Suchergebnisse

BackgroundIn France, approximately 100,000 HIV‐infected patients are regularly followed up in hospitals. Due to the availability and efficacy of antiretrovirals, the number of hospitalised patients is decreasing in favour of outpatient management. In order to optimise the balance between patients' hospitalisation and hospital structures, collection of recent data on the profile of hospitalised patients is essential.ObjectivesDescribe the frequency, causes of hospitalisation and characteristics of hospitalised HIV‐infected patients.MethodsRetrospective study of a cohort of HIV‐infected patients hospitalised more than a day at the Bégin hospital (Saint‐Mandé) between January 1st and December 31, 2011.ResultsDuring this period, 170 hospitalisations were recorded, corresponding to 78 patients (61 M /17 F). Main causes of hospitalisation were: infections (52%), surgical treatments (10%), haemopathies/cancers (8%), cardiovascular diseases (8%), neurological illnesses (7%), hepatic and digestive tract pathologies (6%). Principal admission wards were: an HIV reference unit (67%), the emergency department (7%), cardiology (7%), surgery ward (7%), internal medicine (6%) and intensive care unit (3%). One out of five patients was admitted for an acquired immune deficiency syndrome‐related event (opportunistic infection or cancer). Two‐thirds of patients had one or several co‐morbidities. Only 61% (48/78) of patients had more than 200 CD4+lymphocytes/mm3 and 69% (54/78) an undetectable HIV viral load. The average length of stay was 6.5 days (range: 2–38). Four (5%) fatalities were reported and 85% of patients returned home.DiscussionHospitalisation of HIV‐infected patients remains significant and the causes are diversifying. Infections, in particular in patients screened at a late stage, cancers and management of comorbidities justify a coordinated referral to the different specialists.

BackgroundThe 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.Methods122 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.Results82% 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.ConclusionsPatients 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.

BackgroundThe significant decrease in mortality has resulted in a large number of individuals aged over 50 living with HIV infection. Additionally, the coexistence of certain pathologies suggests premature aging. In this scenario, the presence of aging‐associated symptoms in the physician‐patient dialogue is yet to be explored.MethodsCross‐sectional observational study to evaluate the presence of aging‐associated symptoms in the physician‐patient dialogue and to explore the possible differences between genders in a sample of 100 HIV‐1 infected subjects diagnosed at least 15 years ago. The survey assessed questions/comments made by the patient, questions/comments made by the physician and patients' interest in obtaining more information than was provided. Number of patients and percentages were given and compared using the w2 or Fisher exact test (as appropriate).ResultsParticipants were 60 men and 40 women, diagnosed with HIV infection a median (IQ) of 18 (15.7–21) years ago, who had a nadir CD4 and CD4 cell count at the study entry of 172 (95–272) and 543 (403–677), respectively. Eighty percent of the subjects had VL <25 copies and 42% were HCV/HIV co‐infected (31 subjects with low fibrosis stage). The infection route had been mainly intravenous drug use (37%) and MSM (32%). Men and women had similar demographic and clinical characteristics. Sixty‐two percent of the participants acknowledged asking their physicians about aging‐associated symptoms (58% men vs 66% women; p=0.50), 48% reported that their physicians had provided information without having been asked (48% men vs 55% women; p=0.51) and 75% confirmed that they would like to have more information about aging‐associated symptoms (22% men vs 80% women; p<0.001).ConclusionsAround half of the men and women interviewed had discussed aging‐associated symptoms with their physician. However, this seemed insufficient for four‐fifths of the women, who would have liked to have obtained more information about aging.

