bluuebunny/crossref_metadata_2025_split huggingface dataset:
Determinants of IL‐6 levels during HIV infection
Authors: Borges Álvaro H , O'Connor Jemma L , Phillips Andrew N , Rönsholt Frederikke F , Pett Sarah , Vjecha Michael J , French Martyn A , Lundgren Jens D 
Published: November 2014

IntroductionElevated IL‐6 levels have been linked to increased risk of cardiovascular disease (CVD), cancer and death. Compared to the general population, treated HIV+ persons have 50–100% higher IL‐6 levels, but few data on the determinants of IL‐6 levels during HIV infection currently exist.Material and MethodsParticipants in three international HIV trials (SMART, ESPRIT and SILCAAT) with IL‐6 plasma levels measured at baseline were included (N=9864). Factors independently associated with log2‐transformed IL‐6 level were identified by multivariate linear regression; exponentiated estimates corresponding to fold differences (FDs) in IL‐6 were calculated. Demographics (age, gender, race, BMI) and HIV‐specific variables (nadir and entry CD4 counts, HIV‐RNA, use of different ART regimens) were investigated in all three trials. In SMART (N=4498), smoking, comorbidities (CVD, diabetes, hepatitis B/C [HBV/HCV]), HDL‐cholesterol, renal function (eGFR) and educational level were also assessed.ResultsDemographics associated with higher IL‐6 were older age (FD [95% CI]: 1.09 [1.08–1.11] per 10 yr) and higher BMI (1.02 [1.01–1.04] per 5 kg/m2), whereas black race was associated with reduced IL‐6 (0.96 [0.93–0.99]). As for HIV variables, patients not receiving ART (1.36 [1.29–1.43]) and with higher HIV‐RNA (1.24 [1.01–1.52] for >100,000 vs. ≤500 copies/mL) had increased IL‐6. Participants taking protease inhibitors (PI) had higher IL‐6 (1.14[1.09–1.19]). Higher nadir CD4 count (0.98 [0.97–0.99]/100 cells/µL) was related to lower IL‐6. All evaluated comorbidities were related to higher IL‐6; FDs in IL‐6 were 1.08 [1.04–1.12] for smoking, 1.12 [1.02–1.24] for CVD, 1.07 [1.00–1.16] for diabetes and 1.12 [1.02–1.24] for HBV (1.15 [1.02–1.30]) and 1.53 [1.45–1.62] for HCV. IL‐6 increased with decreasing eGFR (0.98 [0.97–1.00]/10 mL/min) and HDL‐cholesterol (0.98 [0.96–0.99]/10 mg/mL). Lower education was related to higher IL‐6 (1.09 [1.03–1.15] for high school vs. bachelor's degree).ConclusionsHigher IL‐6 levels were associated with older age and non‐black race, higher BMI and lower HDL‐cholesterol, ongoing HIV replication, low nadir CD4 counts, comorbidities and decreased renal function. This suggests that there are multiple causes of inflammation in treated HIV infection. A possible contribution from PI use was also observed. Contribution from inflammation to explain variation in clinical outcomes for these factors should be investigated.
