bluuebunny/crossref_metadata_2025 huggingface dataset:
Nevirapine vs efavirenz in virologically supressed patients: differences in lipoprotein subclasses and inflammatory biomarkers
Authors: Estrada V , Gómez‐Garre M , Santos J , Gutiérrez F , Labarga P , Palacios R , Masiá M , López‐Vázquez M , Isernia V , Vispo E , Fernández‐Cruz A
Published: November 2012

Background

The interaction between lipid disturbances and inflammatory markers is not well known in patients on antiretroviral therapy (ART). As nevirapine (NVP) is associated with a better lipid profile than efavirenz (EFV), we investigated the relationships between lipid profiles, lipoprotein subclasses and inflammatory biomarkers in patients with prolonged viral suppression with either NVP or EFV and no obvious clinical inflammation.

Methods

122 clinically stable HIV‐infected patients with HIV‐1 RNA <20 copies longer than 6 months on NNRTI therapy were studied. 72 (59%) were on EFV and 50 (41%) on NVP. Any potentially inflammatory co‐morbid diseases (concurrent viral hepatitis, diabetes, hypertension, chronic liver or renal diseases), or statin treatment, were exclusion criteria. Inflammatory biomarkers included hsCRP, LpPLA2, sCD40L, IL‐6, IL‐8, t‐PA, MCP‐1, p‐selectin and VCAM‐1. Lipoprotein subclass measures (VLDL, LDL, IDL and HDL particle number and size) were obtained by the use of proton nuclear magnetic resonance spectroscopy.

Results

82% were male; median age 45 years. Median CD4 count 550/μL (IQR 324). Median time since HIV diagnosis 96 months (IQR 102) and accumulated time on ART 50 months (IQR 101). Patients on NVP had higher time since HIV diagnosis (126.9 [66.7] vs. 91.3 [6.6] months, p=0.008) a prolonged time on ART (89.6 [54.6] vs. 62.3 [52.2] months, p=0.01) and were older (47.7 vs. 40.7 years, p=0.001) than those on EFV. NVP‐treated patients presented increased HDL‐c (55.8 [16] vs. 48.8 [10.7] mg/dL, p=0.007) and apoA1 levels (153.4 [31.9] vs. 141.5 [20.5] mg/dL, p=0.02), and reduced apoB/apoA1 ratio (0.68 [0.1] vs 0.61 [0.1], p=0.003) than EFV‐treated patients. No differences in inflammatory markers or lipoprotein subclasses were found between NVP and EFV. In patients with extreme lipid values (less favorable: 75th percentiles of LDL, small/dense LDLp and small HDLp, or more favorable: HDL p75 and apoB/apoA1 ratio p25), no consistent differences in inflammatory biomarkers were found.

Conclusions

Patients with prolonged viral suppression on NVP present significantly higher HDL and apoA1 levels and reduced apoB/apoA1 ratios than those on EFV, but no differences were found in lipoprotein particles nor inflammatory biomarkers. Relationships between lipid parameters and inflammatory biomarkers in NNRTI‐treated patients are complex and do not show a linear relationship in this study.
Too old too soon? Heart age compared with actual age in HIV‐positive individuals
Authors: Davies T , May M , Gompels M
Published: November 2012

Absolute risk of cardiovascular disease (CVD) may be calculated using the Framingham equation. Since risk increases with age, a useful measure of excess risk adjusted for age is ‘heart age’, the age of a reference person with the same estimated risk, but based on ideal values of risk factors defined as non‐smoker, non‐diabetic, untreated SBP of 125 mmHg, total cholesterol of 180 mg/dL and HDL cholesterol of 45 mg/dL [1]. Patients attended the Bristol HIV Cohort between 2008–11. HDL and total cholesterol, SBP, CD4 count and viral load measured within a period of 6 months were available for 749/1013 (74%) patients. The median age was 42 years, 33% were female and 82% were on ART. We calculated heart‐age deviation (heart age‐actual age) by sex and age group. Smoking status was not available and therefore we did all calculations twice assuming all a) non‐smokers b) smokers. We used fractional polynomials to model change in heart‐age deviation with actual age. We used mutually adjusted multivariable linear regression to determine whether sex, age, CD4, viral load, treatment status and year of starting ART were associated with heart‐age deviation. The mean heart‐age deviation in males was 3.4 years (females 1.7) for non‐smokers, and 14.8 years (females 12.5) for smokers. The figure shows that deviation increased with age; eg for male smokers it was 9.7, 15.0, 20.4 and 23.3 years at ages 16–39, 40–49, 50–59 and ≥60 years respectively. On average a 45‐year‐old male smoker had a heart age of 60 years. Compared with males, deviation was lower in younger females, but became higher after age 48 years. Compared with treated patients (assuming non‐smoker) with viral suppression, untreated patients had similar heart age (0.33 [95% CI 1.67, 2.33]) and treated patients with unsuppressed viral replication had higher heart age (3.01 [0.61, 5.42]). Higher CD4 count was associated with higher heart age: those with CD4 between 500–750 and >750 (v.<500) had an increase of 2.25 (0.61, 3.89) and 4.39 (2.41, 6.36) years respectively.

HIV+ve individuals have a considerably increased risk of CVD compared with the ideal reference values, although we do not know if estimated risk translates to CVD events. Heart‐age deviation increases with age and is greater for smokers. Deviation increases more sharply in women, possibly due to lower CVD risk at younger ages or to increased risk postmenopause. Heart age could be a useful communication tool in attempts to reduce CVD risk in HIV+ve individuals.