The plasma specimen is the gold standard for viral load monitoring, the key method to assess the effect of antiviral chemotherapy and to monitor progression of the disease toward AIDS. Nevertheless, several works endorse the use of dried blood spots (DBS) on filter paper for the reliable quantification of the levels needed to take therapeutic decisions, detect of treatment failure and monitor the occurrence of drug resistance. The purpose of this study was to validate the use of Cobas AmpliPrep/Cobas TaqMan HIV‐1 test version 2.0, with DBS. To evaluate the performance of the above mentioned kit, three stages were involved: 1‐ Standardization of DBS working conditions, 2‐ Stability studies at three temperature conditions and 3‐ Performance evaluation of the kit using this alternative specimen. Additionally, the viral load was quantified in parallel (plasma and DBS) to 43 genetically characterized samples, with different levels of viral load. The Pearson correlation coefficient was calculated and the prediction of the value of RNA in plasma starting from the obtained value in DBS was made. Linear regression analysis was performed and coefficients of variation in precision assays were calculated. The best conditions pickups to the work with DBS were: 100 µL of blood (2 spots/50 µl), dried time between 16 and 18 hours at room temperature and, elution of the blood, 2 hours, between 2 and 8°C; in TRIS‐EDTA buffer. The samples on DBS proved to be stable during the study periods. A strong correlation was attained between the measurements of viral load in plasma and DBS samples (r=0.96). The detection rate was 90.7 and the coefficient of variation between the values obtained in plasma‐DBS sample pairs averaged 3.42%. The CAP/CTM HIV‐1 test provided a linear response in DBS, from 330 copies/mL to 420 000 copies/mL. Overall, coefficients of variation in precision tests were below 10%. Cobas AmpliPrep/Cobas TaqMan HIV‐1 test version 2.0 had a good performance using DBS. High detection rate was obtained with DBS specimen. Our results clearly support the use of CAP/CTM HIV‐1 test with DBS, as it reliably quantifies the levels needed for therapeutic decision‐making and detection of treatment failure.

CD4 counts rise following treatment with HAART, the pattern of which however varies between individuals and populations. Host, virus and treatment factors may play a part in shaping the trajectory. Through an HIV clinical cohort study, we aim to describe the natural course of CD4 trajectories and evaluate possible factors associated with different patterns. Between 1997 and 2008, HIV‐1‐infected patients receiving HAART at one major HIV specialist clinic in Hong Kong were included in a study for assessing CD4 changes. The entry criteria were: (a) patients who have been put on HAART according to standard criteria; (b) sustained viral suppression after treatment; (c) having been on HAART for at least 48 months. A total of 141 patients with 3,087 measurements were analysed, covering a total of 11,282 person‐months. The median age at initiation of HAART was 37 (IQR 32–44). A majority were male (74%), Chinese (87%) and who have contracted HIV through heterosexual contacts (84%). At baseline, the median CD4 was 39 cells/µL (IQR 13–127 cells/µL) and viral load was 74,100 copies/mL (IQR 26,800–280,000 copies/mL). Over time, 80 (57%) gave a CD4 count of>500/µL during antiretroviral treatment. Clinically, almost all (96%) had presented with an AIDS‐defining illness before HAART was started. Around half of the patients were on 2NRTI+1 NNRTI and half on 2NRTI+1 PI. Overall, 3 groups of patients can be differentiated by their temporal pattern of CD4 recovery. Group One (n=38; 34%) gave a median peak value of 576/µL within 4 years (median interval 40 months). Group Two comprised 96 (68%) patients whose mean CD4 count continued to rise beyond 48 months. Group Three (n=7) gave little or no response to treatment, as defined by a change of<100 cells/µL in the mean count by year. Group Three patients were relatively older (median age=46 years). Comparing between Group One and Two, there was a higher proportion of men having sex with men whose CD4 had plateaued within 4 years (21% vs 6%, p=0.017). Lower baseline CD4 and higher baseline viral load were associated with continued rise of CD4 beyond 4 years. There was no association of CD4 recovery pattern with the HAART regimen. In conclusion, CD4 rise tends to be prolonged following effective virus suppression in a predominantly Chinese HIV population. The differential patterns were largely associated with host factors with little impacts from HAART regimens.