Once‐daily dolutegravir is superior to once‐daily darunavir/ritonavir in treatment‐naïve HIV‐1‐positive individuals: 96 week results from FLAMINGO
Authors: Molina Jean‐Michel , Clotet Bonaventura , van Lunzen Jan , Lazzarin Adriano , Cavassini Matthias , Henry Keith , Kulagin Valeriv , Givens Naomi , Brennan Clare , de Oliveira Carlos Fernando 
Published: November 2014

IntroductionDolutegravir (DTG) 50 mg once daily was superior to darunavir/ritonavir (DRV/r) 800 mg/100 mg once daily through Week 48, with 90% vs. 83% of participants achieving HIV RNA 50 c/mL (p=0.025) [1]. We present data through Week 96.Material and MethodsFLAMINGO is a multicentre, randomized, open‐label, Phase IIIb non‐inferiority study, in which HIV‐1‐positive ART‐naïve adults with HIV‐1 RNA≥1000 c/mL and no evidence of viral resistance were randomized 1:1 to receive DTG or DRV/r, with investigator‐selected backbone NRTIs (TDF/FTC or ABC/3TC). Participants were stratified by screening HIV‐1 RNA (≤100K c/mL) and NRTI backbone.ResultsA total of 484 adults were randomized and treated; 25% had baseline HIV RNA 100K c/mL. At Week 96, the proportion of participants with HIV RNA 50 c/mL was 80% in the DTG arm vs. 68% in the DRV/r arm (adjusted difference 12.4%; 95% CI 4.7, 20.2%; p=0.002). Secondary analyses supported primary results: per‐protocol [(DTG 83% vs. DRV/r 70%), 95% CI 12.9 (5.3, 20.6)] and treatment‐related discontinuation = failure [(98% vs. 95%), 95% CI 3.2 (−0.3, 6.7)]. Overall virologic non‐response (DTG 8%; DRV/r 12%) and non‐response due to other reasons (DTG 12%; DRV/r 21%) occurred less frequently on DTG. As at Week 48, the difference between arms was most pronounced in participants with high baseline viral load (82% vs. 52% response through Week 96) and in the TDF/FTC stratum (79% vs. 64%); consistent responses were seen in the ABC/3TC stratum (82% vs. 75%). Six participants (DTG 2, none post‐Week 48; DRV/r 4, two post‐Week 48) experienced protocol‐defined virologic failure (PDVF; confirmed viral load 200 c/mL on or after Week 24); none had treatment‐emergent resistance to study drugs. Most frequent drug‐related adverse events (AEs) were diarrhoea, nausea and headache, with diarrhoea significantly more common on DRV/r (24%) than DTG (10%). Significantly more participants had Grade 2 fasting LDL toxicities on DRV/r (22%) vs. DTG (7%), p<0.001; mean changes in creatinine for DTG (~0.18 mg/dL) observed at Week 2 were stable through Week 96.ConclusionsOnce‐daily DTG was superior to once‐daily DRV/r in treatment‐naïve HIV‐1‐positive individuals, with no evidence of emergent resistance to DTG in virologic failure and relatively similar safety profiles for DTG and DRV/r through 96 Weeks.
Predicted savings to the UK National Health Service from switching to generic antiretrovirals, 2014–2018
Authors: Hill Andrew , Hill Teresa , Jose Sophie , Pozniak Anton 
Published: November 2014

IntroductionIn other disease areas, generic drugs are normally used after patent expiry. Patents on zidovudine, lamivudine, nevirapine and efavirenz have already expired. Patents will expire for abacavir in late 2014, lopinavir/r in 2016, and tenofovir, darunavir and atazanavir in 2017. However, patents on single‐tablet regimens do not expire until after 2026.MethodsThe number of people taking each antiretroviral in the UK was estimated from 23,655 individuals in the UK CHIC cohort (2012 database). Costs of patented drugs were taken from the British National Formulary database, assuming a 30% discount. Costs of generic antiretrovirals were estimated using an 80% discount from patented prices, or actual costs where available. Two options were analysed: 1 – all patients use single‐tablet regimens and patented versions of drugs; prices remain stable over time; 2 – all people switch from patented to generic drugs when available, after patent expiry (dates shown above).ResultsThere were an estimated 67,000 people taking antiretrovirals in the UK in 2014, estimated to rise by 8% per year until 2018 (in line with previous rises). The most widely used antiretrovirals in the CHIC cohort were tenofovir (TDF) (75%), emtricitabine (FTC) (69%), efavirenz (EFV) (39%), lamivudine (3TC) (23%), abacavir (ABC) (18%), darunavir (DRV) (21%) and atazanavir (ATV) (16%). The predicted annual UK cost of generic ABC/3TC/EFV (three generic tablets once daily) was £1018 per person‐year. Costs of patented single‐tablet regimens ranged from £5000 to £7500 per person‐year. Assuming continued use of patented antiretrovirals in the UK, the predicted total national costs of antiretroviral treatment were predicted to rise from £425 million in 2014 to £459 m in 2015, £495 m in 2016, £536 m in 2017 and £578 m in 2018. With a 100% switch to generics, total predicted costs were £337 m in 2014, £364 m in 2015, £382 m in 2016, £144 m in 2017 and £169 m in 2018. The total predicted saving over five years from a switch to generics was £1.1 billion.ConclusionsSystematic switching from patented to generic antiretrovirals could potentially save approximately £1.1 billion in the UK over the next five years, compared with continued use of patented versions: this money could be spent on urgently needed HIV prevention programmes. Similar savings are feasible for other European countries, given parallel patent expiry dates. More detailed economic evaluation is required to show when patented single‐tablet regimens provide value for money, compared to bioequivalent generic versions of 3–4 pills once daily.