Heart age deviation by actual age by sex and smoking status (95% CI shown shaded)

image
Carotid intima media thickness changes, endothelial activation and inflammatory markers in advanced naïve HIV patients starting antiretroviral therapy
Authors: Bellacosa C , Maggi P , Leone A , Altizio S , Ladisa N , Uglietti A , Zanaboni D , Maserati R , Viglietti R , Chirianni A , Abbrescia N , De Rosa A , Sofia S , Celesia M , Angarano G
Published: November 2012

PREVALEAT II (PREmature VAscular LEsions and Antiretroviral Therapy II) is an ongoing multicenter, longitudinal cohort study aimed to the evaluation of cardiovascular risk in advanced naïve HIV‐infected patients starting their first HAART. It includes all consecutive naïve pts with <200 CD4 cells/ml who start any PI/r‐based or NNRTI‐based+2 NRTIs regimen. Pts are subjected to epi‐aortic vessels ultrasonography, brachial artery flow mediated dilation (FMD), endothelial cytokine inflammatory markers value at time 0 and after 3, 6 and 12 months. Data about independent risk factors for CV disease are taken at time 0. Viral load, CD4+ counts, serum lipid values, glucose, body mass index (BMI) are recorded at every control. We enrolled 47 pts: 76,6% males, 87,2% caucasians, 40,4% cigarette smokers, 10,6% HCV co‐infected, 6,4% had lipodystrophy. 29,8% homosexuals, 12,8% drug addicts, 51,1% heterosexuals. At baseline, 23,4% of pts had pathologic BMI, 31,91% had a epi‐aortic vessels lesion (IMT and/or plaque), 27,65% had pathologic FMD; ICAM1 was pathologic in 46,80%, VCAM1 in 53,19%, IL‐6 in 51,06%, D‐dimers in 29,79%, hsCRP in 23,40%. 27 pts completed stage T1 of the study (after 3 months); percentages and significance level of variations are the following: 44,44% had a lesion of the epi‐aortic vessels (p=0,28), 48,14% had a pathologic FMD (p=0,08), ICAM1 was pathologic in 59,26% (p=0,30), VCAM1 in 70,37% (p=0,15), IL‐6 in 74,07% (p=0,05), D‐dimers in 14,81% (p=0,12), hsCRP in 25,92% (p=0,80). 27 pts completed stage T2 of the study (6 months). Percentages and significance level of variations in regard of baseline are the following: 51,85% had a epi‐aortic vessels lesion (p=0,462); 25,92% had pathologic FMD (p=0,37). 10 pts completed stage T3 of the study (12 months): 60% had a epi‐aortic vessels lesion (p=0,07); 40% had pathologic FMD (p=0,49). No significant change has been showed in the trend of variation of inflammatory cytokines at T2 and T3. Our data, at baseline, evidence that advanced naïve pts show a relevant deterioration of CV conditions in terms of US data, FMD and cytokine markers. At T1, US and FMD seem to further worsen; cytokines, except D‐dimers, show a worsening trend, too. At T1 and T2, prevalence of vessel lesion and pathologic FMD is yet higher, with a p value closer to significance level. Further data deriving from the follow‐up of missing pts are warranted to better understand the evolution of the CV risk profile in this setting of pts.
Role of maraviroc in a dyslipidemic murine model of atherosclerosis RTV‐induced
Authors: Cipriani S , Mencarelli A , Francisci D , Renga B , Schiaroli E , D'Amore C , Fiorucci S , Baldelli F
Published: November 2012

Purpose

Chemokines and their receptors play a crucial role in the development of atherosclerosis. CCR5 is considered to be crucial to monocyte recruitment during development of atherosclerosis. CCR5, known as a co‐receptor of HIV‐1, is the target of the approved CCR5 antagonist maraviroc (MVC). Therefore we investigated whether MVC reduces inflammation and atherosclerosis in a rodent model of dyslipidemia (ApoE‐/‐mice) treated or not with Ritonavir (RTV).

Methods

Two‐month‐old mice (8 per group): wild type, ApoE‐/‐ plus vehicle; ApoE‐/‐ plus RTV; ApoE‐/‐ plus RTV in combination with MVC. Nine‐month‐old mice (13 per group): wild type; Apo E‐/‐ + vehicle; and Apo E‐/‐ + MVC. Animals were sacrificed after 3 months treatments and plasma, aortas and epididymal fat were collected. Areas of aortas plaque were measured. Immunohistochemistry was performed to evaluate macrophages infiltration, and protein levels of cytokines/chemokines (i.e. ICAM, PAI, VCAM, IL‐10, IL‐17, MCP1, Rantes, TNFα, INFγ) were evaluated in aorta lysates.

Summary of results

RTV enhances the plaque areas percentage in two month old ApoE‐/‐ mice and is significantly reduced by MVC. The ritonavir‐enhanced Mac3 expression on plaques is also reduced by MVC. Treatment with MVC lowers aortic concentration of cytokines/chemokines and plasmatic level of CRP that are increased by RTV. Ritonavir, enhancing mRNA expression of IL‐6, Rantes and Mip1α, induces lipoatrophy in epididymal fat; MVC revertes this lipoatrophy and reduces mRNA levels of these cytokines‐chemokines. Moreover, in ApoE‐/‐ mice 9 months old, MVC significantly reduces the percentage of plaque areas (from 16.6±3.35% to 7.13±1.44%) (en‐face coloration), lowers aortic MAC3 staining and reduces the aortic concentration of cytokines/chemokines.

Conclusions

In a dyslipidemic rodent model the CCR5 inhibitor Maraviroc significantly reduces the percentage of aortic plaque areas, aortic inflammation and lipoatrophy of the epididymal fat. Therefore, the current use of CCR5 antagonists to treat HIV infection, a condition associated with an increased occurrence of cardiovascular disease, should also be exploited to determine any beneficial cardiovascular effects [1,2].
Are we PREPared? Quality of information available to patients in the UK about PREP on the internet
Authors: Duncan S , Duncan C
Published: November 2012