Patients virologically suppressed on TDF/FTC + ATV/r may require alternative regimens that maintain suppression while addressing some drug‐related side effects. We explored two alternative regimens that replace RTV and/or TDF/FTC. This open‐label exploratory pilot trial enrolled 43 patients on TDF/FTC + ATV/r. Subjects were randomized to one of three arms. Arm 1 (n=15) replaced TDF/FTC with RAL 400 mg BID while continuing ATV/r. Arm 2 (n=14) made two changes: TDF/FTC was stopped and RAL BID was used instead; ritonavir was stopped and ATV 300 mg BID was used. Arm CTL (n=14) continued the baseline (BL) regimen. The week 48 final endpoint is summarized. The primary endpoint was maintaining virologic suppression (<40 c/mL); secondary endpoints compared safety measures. Overall mean age was 46, with 74% Caucasian, 21% black race and 12% female; similar characteristics noted across arms. Through week 48, all but two patients maintained virologic suppression; both virologic failures (>200 c/mL on two consecutive tests) were on arm 2; both reported adherence problems and no resistance mutations were detected. Overall CD4 counts were 534/mm3 at BL and 555/mm3 at week 48. There was a significant CD4 cell count difference favoring CTL (+52/mm3) vs. arm 2 (−14/mm3), p=0.03. No significant differences across arms were noted in lipid fractions or other lab tests. There were no clinically significant EKG changes across arms. Among AEs of interest through week 48, there were more neurologic AEs on arm 1 (n=7) and 2 (n=6) vs. CTL (n=1), and more musculoskeletal events noted on arm 2 (n=7) vs. arm 1 (n=3) and CTL (n=1). Quality of life was measured with a self‐assessment Likert scale. Scores were similar across arms despite the BID dosing in two arms. Self‐reported adherence using 3‐day recall was>95% in all three arms at both baseline and week 48. In this randomized pilot study, two of the three arms maintained virologic suppression in all subjects; there were two virologic rebounds in arm 2. No resistance mutations were detected in either, and adherence issues were noted for both subjects. We also noted that the CD4 cell change was significantly less on arm 2, and there were more neurologic and musculoskeletal AEs on arm 2 vs. CTL. In this study, the use of ATV/r with either TDF/FTC or RAL was successful over 48 weeks, but unboosted BID ATV 300 mg+BID RAL 400 mg as an alternative in virologically suppressed patients should be used with caution.

With the introduction of nephrotoxic in recent WHO recommendation, it became necessary to determine prevalence and factors associated with renal dysfunction among patients newly identified HIV‐infected in Brazzaville.MethodsDescriptive and analytical study of patients newly diagnosed HIV‐infected at the Ambulatory Treatment Center in Brazzaville, Republic of Congo between January 1st, 2009 and December 31st, 2010. Estimated glomerular filtration rate (eGFR) was assessed using the Cockroft‐Gault formula (CGCl) and modification of diet in renal disease (MDRD) equation. Patients had renal dysfunction mild, moderate or severe when eGFR were respectively 60–89 ml/min, 30–59 ml/min and<30 ml/min with the GCCl and MDRD. To determine factors associated with renal failure (defined as GCCl<60 ml/min), univariate analysis followed by multivariate logistic regression analysis was performed.ResultsWe evaluated 562 patients newly identified HIV‐infected, median age was 38.84 (interquartile range (IQR): 33.18–46.24) years, all patients were of African origin, 61.1% were female, median BMI was 20.30 (IQR: 17.96–22.89) kg/m2, median CD4 count was 192 (IQR: 81–350) cells/mm3 and 70.8% were at WHO stage III/IV. GFR was lower using CGCl (median 74.99 ml/min, 26.1%<60 ml/min) versus MDRD (95.59 ml/min/1.73 m2, 7.9%<60 ml/min/1.73 m2). Two hundred and fifty‐seven patients (47.2%) using CGCl versus 138 (32.6%) with the MDRD had mild, 126 patients (23.1%) versus 33 (5.9%) respectively had moderate, and 16 patients (3%) versus 11 patients (2%) respectively had severe renal dysfunction. Factors associated with renal dysfunction in multivariate analysis included age superior to 40 years (adjusted odds ratio (aOR): 0.37 [95% CI: 0.22‐0.61]; p=0.0001), CD4+ T‐cell count below 200 cells/mm3 (aOR: 1.72 [95% CI: 1.04–2.83]; p=0.035) and BMI less than 18.5 kg/m2 (aOR: 4.39 [95% CI: 2.63–7.33]; p<0.0001).ConclusionsThis study shows a high prevalence of renal dysfunction in patients newly diagnosed HIV positive in Brazzaville. Necessity is now beside serum creatinine assay performed in the initial assessment as recommended by WHO, to also perform urine dipstick for better monitoring of these patients before initiating antiretroviral therapy.