Efavirenz 400 mg daily remains non‐inferior to 600 mg: 96 week data from the double‐blind, placebo‐controlled ENCORE1 study
Authors: Carey Dianne 
Published: November 2014

IntroductionENCORE1 compared the efficacy and safety of reduced versus standard dose efavirenz (EFV) with tenofovir/emtricitabine (TDF/FTC) as first‐line HIV therapy. The primary analysis at 48 weeks showed 400 mg EFV was safe and virologically non‐inferior to 600 mg. This analysis explores over 96 weeks the durability of efficacy and safety.Materials and MethodsA multinational, double‐blind, placebo‐controlled, non‐inferiority trial in treatment‐naïve HIV‐positive adults randomized to TDF/FTC plus reduced (400 mg, EFV400) or standard dose (600 mg, EFV600) EFV. The difference between proportions of participants with plasma HIV RNA (VL) <200 log10 copies/mL by intention‐to‐treat (ITT missing=failure) was compared using a non‐inferiority margin of −10%. Non‐inferiority was also examined in per protocol (PP) and non‐completer = failure (NC=F) populations. Adverse events (AEs) and serious adverse events (SAEs) were summarized by treatment arm.ResultsThe ITT population comprised 630 patients (EFV400 = 321; EFV600 = 309); 32% were female; 37%, 33% and 30% were African, Asian and Caucasian, respectively. A total of 585 (EFV400 = 299; EFV600 = 286) completed 96 weeks on randomized therapy. At 96 weeks, proportions with VL <200 copies/mL were EFV400 (90.0%) and EFV600 (90.6%) (difference −0.6; 95% CI −5.2 to 4.0; p=0.72) demonstrating continued non‐inferiority. Non‐inferior efficacy was also observed for VL thresholds of <50 and <400 copies/mL irrespective of baseline VL (<100,000 versus ≥100,000 copies/mL). There was no between‐arm difference in time to loss of virological response (>200 copies/mL) (p=0.47) or mean change from baseline VL (p=0.74). Mean change from baseline in CD4 T‐cell counts at week 96 remained significantly higher for EFV400 than EFV600 (difference 25 cells/µL; 95% CI 2–48; p=0.03). There was no difference in the frequency or severity of AEs (EFV400 = 89.4%, EFV600 = 89.3%; difference 0.09; 95% CI −4.73 to 4.90; p=0.97). The proportions ever reporting an AE definitely or probably EFV‐related were EFV400 (37.7%) and EFV600 (47.9%) (difference −10.2%; 95% CI −17.9 to −2.51; p=0.01). SAEs did not differ in frequency (EFV400 = 7.5%, EFV600 = 10.4%; difference −2.9%; 95% CI −7.3 to 1.6; p=0.20).ConclusionsNon‐inferiority of EFV 400 mg to EFV 600 mg when combined with TDF/FTC as initial HIV therapy was confirmed at week 96. Both doses demonstrated similar safety profiles. These results support the use of a lower EFV dose as part of routine HIV management.
