Baiba Berzins

Efficacy of a nucleoside-sparing regimen of darunavir/ritonavir plus raltegravir in treatment-naive HIV-1-infected patients (ACTG A5262).

Objective:To explore darunavir/ritonavir (DRV/r) plus raltegravir (RAL) combination therapy in antiretroviral-naive patients. Design:Phase IIb, single-arm, open-label, multicenter study. Methods:One hundred and twelve antiretroviral-naive, HIV-1-infected patients received DRV/r 800/100 mg once daily and RAL 400 mg twice daily. Primary endpoint was virologic failure by week 24. Virologic failure was defined as confirmed viral load of 1000 copies/ml or more at week 12, or an increase of more than 0.5 log10 copies/ml in viral load from week 4 to 12, or a confirmed viral load of more than 50 copies/ml at or after week 24. Protease and integrase genes were sequenced in patients experiencing virologic failure. Results:Virologic failure rate was 16% [95% confidence interval (CI) 10–24] by week 24 and 26% (95% CI 19–36) by week 48 in an intent-to-treat analysis. Viral load at virologic failure was 51–200 copies/ml in 17/28 failures. Adjusting for age and sex, virologic failure was associated with baseline viral load of more than 100 000 copies/ml [hazard ratio 3.76, 95% CI (1.52–9.31), P = 0.004] and lower CD4 cell count [0.77 per 100 cells/&mgr;l increase (95% CI 0.61–0.98), P = 0.037]. When trough RAL concentrations were included as a time-varying covariate in the analysis, virologic failure remained associated with baseline viral load more than 100 000 copies/ml [hazard ratio = 4.67 (95% CI 1.93–11.25), P < 0.001], whereas RAL level below detection limit in plasma at one or more previous visits was associated with increased hazard [hazard ratio = 3.42 (95% CI 1.41–8.26), P = 0.006]. All five participants with integrase mutations during virologic failure had baseline viral load more than 100 000 copies/ml. Conclusion:DRV/r plus RAL was effective and well tolerated in most patients, but virologic failure and integrase resistance were common, particularly in patients with baseline viral load more than 100 000 copies/ml.

A randomized clinical trial of CPI-1189 for HIV-associated cognitive-motor impairment.

Background: CPI-1189 is a compound with antioxidant properties that blocks tumor necrosis factor-α (TNFα) effects in animal models. It has neuroprotective properties in model systems for HIV-associated neurotoxicity and thus is a candidate for neuroprotective therapy in humans with HIV-associated CNS disease. Objective: To assess the tolerability and safety of CPI-1189 in treating HIV-associated cognitive–motor impairment. Methods: Sixty-four subjects with mild to moderate HIV-associated cognitive–motor impairment were randomized to receive either placebo or 50 or 100 mg daily of CPI-1189 in addition to optimal HIV therapy. Subjects were followed prospectively in a double-masked study for 10 weeks. The primary assessment was tolerability and safety of the compound. Secondary objectives examined neuropsychological and functional change associated with this treatment. Results: The study compound was well tolerated, with 91% of CPI-1189-treated subjects and 76% of placebo-treated subjects completing the trial. Skin rash was seen equally in placebo and active arms, but the only study withdrawals due to skin rash occurred in CPI-1189-treated subjects (n = 2). One subject developed a cataract on drug (100 mg/day). CD4 lymphocyte counts and plasma HIV viral load remained stable in all groups throughout the trial. No significant treatment effects were observed on the change in composite Z-scores for eight neuropsychologic measures (NPZ-8). The Grooved Pegboard Test (nondominant) showed improved performance with CPI-1189 at 100 mg/day (p = 0.01), but no other neuropsychometric or functional measures demonstrated significant improvement. Conclusions: CPI-1189 was well tolerated in HIV subjects with cognitive–motor disorder. This study was not powered to conclusively determine efficacy and showed no consistent treatment-associated improvement in cognitive or functional measures.

Persistent abnormalities in lymphoid tissues of human immunodeficiency virus-infected patients successfully treated with highly active antiretroviral therapy.