Professional bodies in the UK (BASHH/BHIVA) do not currently recommended pre‐exposure prophylaxis (PREP) to prevent HIV aquisition for men who have sex with men (MSM) [1]. Conversely, although Federal Drug Administration approval is awaited, the Centers for Disease Control (CDC) have issued clinicians in the USA with interim guidance to facilitate PREP prescriptions [2]. Increasingly patients search the internet for information on HIV treatment, but disparate international policy can lead to confusing patient messages. This study was conducted to systematically assess the quality of internet information available to patients in the UK about PREP. More than 90% of internet searches in the UK are performed using ‘Google.co.uk’ and ‘Bing’ [3]. Using pre‐specified criteria, we reviewed the first 100 hits retrieved from each search engine when the following searches were performed: [“HIV pre‐exposure prophylaxis”]; [“HIV PREP”]; [“HIV PREP guidelines”]; [“HIV PREP guidelines UK”]; [“truvada prophylaxis HIV”]. Of 172 unique websites identified, 124 websites were active at the time of the review (July 2012). 33 websites were links to academic journals including commentaries and clinical trials, not intended to specifically provide patient information; 5 were internet portals directing users to alternative sites and 10 websites contained no information about PREP. Of the remaining 76 websites, 28 were written by medical professionals and 48 were written by journalists, where 7/48 (15%) were individual blogs. 64/76 (84%) contained a definition of PREP; 63/76 (83%) discussed the rationale and 58/76 (76%) reported efficacy data. Advantages and disadvantages of PREP were presented in 56/76 (74%) and 41/76 (54%) of websites respectively. Only 21/76 (28%) of sites referenced existing national guidelines (CDC/BASHH). A minority of sites described the current clinical practice in the UK (7/76, 9%) with an even smaller number presenting the contrast in clinical stance between the CDC and BASHH/BHIVA (3/76, 4%). The use of PREP is evolving, and the internet is an important patient resource. However, current clinical practice in the UK is seldom described in accessible websites. Avoiding ad hoc and unsupervised use of PREP is crucial to prevent future drug resistance and risky sexual behaviour. More should be done to engage at‐risk groups and ensure patients in the UK have access to comprehensive information including the current UK PREP professional guidance.
2011 UK PEPSE guidelines: new incentive to document HIV‐1 serum viral load of patients’ HIV positive sexual partners
Authors: Duncan S , Pease E , Morgan E , Bennett A , Morgan C , Sherrard J
Published: November 2012

The 2011 UK guidelines for the prescription of Post‐Exposure Prophylaxis for the Prevention of HIV infection following Sexual Exposure (PEPSE) take account of the reduction in the risk of HIV transmission from an HIV‐positive individual who has an undetectable serum HIV‐1 viral load as a result of combination antiretroviral therapy (cART) [1]. Prescription of PEPSE is no longer routinely recommended for individuals who have had sex with a partner who is HIV‐positive and is known to have an undetectable serum HIV‐1 viral load on cART, unless unprotected receptive anal sex is reported. In this study we assessed how the application of the new UK PEPSE guidelines would alter PEPSE prescription in our region. We performed a retrospective case note‐review of all PEPSE prescriptions occurring between the 1st of January 2011 and the 31st of December 2011 in 4 sexual health clinics in the Oxford deanery (Oxford, Banbury, Reading and Slough). 91/ 96 PEPSE prescriptions were available for review. The mean age of each PEPSE recipient was 30.3 years; 71/91 (78%) of recipients were male, of whom 54/71 (76%) were men who have sex with men (MSM). 63/91 (69%) of PEPSE recipients were of white UK ethnicity. In 32/91 (35%) of cases, the patient reported having sex with a partner was known to be HIV‐positive. Of these, 10/32 (31%) reported that their partner was taking antiretroviral therapy, and 4/10 (40%) of this group reported that their partner had an undetectable serum HIV‐1 viral load. Thus of 91 PEPSE prescriptions, 4 (4%) occurred in patients reporting sex with HIV‐positive partners who were taking antiretroviral therapy and had an undetectable HIV‐1 serum viral load: receptive anal sex was reported in 1 case, and vaginal sex in the remaining 3 cases. Despite a significant change in the UK PEPSE guidelines, in only 3/91 cases in which PEPSE was previously given would prescription no longer be recommended. 32/91 patients reported sex with an HIV‐positive partner, and the HIV‐1 viral load was either unknown or not documented in the majority of cases. It may not be possible to corroborate a patient's report of their partner's HIV‐1 viral load in all cases; thus PEPSE will still be required. However, the new PEPSE guidelines increase the incentive for all clinicians to actively seek and accurately document the HIV‐1 viral load of patients' HIV‐positive sexual partners.
HIV‐1 primary drug resistance mutations in antiretroviral therapy‐naïve patients in Istanbul, Turkey
Authors: Sayan M , Aydin O , Mete B , Uzun N , Karaosmanoglu H , Gunduz A , Tabak F
Published: November 2012

According to the official information of Turkish Ministry of Health of HIV/AIDS surveillance data, in the period 1985 to the end of 2011, there are 4826 HIV‐1 infected cases in Turkey. However, there is no data available on the antiretroviral (ART) drug resistance. The objective of this study was to determine primary drug resistance in HIV‐1 infections in newly diagnosed, ART‐naïve Turkish patients in Istanbul, Turkey. The study was carried out between June 2009 and June 2012 and 59 HIV‐1‐infected patients were included (gender; 52 male/7 female, age, median years (range); 37.9 (20–57), CD4+ T‐cell count, median mm3 (range); 280 (3–813), HIV‐RNA load, median IU/ml (range); 4.1 + E5 (2.6 + E3–2.9 + E6)). For HIV‐1 subtyping most widely known algorithm; the HIVdb‐Stanford University genotypic resistance interpretation algorithm has been used. According to population‐based sequencing of the reverse transcriptase and protease genes of HIV‐1, the patients had pre‐existing primary ART drug resistance mutations and were related to NRTIs (M41L, D67N, T215D, T215E, T215S), NNRTIs (V179D) and PIs (I54V, V82A). The prevalence of overall primary ART drug resistance were 11.8% (7/59) in Turkish patients and according to NRTIs, NNRTIs and PIs drug groups were 10% (6/59), 1.7% (1/59) and 1.7% (1/59), respectively (in one patient has been either NRTIs and PIs resistance detected). The high prevalence of HIV‐1 primary drug resistance in ART‐naïve patients suggested the resistance testing must be an integral part of the management of HIV infection and the choice of first‐line therapy regime should be guided by genotypic resistance interpretation in Turkey.
Findings from the WHO/PAHO early warning indicators of HIV drug resistance monitoring system performed in Argentina
Authors: Bissio E , Balleri C , Falistocco C , Curras V , Vila M
Published: November 2012

Background

In the last years, WHO developed a Global Strategy for HIV Drug Resistance Prevention and Assessment using a public health approach. This strategy supports optimal functioning of treatment programs to minimize emergence of preventable HIV drug resistance and to maintain effectiveness of first‐ and second‐line ART regimens. Since 2011, Argentina has been monitoring some of the indicators of this strategy (called early warning indicators [EWIs]). The aim of this study was to analyze the outcomes measured during the mentioned year.