BackgroundRaltegravir is metabolized by glucuronidation via UGT1A1. Among the genetic polymorphisms of UGT1A1, the *6, *27 and *28 alleles are associated with reduced levels of UGT1A1. In particular, the *28 allele accounts for most of the UGT1A1 polymorphisms, and the level of UGT1A1 activity has been the focus of most studies. On the other hand, among Asians, the *6 and *27 alleles are more commonly found in comparison with white populations. In this study, we aimed to clarify the contribution of UGT1A1 polymorphisms (*6, *27) to plasma raltegravir concentrations in Japanese HIV‐1‐infected patients.Materials & MethodsWe analyzed the presence of genotypic variants (*6, *27 and *28) among the 74 patients recruited at the National Hospital Organization Nagoya Medical Center. Genotyping of *6 and *27 in UGT1A1 was performed using the TaqMan drug metabolism genotyping assay. Genotyping of *28 in UGT1A1 was performed using the primers described by Ehmer et al. Plasma raltegravir concentrations were determined by a LC‐MS method.ResultsAmong the 74 patients, the UGT1A1 genotype in 3 patients (two male, one female) was *6 homozygote. Heterozygous variants were found in 20 patients for *6, and in 14 patients for *28, while all of the patients were found to carry wild‐type sequences at the position corresponding to the *27 allele. The male *6 homozygote patient had modestly higher plasma raltegravir concentration (0.53 µg/ml) than other patients who were wild type (0.12 µg/ml) or heterozygous (0.16 µg/ml) for the *6 polymorphism. The other two UGT1A1*6 homozygote patients had a lower plasma raltegravir concentration (0.03 and 0.05 µg/ml). On the other hand, plasma raltegravir concentrations were 0.12 µg/ml (*6−/− *28−/−; n=37), 0.11 µg/ml (*6−/− *28−/+; n=14), 0.16 µg/ml (*6−/+ *28−/−; n=20). There were no statistically significant differences in the plasma raltegravir concentrations between patients carrying wild‐type alleles and those heterozygous for *6 or *28.ConclusionsPatients heterozygous for the *6 or *28 allele did not display significantly different plasma raltegravir concentrations compared to patients homozygous for the respective wild‐type allele. In this study, we showed that heterozygosity for the reduced‐function *6 and *28 alleles had no significant effect on plasma raltegravir concentrations in Japanese HIV‐1‐infected patients.