Effective highly active antiretroviral therapy (HAART) for human immunodeficiency virus type 1 is associated with virus suppression and immune reconstitution. However, in some patients, this reconstitution is partial or incomplete because CD4(+) cell counts do not increase significantly. This may be due to damage in the microenvironment of lymphoid tissues (LTs), where CD4(+) T cells reside. To test this hypothesis, LT samples were obtained from 23 patients enrolled in a prospective trial that compared 3 different HAART regimens. Analysis of LT architecture and CD4(+) T cells populations revealed abnormalities in 100% of the LT samples, especially in the follicles, with 43% showing absence, 14% showing regression, and 43% showing hyperplasia. CD4(+) T cell populations were abnormal in 16 (89%) of 18 tissue samples, with 7 (39%) of 18 decreased by >50% of normal levels. These data are consistent with the hypothesis that persistent abnormalities in the microenvironment can influence immune reconstitution and document persistent LT abnormalities with HAART not detected by measures of peripheral CD4(+) T cell count.

Change to atazanavir/ritonavir treatment improves lipids but not endothelial function in patients on stable antiretroviral therapy.

Objective:Protease inhibitors and other antiretroviral drugs have been associated with dyslipidemia, endothelial dysfunction, and increased cardiovascular disease risk. The protease inhibitor atazanavir has an advantageous lipid profile; we studied its effects on arterial function and other metabolic and inflammatory cardiovascular disease risk factors. Design:Prospective, randomized, multinational trial in HIV-infected patients receiving stable protease inhibitor-based therapy with plasma HIV RNA less than 500 copies/ml and fasting low-density lipoprotein cholesterol more than 130 mg/dl, or triglycerides more than 200 mg/dl. Methods:Patients were randomized to continue their current protease inhibitor or switch the protease inhibitor to atazanavir and continue ritonavir if given as a protease inhibitor booster for 24 weeks. Brachial artery flow-mediated dilation, lipoproteins, and inflammatory and metabolic markers were measured at baseline, week 12, and week 24. Median changes within (signed rank test) and between (Wilcoxon test) arms were calculated. Results:Twenty-six patients switched to atazanavir (all continued on ritonavir); 24 remained on their protease inhibitor regimen. Median CD4 cell count was 499 cells/μl, total cholesterol 204 mg/dl, low-density lipoprotein cholesterol 122 mg/dl, and triglycerides 244 mg/dl. There were no significant changes in flow-mediated dilation after 12 and 24 weeks. At 24 weeks, significant changes in the atazanavir vs. continued protease inhibitor group were observed for total cholesterol (−25 vs. +1.5 mg/dl, P = 0.009), triglycerides (−58 vs. +3.5 mg/dl, P = 0.013), and nonhigh-density lipoprotein cholesterol (−27 vs. −0.5 mg/dl, P = 0.014). Conclusion:In dyslipidemic individuals with suppressed HIV RNA on stable therapy, changing the protease inhibitor to atazanavir/ritonavir for 24 weeks improved lipids; however, endothelial function, inflammatory, and metabolic markers did not change.

Transient Viremia in HIV-Infected Patients and Use of Plasma Preparation Tubes

Using plasma preparation tubes for the collection and storage of plasma resulted in factitious, low-level human immunodeficiency virus type 1 (HIV-1) viremia among patients receiving highly active antiretroviral therapy who incurred unnecessary additional clinic visits, laboratory testing, and medication changes. We caution clinicians against the routine use of plasma preparation tubes for collection of blood samples for HIV-1 level 1 quantification.

Mitochondrial function, morphology and metabolic parameters improve after switching from stavudine to a tenofovir-containing regimen