Patients’ willingness to take separate component antiretroviral therapy regimens for HIV in the Netherlands
Authors: Engelhard Esther , Smith Colette , Vervoort Sigrid , Kroon Frank , Brinkman Kees , Nieuwkerk Pythia , Reiss Peter , Geerlings Suzanne 
Published: November 2014

IntroductionThe costs of combination antiretroviral therapy (cART) consisting of separate, particularly generic, components are generally much lower than of a single tablet regimen (STR) including the same active ingredients. Our aim was to evaluate whether patients in care in the Netherlands would be willing to take separate component regimens (SCR) instead of an STR and to examine whether willingness was associated with particular patient characteristics.Materials and MethodsData from the HIV Monitoring Foundation of all adult HIV‐1‐infected patients in care taking cART>6 months were used to randomly select 1000 patients. As part of a questionnaire developed for a study assessing patient experience, patients were asked whether they were willing to take an SCR instead of an STR. Logistic regression was used to examine associations between age, gender, region of origin, mode of HIV transmission, socioeconomic status, duration of cART and answering “yes” to the question versus “maybe” or “no.” Variables with p<0.1 in the univariate analysis were entered in a multivariate model.ResultsOf the 300 patients who completed the questionnaire, 49% answered “yes,” 24% “maybe” and 27% “no” to the question whether they would be willing to use a SCR. Reasons for answering “no” included difficulties swallowing pills, convenience of STR (especially when travelling/at work), and concerns about side effects. Respondents who answered “maybe” often indicated that they preferred STRs, emphasized the importance of taking the pills once daily, and pointed out that efficacy/safety of an SCR should not be less. Having to pay for medication was reported as a reason to consider switching to an SCR. In the multivariate analysis, respondents who were born outside the Netherlands were less likely; and those with cART use ≥15 yrs were more likely to answer “yes” (Table 1).ConclusionsHalf of the respondents were willing to take SCRs instead of an STR. The likelihood of accepting to switch to SCR seems less for migrants and for those who have commenced treatment more recently. Duration of cART use and region of origin may therefore be factors to take into account when considering to prescribe SCR. Future studies should investigate whether an expressed willingness to switch will translate into maintained high levels of adherence and viral suppression.
Long‐term fat redistribution in ARV‐naïve HIV+ patients initiating a non‐thymidine containing regimen in clinical practice
Authors: Ferrer Elena , Navarro Antonio , Curto Jordi , Medina Pilar , Rozas Nerea , Barrera Gladys , Saumoy Maria , Manuel Tiraboschi Juan , Gomez Carmen , Podzamczer Daniel 
Published: November 2014

IntroductionLipodystrophy is still a matter of concern in HIV+ patients receiving ART. However, long‐term fat change in patients taking non‐thymidine regimens is not well known.Materials and MethodsA prospective ongoing fat change assessment including clinical evaluation and dexa scans (Hologic QDR 4500) is being conducted in all consecutive patients initiating ART from January 2008. Arm, leg, trunk and total fat as well as fat mass ratio (FMR=% trunk fat/% leg fat) were determined. Patients with data at baseline (BL), 12 and 36 m are included in this analysis. ITT and OT were performed. Multivariate general linear models were used to assess changes in fat measures.ResultsOne hundred patients were included. 81% men, 42.9 years, 18% AIDS, CD4 218.5 (6‐756), viral load 5 log (2.9‐6.8), leg fat 4644g, trunk fat 6693g, FMR 0.94. Around 40 patients (40%) initiated a PIr (17 LPVr, 11 ATVr, 9 DRVr, 3 FPVr), 34 (34%) NVP and 21 (21%) EFV. About 83% received TDF/FTC and 10% ABC/3TC. Groups were comparable at BL except for a lower viral load in NVP patients (p=0.047) and lower c‐LDL in PI patients (p=0.043). After 36 m, no patient presented a clinically evident lipodystrophy. At 12 m, an overall significant increase was found from baseline in trunk, leg and FMR (median 759 g, 479.4 g and 0.03, respectively, p<0.05) and at 36 m in trunk and leg fat (median 989.9 g, 566 g, respectively, p<0.05). According to ART, at 12 m a significant increase in trunk and leg fat was observed in EFV and PIr. At 36 m, in NVP patients trunk and leg fat as well as FMR increased, whereas in PIr patients only leg fat increased (see figure). In ITT analysis, adjusted by age, sex, risk practice and BL CD4, EFV was associated with a greater increase in FMR (p=0.036) at 36 m vs PIr. In OT analysis, at 12 m, NVP was associated with a smaller percentage increase in trunk fat (vs PIr and EFV, p=0.006) and in leg fat (vs PIr, p=0.046). These differences did not persist at 36 m.ConclusionsIn this cohort of patients taking non‐thymidine‐based regimens, after 36 m without a clinically evident lipodystrophy, no significant changes in FMR were observed. However, some differences in fat redistribution according to ART were present: PIr was associated with an initial and continuous increase in trunk and leg fat, NVP with a slower and progressive increase in both fat compartments, while in EFV patients, the initial fat increase was followed by a decrease in peripheral fat at 36 m. Longer follow up will help to confirm these trends.