ObjectivesPrimary ‐ evaluate the improvement in psychiatric symptoms attributable to changing the antiretroviral drug responsible for such symptoms to nevirapine (NVP). The tools used were a sleep test (the Pittsburgh Sleep Quality Index [PSQI]) and the Hospital Anxiety and Depression Scale (HADS). Secondary ‐ determine the neuropsychiatric disorders and evaluate adherence to treatment and quality of life.MethodsProspective, observational post‐authorisation study that included HIV‐1 patients from 36 Spanish hospitals who satisfied the following criteria: age over 18 years; change of antiretroviral treatment to NVP due to CNS side‐effects; a PSQI score >5 (significant sleep disturbance); a HADS score ≥10 on the day of starting NVP treatment; and no psychoactive drug treatment initiated during the 6 weeks prior to starting treatment with NVP. Other data gathered from the patients included clinical and demographic details and administration of the Epworth somnolence scale, the Medical Outcomes Study‐short form 30 items (MOS‐SF‐30) quality of life scale and the Simplified Medication Adherence Questionnaire (SMAQ). Evaluations were performed at baseline, 1 and 3 months after the change.Results129 patients were included (73.6% men; mean age, 43.2 ± 9.8 years; 36.5% homosexual, 30.2% heterosexual; 28.7% drug users; 38% AIDS; 33.3% co‐infection). The drug changed was efavirenz in 89.9% of cases. The reason for the change was sleep disturbances in 75.2%, anxiety in 65.1%, other psychiatric disturbances in 38.7%, attention disturbances in 31%, and other reasons in 31%; a mean of 2.4 neuropsychiatric disturbances were detected in each patient. CD4 rose from 582 ± 261 to 619 ± 299 (non‐significant difference). Only three patients had developed an HIV viral load at the end of the study. The differences produced by the change are shown in Table 1. 29 patients withdrew from the study, for the following reasons: 9 for NVP‐related toxicity (7 cases of rash and 2 of hepatitis); 7 for loss to follow‐up; 4 for voluntary withdrawal; 9 for other reasons.












Baseline (n=129)
1 month (n=100)
3 months (n=100)
p value, baseline‐1 mo
p value, baseline‐3 mo




Percentage of patients with a PSQI score >5, suggestive of a significant alteration of sleep
96.9%
60.7%
44%
<0.001
<0.001


Percentage of patients with clinical problems of anxiety and depression, HADS
86.8%
46.4%
32%
<0.001
<0.001


Mean score and percentage of patients with normal somnolence, Epworth scale
8.3±4.7/(65.9%)
6±4 (89.3%)
5.5±3.6 (91%)
<0.001/0.001
<0.001/0.001


Percentage of compliant patients, SMAQ
65.9%
75.9%
81%
0.036
0.013


Percentage of patients with a good quality of life, MOS‐SF‐30
57.5±18.9%
69.8±19.7%
73.6±16.8%
<0.001
<0.001




DiscussionThe study shows that the change to NVP from a drug that is causing neuropsychiatric disturbances (principally, efavirenz) is effective in resolving those disturbances, with an improvement in all the parameters studied (quality of sleep, anxiety/depression and somnolence). This leads to better adherence and a better quality of life with no detriment to their immunological and virological control.

IntroductionHepatitis C virus (HCV) infection remains a major silent killer, worldwide, particularly in resource poor settings where treatment of hepatitis C is mainly impossible. Pegylated interferon‐α (PEG‐IFN) plus ribavirin (RBV) are the recommended treatment for patients with chronic hepatitis C genotype 2/3. Recent study revealed that treatment responses against HCV infection by PEG‐IFN and RBV are significantly associated with the single nucleotide polymorphisms (SNPs) of interleukin‐28B (IL‐28B) gene. There is limited data about the HCV genotype and SNPs of IL‐28B in HIV‐infected Thai population. Therefore, we aimed to investigate HCV genotype and the SNP patterns of the IL‐28B gene in our HIV/HCV coinfection.MethodsQuantification of HCV RNA was done by a real‐time polymerase chain reaction assay (Abbott with lower limit of detection of <12 copies/ml). HCV RNA‐positive samples based on reverse transcriptase‐polymerase chain reaction (RT‐PCR) of the 5'UTR were amplified with primer specific for the core and NS5B regions. Nucleotide sequences of both regions were analyzed for the genotype by phylogenetic analysis. DNA sample was extracted from PBMCs or sera. Then SNPs within IL‐28B gene were detected by TaqMan real‐time PCR (rs8099917 and rs12979860). The data were analyzed by allelic discrimination (AD) software on the ABI‐7900HT.ResultsTotally 60 HIV/HCV‐coinfected patients were studied. Median HCV RNA were 5.8 log10 copies/mL, 70% of them had HCV RNA >100,000 copies/mL. After sequencing, the phylogenetic analyses in this study showed that genotype 3 was the most prevalent in this population (56%); following by genotype 1 (30%) and 6 (13%). Approximately 4% of them had infected for both genotypes 1 and 3. For IL‐28B at rs8099917 and rs12979860 position, 95% of them were major allele (T/T or C/C) and 5% were heterozygous (T/G or C/T).ConclusionsHCV genotype 3 is the most prevalent in our HIV/HCV coinfection. 95% of our patients have favorable IL‐28B gene. This data is useful for further chronic hepatitis C treatment in Thailand.