OBJECTIVES HIV-associated lipoatrophy has been associated with mitochondrial dysfunction induced by nucleoside reverse transcriptase inhibitor therapy. We hypothesize that lipid profiles and markers of mitochondrial function will improve in HIV-lipoatrophic patients switched to the nucleotide analogue tenofovir. METHODS Ten patients receiving stavudine, lamivudine and lopinavir/ritonavir (Kaletra(R)) for over 6 years were switched from stavudine to tenofovir for 48 weeks. Subcutaneous fat tissue biopsies, fasting metabolic tests, HIV RNA, CD4 cell count and whole body dual energy X-ray absorptiometry (DEXA) scans were obtained at study entry and week 48. Mitochondrial DNA (mtDNA) copies/cell and mitochondrial morphology were assessed in adipose tissue biopsies, mtDNA 8-oxo-deoxyguanine in peripheral blood mononuclear cells, and glutathione (GSH) and F2-isoprostane in plasma. RESULTS There was no change in limb fat mass by DEXA; however, trunk fat mass increased by 18.9% (P = 0.01). Fasting total cholesterol decreased by 33 mg/dL (P = 0.005) and serum glucose decreased by 4 mg/dL (P = 0.039). mtDNA copies/cell increased from 386 to 1537 (P < 0.001). Transmission electron microscopy showed that mitochondrial cristae were lacking or poorly defined at study entry, whereas mitochondrial inner structures were more well defined and outer membranes were intact at 48 weeks. Oxidative damage decreased in 8/10 patients, GSH increased and F2-isoprostane decreased. CONCLUSIONS The results from this study demonstrate that systemic and peripheral fat mitochondria improve in patients switched to tenofovir following long-term exposure to stavudine, while continuing protease inhibitor therapy.

Peripheral and visceral fat changes following a treatment switch to a non-thymidine analogue or a nucleoside-sparing regimen in HIV-infected subjects with peripheral lipoatrophy: results of ACTG A5110

BACKGROUND Switching a thymidine analogue to a non-thymidine analogue or changing to a nucleoside-sparing regimen has been shown to partially reverse peripheral lipoatrophy. The current study evaluated both approaches. METHODS Subjects at 15 AIDS Clinical Trial Group sites receiving thymidine analogue stavudine- or zidovudine-containing regimens with plasma HIV RNA < or =500 copies/mL and lipoatrophy were prospectively randomized to: (i) switch the thymidine analogue to abacavir; (ii) discontinue all antiretrovirals and switch to lopinavir/ritonavir plus nevirapine (LPV/r+NVP); or (iii) delay switching for 24 weeks (ClinicalTrials.gov identifier: NCT00028314). Single-slice computer tomography of mid-thigh and abdominal fat and metabolic and virological/immunological parameters were measured at baseline and weeks 24 and 48. RESULTS Among the 101 patients enrolled, there were significant subcutaneous thigh fat and subcutaneous abdominal tissue (SAT) increases over time and decreases in visceral adipose tissue to total adipose tissue (VAT:TAT) ratios for both interventions, and a decrease in VAT for abacavir. CD4 increased in the LPV/r+NVP arm. LPV/r+NVP had a significantly shorter time to grade 3 or higher toxicity (P = 0.007), but discontinuation rates were similar. Glucose levels did not change, but insulin decreased in the LPV/r+NVP arm. Lipids tended to increase in the LPV/r+NVP arm. CONCLUSIONS Switching stavudine or zidovudine to a non-thymidine analogue or changing to a nucleoside reverse transcriptase inhibitor-sparing regimen is associated with qualitatively similar improvements in thigh fat, SAT and VAT:TAT ratio at 48 weeks. Abacavir also resulted in VAT reductions and LPV/r+NVP resulted in CD4 count increases.

A multinational study of neurological performance in antiretroviral therapy-naïve HIV-1-infected persons in diverse resource-constrained settings

Little is known about how the prevalence and incidence of neurological disease in HIV-infected patients in resource-limited settings. We present an analysis of neurological and neurocognitive function in antiretroviral naïve individuals in multinational resource-limited settings. This prospective multinational cohort study, a substudy of a large international randomized antiretroviral treatment trial, was conducted in seven low- and middle-income countries in sub-Saharan Africa, South America, and Asia. Subjects were HIV-infected and met regional criteria to initiate antiretroviral therapy. Standardized neurological examination and a brief motor-based neuropsychological examination were administered. A total of 860 subjects were studied. Overall 249 (29%) had one or more abnormalities on neurological examinations, but there was a low prevalence of HIV-associated dementia (HAD) and minor neurocognitive disorder (MND). Twenty percent of subjects had evidence of peripheral neuropathy. There were significant differences across countries (p < 0.001) in neuropsychological test performance. In this first multinational study of neurological function in antiretroviral naïve individuals in resource-limited settings, there was a substantial prevalence of peripheral neuropathy and low prevalence of dementia and other CNS diseases. There was significant variation in neurocognitive test performance and neurological examination findings across countries. These may reflect cultural differences, differences in HIV-related and unrelated diseases, and variations in test administration across sites. Longitudinal follow-up after antiretroviral treatment initiation may help to define more broadly the role of HIV in these differences as well as the impact of treatment on performance.