Polymorphisms in LPL, CETP, and HL protect HIV‐infected patients from atherogenic dyslipidemia in an allele‐dose‐dependent manner
Authors: Echeverría Patricia , Guardiola Montse , González Marta , Carles Vallvé Joan , Puig Jordi , Bonjoch Anna , Clotet Bonaventura , Ribalta Josep , Negredo Eugenia 
Published: November 2014

IntroductionHIV‐infected patients treated with Highly Active Antiretroviral Therapy (HAART) may be predisposed to hypertriglyceridemia, which gives rise to a highly atherogenic lipid profile known as atherogenic dyslipidemia (AD). We propose that genetic variability leaves some HIV‐infected patients more predisposed to AD than others [1, 2].MethodsThis was a cross‐sectional, observational study conducted in 468 antiretroviral‐treated HIV‐infected patients attending at the outpatient clinic of a tertiary hospital over a 6‐month period, who were classified as normolipidemic (n=173) or presenting with AD (triglycerides: 1.7 mmol/L and HDLc < 1.02 [men] or 1.28 mmol/L [women]) (n=148). Polymorphisms were identified in the APOA5, APOC3, LPL, CETP, HL, MTP, APOE, LRP5 and VLDLR genes.ResultsAtherogenic dyslipidemia was detected in 31% of patients, most of whom were men (77%). This group was also older and had higher levels of remnant lipoprotein cholesterol (RLPc) than normolipidemic patients. The polymorphisms rs328 in LPL, rs708272 in CETP and rs1800588 in HL were 10–40% significantly more frequent in normolipidemic patients. At least 1 of these polymorphisms was detected in 90% of normolipidemic patients; in AD patients, the percentage decreased to 75% (p=0.003). This effect was dependent on both the allele and the dose of HAART and independent of the regimen administered. The protective combination showed a trend towards higher HDLc (1.13 [0.40] vs 1.24 [0.23] mmol/L), lower triglycerides (2.23 [2.34] vs 1.89 [1.24] mmol/L) and lower RLPc (16.41 [11.42] vs 12.99 [11.69] mmol/L).ConclusionsPolymorphisms in LPL, CETP and HL protect HIV‐infected patients from developing AD in a dose‐dependent manner [3].
Clinical significance of the UGT1A1*28 allele detection in HIV‐infected patients
Authors: Kanestri Veronika , Mironov Konstantin , Kravchenko Alexey , Pokrovskaya Anastasiya , Dribnohodova Olga , Dunayeva Elena , Tsiganova Galina , Harbutly Marina , Goliusova Marina , Konnov Vladislav , Kozirina Nadezhda , Shahgildyan Vasiliy , Kuimova Ulyana , Popova Anna , Efremova Oksana , Konnov Danila 
Published: November 2014

IntroductionThe UGT1A1*28 (rs8175347) polymorphism is associated with hyperbilirubinemia. The presence of 6 TA‐repeats in the UGT1A1 gene promoter region corresponds to normal UGT1TA1 activity. A detection of 7 TA‐repeats in hetero‐ or homozygous individuals [(TA)6/(TA)7 and (TA)7/(TA)7] is associated with lower UGT1TA1 activity, which may eventually result in the development of Gilbert syndrome and/or modified individual response to drugs metabolized by this enzyme. ATV contributes to the decreased levels of UGT1A1, which may lead to elevations of indirect bilirubin, jaundice and even to therapy discontinuation. We evaluated the prevalence of the UGT1A1*28 among HIV‐infected patients and the dependence of the frequency and severity of AE during ATV treatment on individual genetic characteristics.Materials and Methods47 HIV‐infected patients was screen for UGT1A1 genotype and the presence of UGT1A1*28. All patients received ATV in the HAART regimen for 48 weeks. Changes in the total, direct and indirect bilirubin, ALT, AST, GGT and jaundice were evaluated. Statistical analysis was performed using Microsoft Office Excel for Windows XP Professional 2007 and Biostat.ResultsAll patients were followed up in the AIDS Center (males 72.3%, median age 33 years, median CD4+ count‐282 cells/µl (19.5%)). HBV/HCV was in 36.2% patients. Ten patients had risk