The efficiency of transmission of HIV depends on the infectiousness of the index case and the susceptibility of those exposed. Infectiousness is dictated by the concentration of HIV‐1 in relevant fluids (regardless of route of transmission) and the viral genotype and phenotype. People newly infected with HIV‐1 (i.e. acute infection) and those with STI co‐infections excrete such a large concentration of virus as to be "hyperinfectious." The actual transmission of HIV likely occurs in the first few hours after exposure. The probability of transmission may be as low as 1/10,000 episodes of intercourse or 1/10 sexual exposures when anal intercourse is practiced. The transmission of HIV is generally limited to one or a small number of founder variants which themselves may be "hyperinfectious." Synergistic behavioural and biologic HIV prevention strategies have been developed and implemented. Safer sex includes limiting the number of sexual partners, use of male latex condoms, and structural interventions to reduce exposure. These strategies appear to have contributed to reduced HIV incidence in many countries. Biological interventions have proved catalytic: these include treatment of inflammatory cofactors, voluntary male circumcision and use of antiviral agents either for infected people (who can be rendered remarkably less contagious) or as pre‐ and post‐exposure prophylaxis (PrEP and PEP). Ecologic evidence suggests that broader, earlier antiviral treatment of HIV may be reducing incidence in some (but not all) populations. However, maximal benefit of HIV "treatment for prevention" and application of PrEP will likely require a program of universal "test and treat," where many more infected patients are identified, linked to care, and treated very early in disease and for life. Community randomized trials designed to support this approach are under way in Africa. The "test and treat" prevention strategy is resource‐intensive and serves to emphasize research that searches for a cure for HIV infection so that people living with HIV can eventually reduce or stop treatment. Likewise, success in HIV prevention emphasizes the importance of development of an HIV vaccine, which remains focused on agents that may evoke CTL responses, antibody dependent cytotoxicity, and (perhaps most important) broad neutralizing antibodies. A human clinical trial (RV144) and animal experiments have provided hope, excitement and a roadmap for development of an HIV vaccine.

As the published literature on HIV therapy continues to grow, it becomes increasing difficult for treating physicians to keep up to date with the latest developments. For example, several thousands of papers have been published since HIV10 in the HIV literature. Websites such as HIV Drug Therapy, which includes a section on new HIV publications, can be a great help, providing a brief summary of interesting papers that have been recently published. In my presentation, I will review what I believe to be some of the most useful and key papers that have been published in the last 2 years.

PurposeChemokines 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).MethodsTwo‐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 resultsRTV 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.ConclusionsIn 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].

