Efficacy and safety of a quadruple combination Combivir + abacavir + efavirenz regimen in antiretroviral treatment-naive HIV-1-infected adults: La Francilienne

OBJECTIVE: To evaluate the safety and efficacy of a protease inhibitor sparing, quadruple therapy (Combivir + abacavir + efavirenz) in antiretroviral treatment-naive HIV-1-infected adults. DESIGN: Multicenter open-label pilot study. Clinical and biological assessments were performed at baseline and at weeks 2, 4, 8, 16, 24, 32, 40, 48. RESULTS: Thirty-one subjects enrolled with a median baseline viral load (VL) of 4.69 log10 copies/mL and CD4 cell count of 322 cells/mm3. At week 48, 90% (intention-to-treat [ITT] switch included) and 77% (ITT switch = failure) patients had a VL <50 copies/mL. These results were similar in the population (n = 13) with a VL >100,000 copies/mL at baseline. Combivir + abacavir + efavirenz demonstrated an early antiretroviral response: 58% of patients had plasma HIV-1 RNA <50 copies/mL at week 8. Using a modified assay, the percentage of patients with VL <5 copies/mL at week 48 was 55% (17/31) and 42% (13/31) using ITT (switch included) and ITT (switch = failure), respectively. Median VL decreased by -4.0 log10 copies/mL at week 48 (ITT). Median CD4+ cell count change from baseline at week 48 was +129 cells/mm3 (ITT). Most patients experienced at least one drug-related adverse event that was not considered treatment-limiting by the investigator. There were no cases of abacavir hypersensitivity reactions. CONCLUSIONS: Safety and efficacy results from this study demonstrated that the quadruple regimen Combivir/abacavir/efavirenz is generally safe and displays potent and durable antiretroviral activity in antiretroviral treatment-naive HIV-1-infected patients, offering a promising therapeutic option in a PI-sparing strategy.     

Natural polymorphisms in HIV-1 protease: impact on effectiveness of a first-line lopinavir-containing antiretroviral therapy regimen

Mutations on HIV protease lead to resistance to protease inhibitors. However, resistance development may be different according to primary, secondary or polymorphic mutations. The present study was designed to assess the impact of natural protease mutations on the effectiveness of a first-line antiretroviral therapy (ART), and secondarily, their effect on the initial viral load (VL). The study was conducted in 175 HIV-1-infected patients, who initiated a first-line lopinavir/r-containing ART regimen and who had an available genotype resistance testing before initiating therapy. We assessed the association between mutations (prevalence > or = 10%) and the initial VL. We assessed the association between mutations and ART effectiveness using two surrogate markers: the slope of VL decrease at 1 month and the time to VL undetectability. For the 175 patients, the initial median VL was 4.94 log(10) copies/ml [interquartile range: 4.44-5.47] and the initial median CD4 lymphocyte count, 219/microl [129-296]. Eighteen mutations had a prevalence > or = 10%. At 1 month, the median VL decrease was 2.35 log(10) copies/ml [1.76-2.82]. The median time to VL undetectability was 128 days [91-196]. No mutation was associated significantly with the initial VL, the slope of VL decrease at 1 month or the time to VL undetectability. This study of antiretroviral-naive patients showed that protease polymorphisms had no impact on the effectiveness of a lopinavir/r-containing ART regimen. However, polymorphisms may affect ART effectiveness differently in other populations, such as ART-experienced patients and/or patients treated with protease inhibitors other than the one used here.     

Decreased CD127 expression on T Cells in HIV-1-infected adults receiving antiretroviral therapy with or without intermittent IL-2 therapy

BACKGROUND: The interleukin-7 (IL-7)/IL-7 receptor alpha (IL-7Ralpha) system is an important regulator of T-cell homeostasis. We evaluated the IL-7/IL-7Ralpha system in a large cohort of HIV-infected patients, including a subset treated with intermittent IL-2. METHODS: IL-7 serum levels and CD127 (IL-7Ralpha) expression on T cells were evaluated in a cross-sectional study of 36 healthy volunteers, 151 HIV-infected patients, and 83 HIV-infected patients who had received IL-2 therapy. Multivariate regression models were used to determine predictors of CD127 expression. RESULTS: HIV-infected patients had higher IL-7 levels compared with healthy volunteers (P = 0.022) and IL-2-treated patients (P = 0.012). CD127 expression was significantly lower on CD4 and CD8 T cells of HIV-infected patients compared with healthy volunteers (P = 0.008 and P < 0.001, respectively), and CD127 median fluorescence intensity was lowest on CD4 T cells in IL-2-treated patients (P < 0.001 compared with HIV-infected patients). The proportion of naive and effector memory/effector T cells were significant predictors of CD127 expression on T cells. IL-2 immunotherapy led to the expansion of a CD25/CD127-low subset of CD4 T cells. CONCLUSIONS: CD127 expression on T cells remains low in HIV-infected patients despite antiretroviral therapy, reflecting persistent aberration in the subset composition of the T-cell pool.     