Methods

Based on the availability of information in the hospitals’ pharmacies, where the data collection took place, and on the relevance for Argentina, some of the EWIs proposed by WHO were selected and adapted. The information is being collected since beginning of 2011, and a first analysis was performed at the end of that year. Since this was a pilot phase, 6 representative hospitals’ pharmacies participated.

Results

Data are available for 4 of the sites. The data produced the following indicators: EWI 1a: Percentage of adult patients initiating ART who are prescribed a non‐recommended first‐line ART regimen (goal 0%). Site A: 22.5%; Site B: 11.1%; Site C: 0%; Site D: 2.7%. EWI 1b: Percentage of adult patients initiating ART who withdraw a non‐recommended first‐line ART regimen (goal 0%). Site A: 22.5%; Site B: 25.8%; Site C: 15.5%; Site D: 16.1%. EWI 2: Percentage of patients lost to follow‐up 12 months after ART initiation (goal less than 20%): Site A: 41.6%; Site B: 9.3%; Site C: 22.2%; Site D: 0%. EWI 4: percentage of patients who picked up prescribed ARV drugs on time (goal:>90%): Site A: 39.1%; Site B: 72.4%; Site C: 44.5%; Site D: N/D

Conclusions

There is a high proportion of patients in Argentina which are prescribed non‐recommended regimens, and a higher proportion withdraw these regimens from pharmacies: 75% of sites do NOT reach the goal of EWI 1a; 100% do NOT reach the goal for EWI 1b. There is also a high proportion of patients lost to follow up during the first year after treatment initiation: 50% of sites reach the goal of EWI 2. A very high proportion of patients do NOT pick‐up ART on time: none of the sites reach EWI 4 goal. The use of these indicators allowed us to visualize that there is a high proportion of patients that would be nonadherent. With these data the Directorate of AIDS will improve efforts to know better the situation, understand the causes and implement strategies to increase adherence.
Community viral load in patients harboring HIV drug‐resistant strains and new cases of TDR in Northern Greece‐a retrospective cohort study
Authors: Pilalas D , Metallidis S , Skoura L , Haidich A , Chrysanthidis T , Tsachouridou O , Papadimitriou E , Kollaras P , Malisiovas N , Nikolaidis P
Published: November 2012

Purpose of the study

Recent studies suggest an association between community viral load and new diagnoses of HIV infection. Aim of our study was to explore a potential association between the pattern of new cases of transmitted drug resistance (TDR) in Northern Greece and the community viral load in the subset of patients who harbored HIV drug‐resistant strains during 2000–2007.

Methods

Data on viral load measurements and genotypic HIV drug resistance were extracted from the respective databases of the Infectious Diseases Division of the AHEPA University Hospital and the National Reference Laboratory for AIDS of Northern Greece which provide healthcare services free of charge for the majority of HIV‐positive individuals in Northern Greece. Patients who had undergone at least once genotypic resistance testing were included in the study. The 2009 SDRM list was used to categorize patients in subsets with regard to genotypic resistance results. Community viral load (CVL) was calculated as follows: The per‐year weighed mean viral load was calculated for each individual patient and the median value of this set was defined as the community viral load. Poisson log‐linear regression models with robust estimators were employed to examine the association between new cases of TDR and CVL of patients with genotypic drug resistance, patient number and year.

Results

512 patients out of 701 ever recorded had undergone genotypic HIV drug resistance testing at least once (73%). Overall, 202 out of 512 patients (39.4%) were identified with at least one resistance mutation (106/512 NNRTI, 175/512 NRTI, 104/512 PI). Poisson log‐linear multivariate models correlated new cases of TDR with either log CVL (p = 0.068, RR: 7.59, 95% CI: 0.863–66.71) and year (p = 0.013, RR: 2.19, 95% CI: 1.18–4.08) or log CVL (p = 0.030, RR: 5.08, 95% CI: 1.17–22.06) and number of patients with drug resistance (p = 0.0001, RR: 1.03, 95% CI: 1.01–1.06).

Conclusions

Our results indicate that the community viral load of patients with HIV drug resistance may affect the number of new patients with TDR, underline the need for successful viral suppression in patients with resistant HIV strains from a public health standpoint and, should they be supported by further studies, suggest that community viral load could be used as a biomarker for TDR surveillance.
Cholecalciferol supplementation, vitamin D status and T‐cell immune phenotype in HIV‐infected children: a randomised controlled trial
Authors: Vigano A , Giacomet V , Manfredini V , Bedogni G , Mora S , Cerini C , Borelli M , Trabattoni D , Zuccotti G
Published: November 2012

Purpose of the study

Besides its known effects on bone metabolism, vitamin D may regulate immune function. We performed a randomized controlled trial (RCT) to test whether cholecalciferol supplementation can improve vitamin D status and modulate immune responses in HIV‐infected children and youth.

Methods

Caucasian vertically HIV‐infected patients (aged 8 to 26 years) with vitamin D deficiency and normal parathormone (PTH) levels were randomized into an experimental (n=25) and control (n=25) group to receive 100,000 IU of oral cholecalciferol every 3 months for a total of 4 doses, or placebo. A pre‐randomization period (−3 months) was also taken into account to better model within‐individual variability. Mixed linear regression models were used to evaluate the between‐group changes in the outcomes of interest. The analysis was intention to treat.

Summary of results

47 subjects completed the RCT. Cholecalciferol supplementation produced an early decrease in PTH levels (3 months) and a later concomitant increase in 25(OH)D and 1,25(OH)2D levels (6 months), both persisting up to 12 months.