Highly effective regimens have drastically improved HIV morbidity and mortality although anti‐retro viral resistance remains a limiting factor in disease management. Therefore, analysis of large sequence datasets may provide better insight into drug resistance & assist policy makers to select optimized treatment strategies. Using a secure, web‐based sequence submission tool (vircoNETTM, Janssen Diagnostics BVBA), centers within EU have been able to retrieve the CE‐marked vircoTYPETM HIV‐1 (VTY) genotyping reports for their patients. The purpose of this study is to perform a descriptive analysis of the prevalence of HIV‐1 PR & RT resistance‐associated mutations (RAMs) from submitted nucleotide sequences, collected during an 8 year period, from 5 West‐European countries & Switzerland. From January 2005‐June 2012, 27,262 sequences were submitted via vircoNETTM & analyzed using VTY. Approximately 50% of the sequences were submitted from Spain (n=14120) & 24% from Italy (n=6415). The remaining sequences were from UK (n=2097), France (n=1508), Germany (n=1041) & Switzerland (n=2081). The majority (80%, 21,647/27,262) of the sequences were Clade B. For NRTI RAMs, M184V was the most prevalent mutation (36%, n=9944) followed by M41L (25%, n=6701). For NNRTI RAMs, K103N mutation was most prevalent (24%, n=6481) followed by Y181C (10% n=2704). For PIs, L90M (16%, n=4453) and M46I (12%, n=3397) were the most prevalent. The overall RAM prevalence has declined over the 8 year period. 7602 (28%) sequences had no major RAMs and were sensitive to all 18 FDA & EMA‐approved drugs present on VTY. In the PI class, VTY predicted 95% (20097/21243) of the sequences as sensitive & 5% (1146/21243) resistant to darunavir, followed by tipranavir, lopinavir & saquinavir with equal sensitivity rate (SR) of 81% & a resistance rate (RR) of 13%, 18% & 19% respectively. In the NNRTI class, etravirine had a better SR (81%, 8628/10683) & RR (19%, 2055/10683) when compared to nevirapine and efavirenz, with a SR of 59% & RR of 41% for both drugs. For NRTIs, the highest SR was found for stavudine (77%, 20889/27262) followed by tenofovir (67%, 18249/27262) with 23% (6499/27262) resistant sequences observed for stavudine & 33% (9114/27262) for tenofovir. The current analysis provides some preliminary insight into HIV mutation pattern prevalence and resistance within Western Europe, suggesting good therapeutic opportunities for regimens containing new generation PIs & NNRTIs.

Various items are complicating the treatment of HIV‐2 infected patients. Compared to HIV‐1 there is much less treatment experience, no evidence from randomized control trials, a reduced number of effective drugs and no broadly available test for viral load monitoring. In case of treatment failure there is only limited guidance and presently no easy accessible tool for nucleic acid sequence interpretation available. To solve this problem, we initiated an expert workshop to address some of these problems. A panel of experts from four different European countries voted on a rule set for interpretation of mutations in the HIV‐2 protease, reverse transcriptase and integrase. Rules were proposed by each member and were then modified during discussion by considering data gained from HIV‐1 and accumulated experience of the follow up of HIV‐2‐infected patients. Based on the HIV‐GRADE internet‐tool an online tool was developed to make the rule set easily accessible and usable. Rules were laid down for the interpretation of HIV‐2 drug resistance to NRTIs, PIs and INIs (integrase inhibitors). Due to natural resistance of HIV‐2, usage of NNRTIs and T‐20 was not recommended as part of an antiretroviral regimen for HIV‐2. These rules were then translated in a machine interpretable format (algorithm specification interface, ASI) and the HIV‐GRADE tool was extended for usage of HIV‐2 sequences. Further consensus sequences were generated from the reference sequence data set provided by Los Alamos National Laboratories. In contrast to HIV‐1, mutations were compared to a group specific consensus sequence (Group A or Group B) and not to a consensus sequence from the most predominant HIV‐2 Group A. This change was necessary due to significant differences between the various HIV‐2 strains. We developed a rule set and an automated tool for HIV‐2 drug resistance analyses. This tool and the rules will be freely available on the internet. Access to the pre‐publication versions can be granted by each of the group members. To keep the algorithm rules up‐to‐date it will be actualized on a yearly basis.