Less Bone Loss With Maraviroc- Versus Tenofovir-Containing Antiretroviral Therapy in the AIDS Clinical Trials Group A5303 Study

BACKGROUND There is a need to prevent or minimize bone loss associated with antiretroviral treatment (ART) initiation. We compared maraviroc (MVC)- to tenofovir disoproxil fumarate (TDF)-containing ART. METHODS This was a double-blind, placebo-controlled trial. ART-naive subjects with human immunodeficiency virus type 1 RNA load (viral load [VL]) >1000 copies/mL and R5 tropism were randomized to MVC 150 mg or TDF 300 mg once daily (1:1), stratified by VL <100 000 or ≥100 000 copies/mL and age <30 or ≥30 years. All subjects received darunavir 800 mg, ritonavir 100 mg, and emtricitabine 200 mg daily. Dual-energy X-ray absorptiometry scanning was done at baseline and week 48. The primary endpoint was percentage change in total hip bone mineral density (BMD) from baseline to week 48 in the as-treated population. RESULTS We enrolled 262 subjects. A total of 259 subjects (130 MVC, 129 TDF) contributed to the analyses (91% male; median age, 33 years; 45% white, 30% black, 22% Hispanic). Baseline median VL was 4.5 log10 copies/mL and CD4 count was 390 cells/µL. The decline in hip BMD (n = 115 for MVC, n = 109 for TDF) at week 48 was less with MVC (median [Q1, Q3] of -1.51% [-2.93%, -0.11%] vs -2.40% [-4.30%, -1.32%] for TDF (P < .001). Lumbar spine BMD decline was also less with MVC (median -0.88% vs -2.35%; P < .001). Similar proportions of subjects in both arms achieved VL ≤50 copies/mL in as-treated and ITT analyses. CONCLUSIONS MVC was associated with less bone loss at the hip and lumbar spine compared with TDF. MVC may be an option to attenuate ART-associated bone loss. CLINICAL TRIALS REGISTRATION NCT01400412.

Associations of T cell activation and inflammatory biomarkers with virological response to darunavir/ritonavir plus raltegravir therapy

OBJECTIVES One of the goals of antiretroviral therapy (ART) is to attenuate HIV-induced systemic immune activation and inflammation. We determined the dynamics of biomarkers of immune activation, microbial translocation and inflammation during initial ART with a nucleos(t)ide-sparing regimen of darunavir/ritonavir plus raltegravir. We also evaluated associations between these biomarkers and the virological response to the regimen. METHODS We determined baseline and week 24 and 48 levels of CD4+ and CD8+ T cell activation (% HLA-DR+/CD38+), interleukin-6 (IL-6), interferon-γ-inducible protein-10 (IP-10), soluble CD14 (sCD14), D-dimer and lipopolysaccharide. Associations between the biomarkers at baseline were assessed using Spearmans rank correlation. The Wilcoxon signed rank test analysed changes from baseline. Comparisons between groups were made using the Wilcoxon rank sum test, and Cox proportional hazards models assessed predictors of virological failure (VF). RESULTS Assays were completed on 107 of 112 subjects after excluding five subjects who had only baseline samples. The subjects included were 94 (88%) men with a median age of 37 years, a median baseline CD4 count of 261.5 cells/mm(3) and a median baseline viral load (VL) of 75 876 copies/mL. Subjects with a baseline VL >100 000 copies/mL had higher baseline T cell activation, IL-6, IP-10, sCD14 and D-dimer. These biomarkers declined during treatment (P < 0.05). Although subjects who experienced VF had higher baseline CD4+ T cell activation (P = 0.035), only baseline VL independently predicted VF (hazard ratio for >100 000 versus ≤100 000 copies/mL was 4.5-5.6, P ≤ 0.002). CONCLUSIONS Darunavir/ritonavir plus raltegravir attenuated immune activation, inflammation and microbial translocation. T cell activation remained higher in subjects with VF than those without. Baseline VL >100 000 copies/mL remained the primary driver of VF.