factors that could affect bilirubin turnover (chronic cholecystitis, biliary dyskinesia, etc.). Genotype (TA)6/(TA)6 was found in 42.6% patients, (TA)6/(TA)7‐42.6% and (TA)7/(TA)7‐14.9%. Overall prevalence of UGT1A1*28 was 57.4%, and homozygous allele frequency was 14.9%. G3/4 of indirect bilirubin were detected in 36.2% patients [(TA)6/(TA)6 in 10–20%, (TA)6/(TA)7‐25‐40%, (TA)7/(TA)7‐72‐86%], and significant jaundice in 10.6% [80% with (TA)7/(TA)7]. The OR for hyperbilirubinemia>40 µmol/L in patients with heterozygous UGT1A1*28 was increased 3 times over patients without this allele (OR 3.07, 95% CI 1.54–4.6) and 34 times as compared with homozygotes (OR 33.9, 95% CI 31.45–36.35). The presence of additional risk factors increased the probability of G3/4 hyperbilirubinemia. No significant changes in the ALT, AST, and GGT levels were observed.ConclusionsThe risk of severe hyperbilirubinemia during ATV treatment is minimal for patients without UGT1A1*28 and no more than one additional risk factor and for patients with UGT1A1*28 and no additional risk factors; patients with homozygous genotype UGT1A1*28 are at the highest risk.
Using social network methods to reach out‐of‐care or ART‐nonadherent HIV+ injection drug users in Russia: addressing a gap in the treatment cascade
Authors: Amirkhanian Yuri , Kelly Jeffrey , Kuznetsova Anna , Meylakhs Anastasia , Yakovlev Alexey , Musatov Vladimir , Chaika Nikolay 
Published: November 2014

IntroductionHIV treatment to reduce downstream HIV incidence and to decrease disease mortality and morbidity at a population level both require that hidden, out‐of‐care people living with HIV (PLH) in the community be reached and engaged to enter care. This research evaluated the feasibility of reaching out‐of‐care or non‐adherent PLH through members of their social networks in St Petersburg, Russia.Materials and MethodsTo recruit a social network sample of HIV‐positive injection drug users, 16 HIV+ seeds were enrolled into the study through PLH‐oriented websites and online forums using recruitment ads or approached in needle exchange sites. Interested persons called the study phone number and completed a brief eligibility interview. Seed inclusion criteria were HIV+ status, being 18 years or older, having ever injected drugs, and having not visited an HIV doctor in the past 6 months. Seeds provided blood specimens tested for HIV to confirm their self‐reported status. Eligible seeds were enrolled, completed brief network elicitation interview, and were asked to invite their own HIV+ friends into the study. Incentives were provided as compensation for participants’ time and additional smaller incentives were provided for inviting each HIV+ network member to also participate. The seed's PLH friends established the first ring of participants who, in turn were asked to invite their own PLH friends (second ring). All study participants completed assessment of psychosocial wellbeing and sexual and injection‐related HIV risk behaviour. Blood samples were collected from all participants to confirm their HIV+ status.ResultsThrough this chain referral process, the initial 16 seeds led to the enrolment of a total of 66 PLH from the community (mean=4 per initial seed), most of whom – like the seed – were not presently in HIV care or were ART non‐adherent.ConclusionsImplementation of treatment cascade goals requires complementing conventional paths of identifying PLH with feasible and effective community‐based approaches such as described in this study. This research establishes that PLH are connected in their day‐to‐day social networks with other HIV+ persons and shows that social network methods can be employed to reach infected persons through their connections with other PLH. This method has the potential to expand the reach of medical care efforts and ART uptake.