < 250 x 10(6)/l. Sequential VL determinations < 60,000 are associated with a better prognosis.