The supplementation had no effect on CD4+T‐cell numbers or percentage while was associated with a decreased loge Th1, an increased loge Th2 (*p<0.05), an increased loge Treg (**p<0.01), and and a decreased loge Th17:Treg(*p<0.05).

Loge VDR
Loge Th1
Loge Th2
Loge (Th1:Th2)
Loge Th17
Loge Treg
Loge (Th17:Treg)

Month 3
0.5 (−0.1 to 1.2)
−1.6 (−3.6 to 0.5)
−0.1 (−0.6 to 0.5)
−1.4 (−3.5 to 0.7)
−1.5 (−3.2 to 0.2)
0.6 (−0.3 to 1.6)
−2.5 (−4.5 to−0.4)*

Month 12
0.7 (−3.0 to 1.7)
−0.7 (−2.5 to 1.1)
1.1* (0.02 to 2.1)
−1.6 (−3.7 to 0.5)
0.3 (−1.2 to 1.8)
1.7** (0.6 to 2.7)
−1.3 (−3.3 to 0.7)

Conclusions

In our cohort, supplementation with oral cholecalciferol was effective in increasing serum 25(OH)D and 1–25(OH)2D while decreasing serum PTH levels, had no effect on CD4+T‐cell count, but was associated with T‐cell phenotype changes mainly favoring Tregulatory subset.
VERxVE 144 week results: nevirapine extended‐release (NVP XR) QD versus NVP immediate‐release (IR) BID with FTC/TDF in treatment‐naïve HIV‐1 patients
Authors: Brinson C , Bogner J , Nelson M , Podzamczer D , Quinson A , Drulak M , Gathe J
Published: November 2012

Background

Here we report 96‐ and 144‐week follow‐up data from VERxVE, which demonstrated that NVP XR (400 mg QD) was non‐inferior to NVP IR (200 mg BID), each on a backbone of emtricitabine/tenofovir at 48 weeks.

Methods

VERxVE was a double‐blind, double‐dummy, non‐inferiority study in adults with screening viral‐load (VL) >1000 copies/mL and CD4+ cell count <400 cells/mm3 (males) and <250 cells/mm3 (females). Randomization was stratified by baseline VL (copies/mL), ≤100,000 or >100,000. Primary endpoint was confirmed virologic response (<50 copies/mL) at Week 48. Cochran's statistic incorporating baseline‐VL strata tested non‐inferiority of XR efficacy to IR. Secondary endpoints included 144‐week sustained virologic response and safety.

Results

1011 patients were randomized and treated; 736 (NVP XR: 378, NVP IR: 358) completed 144 weeks. Virologic response was 63.6% for NVP XR and 58.5% for NVP IR (adjusted difference of 4.8% [95% CI: −1.1%, 10.8%] favoring NVP XR). No significant differences were seen in changes in CD4+ T cell counts from baseline, virologic failures, and total discontinuation rates between treatment arms regardless of demographic or baseline characteristics.

48 Weeks
96 Weeks
144 Weeks

NVP IR 200 mg BID
NVP XR 400 mg QD
NVP IR 200 mg BID
NVP XR 400 mg QD
NVP IR 200 mg BID
NVP XR 400 mg QD

% Virologic response
75.9
81.0
66.6
69.3
58.5
63.6

Change from baseline in CD4+ Count (cells/mm3)
207
213
257
275
286
317

Virologic failures (%)
5.9
3.2
10.7
11.1
15.8
15.1

Discontinuation rate (%)
19.2
16.6
26.1
23.6
29.2
25.1

Discontinuations due to AEs
8.3
6.3
9.5
8.3
10.7
8.5

Conclusions

NVP XR continued to demonstrate non‐inferior virologic efficacy to NVP IR in prior treatment‐naïve HIV infected patients out to week 144. NVP XR continued to be well‐tolerated with a safety profile similar to NVP IR.
Low plasma zinc level and response to zinc supplement in HIV‐infected patients who have immunological discordance after antiretroviral therapy
Authors: Asdamongkol N , Phanachet P , Sungkanuparph S
Published: November 2012

Purpose of the study

Immunological discordance in HIV‐infected patients is associated with the higher risk of mortality and disease progression. Zinc is an essential micronutrient for immune function. We aimed to determine plasma zinc level and immunological response after zinc supplementation in HIV‐infected patients with immunological discordance after antiretroviral therapy (ART).

Methods

A pilot study of 2 phases including a cross‐sectional study to determine plasma zinc level in patients with immunological discordance and a prospective, randomized, open‐label, placebo‐controlled trial was conducted in HIV‐infected patients with immunological discordance in a medical‐school hospital. Immunological discordance was defined as patients who received ART, had complete virological response (HIV RNA<40 copies/ml), and had immunological response with CD4 cell count<200 cell/mm3 and increased less than 30% from baseline after ART with undetectable HIV RNA for at least 6 months. Plasma zinc level was measured and stratified into low (<75 µg/dL) and normal plasma zinc level. Patients were randomly assigned to receive zinc or placebo supplementation for 6 months. CD4 cell count was monitored every 3 months.

Summary of results

Of 31 patients, median (IQR) plasma zinc level was 76 (66–88) µg/dL (IQR) and 12 (38.7%) patients had low plasma zinc level. Five of 12 patients with low plasma zinc level and 8 of 19 patients with normal plasma zinc level were randomized to receive zinc supplementation. Median (IQR) change of plasma zinc level after zinc supplementation in patients with low and normal plasma zinc level were 29 (−2–50) and−8 (−17–10) µg/dL, respectively. Significant increase of CD4 cell count after zinc supplementation was observed in patients with low plasma zinc level. Median (IQR) CD4 cell count at baseline and after zinc supplementation were 176 (161–200) and 250 (192–262) cells/mm3. The effect of zinc supplementation compared to placebo on the rising of CD4 cell count was not significantly different in both patients with low and normal plasma zinc level.