Lipodystrophic syndromes and hyperlipidemia in a cohort of HIV-1-infected patients receiving triple combination antiretroviral therapy with a protease inhibitor

OBJECTIVES: To assess the frequency and features of lipodystrophic syndromes in HIV-1-infected patients receiving highly active antiretroviral therapy (HAART) with a protease inhibitor (PI), and examine whether clinical and biologic abnormalities are always associated in these conditions. METHODS: Retrospective-prospective single-center observational study of 175 patients. Comparisons for continuous variables by t-test and paired t-test, and Kaplan-Meier analysis of time to onset of lipodystrophy were performed. RESULTS: In all, 51 patients (29%) had morphologic changes, after a mean HAART duration of 20.0 +/- 6.1 months, and were categorized into pure lipoatrophy (n = 16), mixed syndrome (truncal fat accumulation and face or limb lipoatrophy) (n = 30) or pure truncal fat accumulation (n = 5). Because of the small number, the latter group was not analyzed statistically. No differences were found among patients with lipoatrophy, mixed syndrome, or no lipodystrophy, in terms of gender, CD4 count, and HIV RNA plasma load at time of HAART initiation, nor in response to treatment. Patients with a mixed syndrome were older. Patients with lipoatrophy had longer duration of HIV disease, pre-HAART exposure to nucleoside analog therapy, and HAART. Baseline and pre-HAART fasting triglyceride levels were higher in patients who developed lipoatrophy, whereas weight and fasting cholesterol were higher in patients who developed a mixed syndrome. After 12 and 24 months on HAART, triglycerides and cholesterol rose significantly in all patients, independently of lipodystrophy, whereas these parameters were not increased during nucleoside analog therapy. CONCLUSIONS: Nucleoside analog exposure appears as a risk factor for lipoatrophy. Age and nutritional status (reflected by baseline weight, triglycerides and cholesterol) may influence the evolution to lipoatrophy or a mixed syndrome. Hyperlipidemia is observed in the absence of lipodystrophy and depends on PI exposure.     

Increased body mass index does not alter response to initial highly active antiretroviral therapy in HIV-1-infected patients

BACKGROUND: Body mass index (BMI) can influence drug metabolism, thus affecting efficacy and risk for toxicities. Hypothesizing that persons with an increased BMI and larger volumes of distribution may experience a suboptimal response to highly active antiretroviral therapy (HAART), we evaluated the effect of BMI on virologic and immunologic response in previously ART-naive patients initiating therapy. METHODS: Using data from the HIV Outpatient Study, we analyzed the statistical association of BMI and other selected demographic variables with achieving an undetectable viral load and experiencing a CD4 cell count increase of more than 100 cell/microL after 3 to 9 months of therapy among antiretroviral-naive patients initiating HAART. RESULTS: Among 711 patients included in analysis, 43% had a BMI of more than 25 (overweight-obese). Higher BMI was associated with being female, having black or Hispanic race/ethnicity, being heterosexual, and using injection drugs (all P<0.001). The patients in BMI groups did not differ significantly by baseline CD4 cell count or the duration of the initial HAART regimen. Although median baseline viral loads were significantly lower in obese participants (P=0.008), overweight or obese BMI did not significantly alter the likelihood of achieving an undetectable viral load and a CD4 cell count increase of more than 100 cells/microL compared with normal weight persons. CONCLUSION: A substantial proportion of HIV-infected outpatients in this cohort were overweight or obese. Increased BMI was not associated with decreased virologic and immunologic responses to initial HAART. Responses were equivalent and within expected ranges between normal weight patients, overweight patients, and obese patients at 3 to 9 months of observation.     

IL-2 and IL-10 serum levels in HIV-1-infected patients with or without active antiretroviral therapy

We analyzed IL-2 and IL-10 serum levels in 26 HIV-1-infected patients naive of antiretroviral treatment and in 34 patients receiving highly active antiretroviral therapy (HAART). All patients without treatment were asymptomatic. When they were stratified according to levels of CD4+ T cells, IL-2 levels were significantly increased in patients with > or =200 CD4+/microl and IL-10 levels were significantly increased in patients with <200 CD4+/microl compared to controls. A significant negative correlation was observed between IL10 levels and CD4+ T-cell counts. No correlation was observed between IL-2 and IL-10 levels and viral load due to the wide range of variability in the number of HIV copies/ml present in the different patients. However, IL-2 levels were higher in patients with high viral load than in patients with low viral load. In patients with HAART, IL-2 and IL-10 levels were similar to the control group and no differences were detected respecting CD4+ T cells counts and viral load. Our findings show that the modifications in IL-2 and IL-10 serum levels in HIV-1-infected patients naive of antiretroviral treatment are associated with the progression of immunological damage. Furthermore, they show a dysbalance of type-1/type-2 cytokines with an involvement of type-2 cytokines in later stages of HIV infection. Cytokine dysregulation can be reversed by HAART in the context of immune restoration and viral suppression.