Conclusions

Low plasma zinc level is observed over one‐third of patients with immunological discordance. Zinc supplementation increases plasma zinc level and CD4 cell count in patients with low zinc level but the effect was not significant different from placebo. Further large‐scale study to determine long‐term benefit of zinc supplementation in patients with immunological discordance is needed.
Etravirine in protease inhibitor‐free antiretroviral combination therapies
Authors: Schuelter E , Luebke N , Jensen B , Zazzi M , Sönnerborg A , Lengauer T , Incardona F , Camacho R , Schmit J , Clotet B , Kaiser R , Pironti A
Published: November 2012

Etravirine (ETR) is a next generation non‐nucleoside reverse transcriptase inhibitor (NNRTI). The studies for ETR EMA approval were almost exclusively performed together with the protease inhibitor (PI) darunavir. However the fact that ETR can be active against NNRTI‐pretreated HIV variants and that it is well tolerated suggests its application in PI‐free antiretroviral combination therapies. Although approved only for PI‐containing therapies, a number of ETR treatments without PIs are performed currently. To evaluate the performance of ETR in PI‐free regimens, we analyzed the EURESIST database. We observed a total of 70 therapy switches to a PI‐free, ETR containing antiretroviral combination with detectable baseline viral load. 50/70 switches were in male patients and 20/70 in females. The median of previous treatments was 10. The following combinations were detected in the EURESIST database: ETR+MVC+RAL (20.0%); ETR+FTC+TDF (18.6%); 3TC+ETR+RAL (7.1%); 3TC+ABC+ETR (5.7%); other combinations (31.4%). A switch was defined as successful when either ≤50 copies/mL or a decline of the viral load of 2 log10, both at week 24 (range 18–30) were achieved. The overall success rate (SR) was 77% (54/70), and for the different combinations: ETR+MVC+RAL=78.6% (11/14); ETR+FTC+TDF=92.3% (12/13); 3TC+ETR+RAL =80.0% (4/5), 3TC+ABC+ETR=100% (SR 4/4); and for other combinations=67.6% (23/34). These SR values are comparable to those for other therapy combinations in such pretreated patients.
A phase 4, single‐arm, open‐label, pilot study of maraviroc, raltegravir and darunavir/r in HIV‐1 adults with triple class failure: TERCETO study
Authors: Patterson P , Magneres C , Sued O , Fink V , Figueroa M , Cesar C , Gun A , Cahn P , Krolewiecki A
Published: November 2012

The purpose of this phase 4, single‐arm, open‐label study was to evaluate the safety, tolerability, efficacy, antiviral and immunological activity of maraviroc (MVC) in combination with raltegravir (RGV) and darunavir/r (DRV/r) in adult HIV‐1 infected patients (pts) with limited treatment options. HIV‐1 pts with documented virologic triple class failure or multi‐drug class resistance defined as the presence of Q151 complex, 69 insertion complex and/or≥3 TAMs for NRTIs and K103N, G190S+Y181C or Y188L mutants for NNRTIs and≥3 RAMs (L10F/I/R/V; M46I/L; I54V/M/L; V82A/F/T/S; I84V; L90M) for protease inhibitors (PIs) were offered a triple drug regimen consisting of MVC 150 mg BID, RGV 400 mg BID and DRV/r 600/100 mg BID. Safety, lipid profile and virologic efficacy were evaluated at week 4, 12, 24, 36 and 48. Between January 2010 and March 2012, 27 pts were enrolled. Screening failure rate was 52% due to undetectable viral load (pVL) or non R5 tropism type (Trofile™). Despite being heavily pre‐treated pts, only 26% had negative tropism test at SCR. Baseline characteristics of 13 included pts were: 77% male, median age 43 years (IQR: 40.1–48.6), 38% had a prior AIDS‐defining condition. Median BSL pVL was 23,350 cps/mL (4.4 log10) (IQR: 11,236–55,785) and median CD4 was 222 cells/mm3 (IQR: 179–318). Median time on NRTIs, NNRTIs and PIs were 10.7 (8.6–13.7), 1.7 (1.3–7.6) and 5.4 (4.7–10) years respectively. Pts had received a median of 2 PIs (IQR: 2–3). 8/13 pts showed thymidine analogue‐associated mutations (TAMs), and≥2 were present in 5/13. Detectable NNRTI resistance‐associated mutations (RAMs) were present in 10/13 patients. 9/13 had≥4 primary PI RAMs. At 48 weeks, 2 pts had discontinued therapy (OIs related death (cryptococcal meningitis)=1, withdrawn from the study on W36 due to blips despite not achieving criteria for virologic failure=1) and the remaining pts (11/13) achieved undetectable pVL and increased CD4 in 133 cell/mm3 from BSL (IQR: 81–174.5). Median total cholesterol levels increased from 162 mg/dL (IQR: 135‐188) to 215 mg/dL (IQR: 182–237) between BSL/W48; median change in cholesterol levels: 40 mg/dL (IQR: 6.5‐66). Salvage therapy including MVC, RGV and DRV/r achieved sustained reductions in pVL (<50 copies/mL) through 48 weeks of therapy in this pilot study with no treatment limiting toxicity.

Acknowledgements

TERCETO study was sponsored through an investigator‐initiated research (IIR) grant from Pfizer Inc. Merck provided raltegravir.
HIV‐infected patients show functionally defective high‐density lipoprotein (HDL) paralleled with changes in HDL‐associated proteins
Authors: Estrada V , Gómez‐Garre M , Ortega‐Hernandez A , Muñoz‐Pacheco P , Serrano‐Vilar S , Sainz‐Costa T , Carranza M , Rodrigo M , Fernández‐Cruz A
Published: November 2012

Purpose of the study

Epidemiological studies have consistently demonstrated an inverse association between plasma HDL concentrations and cardiovascular risk. Although this cardioprotective role has been mainly attributed to its role in promoting cellular cholesterol efflux, there is an emerging interest in the anti‐inflammatory and antioxidant properties of HDL. The aim of the study is to investigate the anti‐inflammatory properties of HDL isolated from HIV‐infected patients.

Methods

Cross‐sectional study of 113 HIV‐infected patients and 70 non‐infected control subjects without evident CVD. From each subject, HDL was isolated by ultracentrifugation and its anti‐inflammatory status was tested as its ability to inhibit MCP‐1‐induced migration of the monocytic cell line THP‐1 using transwell cell culture chamber inserts with micropore filters of 5 microns pore size. HDL‐associated proteins were measured by commercial ELISAs.

Results

Twenty‐three HIV‐infected patients were ART‐naïve (32±15 years, 66.7% male) and ninety were currently on ART (46±11 years, 78.9 % male). Most patients on ART (91.1%) had undetectable viral load (<50 copies/mL). When compared to healthy subjects, both naïve and treated HIV‐infected patients had lower plasma HDL‐cholesterol levels (naïve: 45±12, ART: 50±10, controls: 55±10 mg/dL, p<0.05). HDL isolated from HIV naïve patients showed a significantly reduced anti‐inflammatory activity (THP‐1 monocyte migration capacity was 203% times higher in HIV patients than in control subjects). The anti‐inflammatory activity of HDL from ART‐treated HIV‐infected patients was significantly improved when compared to naïve patients, although it remained significantly lower than controls (130% THP‐1 monocyte migration vs controls). HDL from HIV‐infected patients had a decreased concentration of the anti‐inflammatory proteins Apo A1 (controls: 2.1±0.3, naïve: 1.4±0.2, ART: 1.6±0.1 mg/ml) and LCAT (controls: 0.53±0.09, naïve: 0.34±0.06, ART: 0.48±0.05 μg/ml), and increased of the pro‐inflammatory protein serum amiloid (controls: 1.42±0.53, naïve: 3.23±1.29, ART: 2.72±0.70 μg/ml) than healthy controls.

Conclusions

Our data demonstrate HIV‐infected patients, even with effective therapy, showed a marked reduction of HDL anti‐inflammatory properties. This dysfunctional HDL seems to be associated with changes HDL composition and may contribute to the increased CVD risk observed in HIV infection.
Incidence and risk factors of major cardiovascular events in a multicentre HIV cohort
Authors: Carenzi L , Meraviglia P , Menzaghi B , Valsecchi L , Capetti A , Rizzardini G
Published: November 2012

Cardiovascular (CV) [1] and cerebrovascular [2] events threaten HIV+ subjects, affecting them earlier as compared to the general population and the current algorithms seem inadequate to estimate the CV risk, in particular concerning the weight of drugs, immunity and virus‐related inflammation as risk factors. We analysed three Italian HIV cohorts from January 2005 to August 2011, extracting cases of acute myocardial infarction (AMI) or stroke. We analysed at the time of the event the subjects’ age, the risk factors, the Framingham score, the antiviral regimen and the time spent on each drug, the CDC stage, the nadir CD4+ T cells and the outcome. Out of 4893 patients 92 experienced major CV events (76 AMI and 19 stroke, 2 subjects having both) and 10 died, at a median age of 50 years (range 33–77). Classical risk factors were widely represented, mainly smoke (72.8%) and dyslipidemia (53.3%). Three young subjects had no risk factors and dramatic coronary patterns, leading in one case to transplantation. No one ever had pathological bone fractures, and only 4/81 had GFR <60 mL/min (range 33.6–57.4). The median 10 years’ Framingham score was 10.5 (range 1–31). Abacavir had been taken by 19 subjects, equal to tenofovir and less than zidovudine (n=55), and lopinavir/ritonavir by 20, and no single drug emerged as risk. The median time spent on abacavir and/or on lopinavir/ritonavir was 48 weeks (range 1–552) and 106 weeks (range 8–256), respectively. One patient was antiretroviral–naïve. The CD4 nadir was 183/mm3 and 41.3% were CDC stage C. Although infrequent (1.8%), major CV events affect HIV people at younger age. Classical risk factors are common, while no drug effect emerged clearly. HIV infection was managed late in most of the patients. Early initiation of HAART [3] and reduction of risk factors seem the key points for preventing the occurrence of CV disease.
Effectiveness of antihypertensive therapy in HIV‐positive patients: evaluation to 144 weeks
Authors: Falasca K , Ucciferri C , Vignale K , Ripani P , Pizzigallo E , Vecchiet J
Published: November 2012

Hypertension is more prevalent among HIV‐infected subjects than in the general population, contributing to increased cardiovascular risk in HIV+ patients. The angiotensin II receptor blocker telmisartan is also a partial peroxisome proliferator activated receptor (PPAR)‐γ agonist, with documented effects on improving hypertension, lipid metabolism and renal function. Therefore telmisartan was found to be the first choice for treatment of HIV+ hypertensive patients. Aim of this study was to evaluate the durability on 144 weeks of treatment with telmisartan in HIV+ patients. 13 HIV+ Caucasian male patients treated with combined antiretroviral therapy (cART) and discovered to be naïve hypertensive, were given 80 mg telmisartan daily. Systolic (SBP) and diastolic (DBP) blood pressure, viro‐immunological, lipid and metabolic parameters, including triglycerides, cholesterol, insulin resistance (HOMA‐IR), inflammatory markers, C‐reactive protein (CRP), erythrocyte sedimentation rate (ESR), indexes of renal function and cardiovascular risk, microalbuminuria, cystatin C, were measured at baseline (T0), and after 24 (T24), 48 (T48), 72 (T72), 96 (T96), 120 (T120) and 144 (T144) weeks. Treatment with telmisartan decreased SBP and DBP levels during the 144 weeks of observation. We also observed improved HDL‐cholesterol, HOMA‐IR, microalbuminuria and cystatin C at the end of study. Triglycerides and total cholesterol significantly decreased and HDL‐cholesterol significantly increased. Total cholesterol/HDL cholesterol ratio improved significantly. Throughout in the course of the trial our patients showed a significant improvement of the percentage of CD4+ and CD8+. Eventually in all 144 weeks of therapy with telmisartan 80 mg/day have not observed adverse events or dropouts. Telmisartan was effective in improving hypertension, lipid metabolism and renal function in 144 weeks of evaluation. It determines the improvement of cystatin C and microalbuminuria, markers of renal function and cardiovascular risk. Telmisartan doesn't interfere with cART, not interfering with the recovery of immunological HIV patients. Telmisartan has confirmed durability and effectiveness, excellent tolerability and an high persistance with a good blood pressure control. Therefore telmisartan reveals the first choice in the treatment of hypertension in HIV+ because of significant morbidity in this group of patients.
Effects of switching to PI monotherapy on measures of lipoatrophy: meta‐analysis of six randomized HIV clinical trials
Authors: Arribas J , Bernardino J , Hill A , Sawyer W , van Delft Y , Moecklinghoff C
Published: November 2012

Background

Switching from triple combination treatment to protease inhibitor (PI) monotherapy may prevent or reverse adverse events related to long‐term nucleoside analogues. Lipoatrophy is associated with long‐term use of thymidine analogues (zidovudine and stavudine).

Methods

A detailed MEDLINE search was conducted to identify randomised clinical trials of triple combination treatment versus PI monotherapy. Summary results from analysis of changes in body composition (DEXA analysis) were collected: the mean change in limb fat and trunk fat to Week 48 or 96, and the percentage of patients with lipoatrophy (20% reduction from baseline in limb fat) or lipohypertrophy (20% rise from baseline in trunk fat).

Results

Six randomised trials of PI monotherapy versus triple therapy with data on body composition changes, measured by DEXA scanning at baseline and Week 48 or 96, were identified: Abbott‐613 (LPV/r vs ZDV/3TC/EFV, induction‐maintenance trial, n=105), Monark (LPV/r vs ZDV/3TC/LPV/r, first‐line trial, n=63), Kalesolo (LPV/r vs LPV/r +2NRTIs, switch trial, n=42), MONOI (DRV/r vs DRV/r + 2NRTIs, switch trial, n=156), MONARCH (DRV/r vs DRV/r + 2NRTIs, switch trial, n=30) and KRETA (LPV/r vs LPV/r + ABC/3TC, switch trial, n=74). In the meta‐analysis, there were greater rises in limb fat in the PI monotherapy arms than the triple therapy arms (mean difference =277g, 95% CI=+36 to+517g, p=0.024). The percentage of patients with lipoatrophy was significantly lower in the PI monotherapy arms (4%) than the triple therapy arms (20%), (p=0.0005). There was no difference between PI monotherapy and triple therapy for mean change in trunk fat (mean difference=−73g, 95% CI = −621 to +475g, p=ns). There was also no significant difference in the risk of lipohypertrophy between the PI monotherapy arms (32%) and the triple therapy arms (27%) (p=ns). In each of the four analyses, there was no evidence for heterogeneity of treatment effects between the trials (Cochran's Q tests, p=ns for each comparison).

Conclusions

In this meta‐analysis, the risk of lipoatrophy was significantly lower for patients taking PI monotherapy, compared to triple therapy. There was no significant difference between the arms for lipohypertrophy. However, several of the trials included zidovudine in the control arm, which carries a higher risk of lipoatrophy than tenofovir and abacavir, which are now more widely used.
Longitudinal comparison of inflammatory, coagulation and metabolic biomarkers in patients who start ART versus patients who remain ART‐naïve
Authors: Bernardino J , Merino J , Serrano L , Estébanez M , Montes M , Zamora F , Pérez‐Valero I , González‐García J , Arribas J
Published: November 2012

There are very limited data on the impact of ART initiation on inflammatory and coagulation biomarkers compared to patients who remain ART naïve [1]. We designed a prospective comparative study to evaluate these changes. Prospective observational cohort study of HIV‐infected patients who start ART and a group of age‐matched controls who remain ART‐naïve. Blood levels of insulin, fibrinogen, D‐dimer, high‐sensitivity PCR, inflammatory (IL‐1β, IL‐6, MCP‐1 and sCD40) and anti‐inflammatory cytokines (IL‐4), were compared at baseline, 24 weeks and 48 weeks. Summary of results: 94 patients included (57 treated, 37 controls). Baseline characteristics were balanced except for (treated/controls): median [IQR], HIV duration (0.9 [0.4–2.4] / 2.7 [0.6–5.5]) years, CD4 nadir (262 [198–317] / 452 [367–553]) cells/µl, viral load (4.4 [4–5.1] / 3.8 [3.1–4.4]) log cop/ml, current CD4 count (283 [213–323] / 525 [449–669]) cells/µl, HDL cholesterol (38 [29–45] / 41 [36–50]) mg/dl and female gender (8.8%/35%). There were no differences between groups in baseline biomarkers levels except that those starting ART had lower median [IQR] IL‐1β (4.1 [3.5–4.7] vs. 4.6 [3.7–6.8] pg/ml; p= 0.019) and lower IL–6 levels (4 [3.4–4.6] vs. 5.2 [4.2–6.6] pg/ml; p< 0.001). No significant correlation was found between biomarkers and baseline viral load. 91% of treated patients achieved viral suppression (<50 c/ml). There were statistically significant differences between groups at week 48 with lower (mean [95% CI]) D‐dimer (−138.2 [−268.0, −8.4] mg/L; p=0.001), IL‐1β (−0.6 [−0.9, −0.4] pg/ml; p<0.001) and higher IL‐4 (0.6 [0.2, 0.9] pg/ml; p=0.004) in those starting ART. In the ART‐naïve group there were significant increases of IL‐1β (1.3 [0.9, 1.6] pg/ml; p<0.001), sCD40 (22.7 [0.8, 44.6] AU; p=0.043), IL‐6 (0.5 [0.0, 0.9] pg/ml; p= 0.049) and a significant decrease of IL‐4 (−0.7 [−1.1, −0.3] pg/ml; p=0.001) levels. After 48 weeks of ART there were statistically significant decreases in pro‐inflammatory and coagulation markers (Figure 1) while levels of anti‐inflammatory cytokines (e.g. IL‐4) were significantly increased. Opposite trends were found in controls.

In conclusion, compared to untreated controls, 48 weeks of effective ART significantly reduces pro‐inflammatory (IL‐1β, IL‐6), coagulation (fibrinogen, D‐dimer), and metabolic (insulin) markers and increases levels of an anti‐inflammatory cytokines like IL‐4.

Median percentage changes in bio markers from baseline to week 48.

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