bluuebunny/crossref_metadata_2025 huggingface dataset:
Rate of viral load failure over time in people on ART in the UK Collaborative HIV Cohort (CHIC) study
Authors: O'Connor Jemma , Smith Colette , Lampe Fiona , Johnson Margaret , Sabin Caroline , Phillips Andrew
Published: November 2014

Introduction

Most people achieve and maintain viral load (VL) suppression on first‐line antiretroviral therapy (ART) but for a minority this does not happen. It is unclear whether those who have maintained VL suppression for several years will be able to continue to do so, or if rates of VL failure – due to poor adherence, ART interruption and/or resistance – remain at appreciable levels.

Methods

Eligible participants were ART‐naïve and started treatment after 1st January 2000, with ≥3 antiretrovirals and ≥9 months follow‐up. VL failure was defined as failure to achieve VL suppression (≤50 copies/mL) by 9 months on ART or a single VL >200 copies/mL after 9 months after start of ART. Kaplan‐Meier estimates were used to examine the cumulative probability of experiencing a VL >200 copies/mL over time, irrespective of treatment interruption (Figure 1). Follow‐up was censored at last VL assessment but not at treatment interruption. In a sensitivity analysis, VL failure was instead defined as two consecutive VL >1000 copies/mL.

Results

A total of 13,556 participants were included. Median (IQR) age at start of ART was 37 (32–43), median follow‐up 4.1 (2.3–6.7) years, pre‐ART VL 71,400 (17,400–221,900) copies/mL and pre‐ART CD4 count 204 (110–290) cells/mm3. Fifty‐one percent were white, 71% male and 50% MSM. Of which, 5,351 (39%) participants experienced a VL >200 copies/mL. In sub‐groups of participants the proportion experiencing a VL >200 copies/mL by one year after start of ART were: <50 years 22%, ≥50 years 17%, men 20%, women 26%, MSM 19%, black heterosexuals 23%, white heterosexuals 26% and other 23%. The median time to VL >200 copies/ml was 8 years. In sensitivity analyses based on 12,811 participants, 4274 (33%) experienced two consecutive VL >1000 copies/mL. Table 1 presents the rate of experiencing a VL >200 copies/mL (two consecutive VL >1000 copies/mL) by time since start of ART. The rate of VL >200 copies/mL declines over time, from 30 per 100 person‐years after up to two years after ART, to two per 100 person‐years after up to 11.5 years after ART. A sum of 2,047 (15%) participants stopped ART at some point (10, 14 and 17% had stopped ART by 1, 3, and 5 years, respectively).

Conclusions

Although resistance will often not be present and, even if present, several drug options will likely remain, first occurrence of VL > 200 copies/mL after having attained viral suppression continues to occur after 10 years on ART.
HIV‐1 attachment inhibitor prodrug BMS‐663068 in antiretroviral‐experienced subjects: week 24 sub‐group analysis
Authors: Brinson Cynthia , Lalezari Jacob , Gulam Latiff H , Thompson Melanie , Echevarria Juan , Treviño‐Pérez Sandra , Stock David , Samit Joshi R , George Hanna J , Lataillade Max
Published: November 2014

Introduction

BMS‐663068 is a prodrug of BMS‐626529, an attachment inhibitor that binds directly to HIV‐1 gp120, preventing initial viral attachment and entry into the host CD4+ T‐cell. AI438011 is a Phase IIb, randomized, active‐controlled trial investigating the safety, efficacy and dose–response of BMS‐663068 versus atazanavir/ritonavir (ATV/r) in treatment‐experienced (TE), HIV‐1‐positive subjects.

Materials and Methods

Antiretroviral TE subjects (exposure to ≥1 antiretroviral for ≥1 week) with susceptibility to all study drugs (BMS‐626529 IC50 100 nM), were randomized equally to four BMS‐663068 arms (400 or 800 mg, BID; 600 or 1200 mg, QD) and a control group (ATV/r 300/100 mg QD) with tenofovir disoproxil fumarate (TDF) + raltegravir (RAL). A sub‐group analysis of viral efficacy and immunologic reconstitution is presented.

Results

A total of 251 subjects were treated. Median age was 39 years, 60% were male and 38% were white. Median baseline (BL) viral load (VL) was 4.85 log10 c/mL (43%; 100,000 c/mL) and median CD4+ T‐cell count was 230 cells/mm3 (38%; 200 CD4 cells/mm3). Through Week 24, response rates (HIV‐1 RNA 50 c/mL) were comparable across all BMS‐663068 arms and the ATV/r arm regardless of gender, age and race. Response rates for subjects with BL VL 100,000 c/mL (BMS‐663068, 82‐96%; ATV/r, 93%) were higher than those for subjects with BL VL ≥100,000 c/mL (BMS‐663068, 70‐87%; ATV/r, 73%); however, there were no substantial differences in response across the BMS‐663068 and ATV/r arms in either sub‐group. Response rates for subjects with BL CD4+ cell counts ≥200 cells/mm3 (87‐96%) were higher than those for subjects with BL CD4+ cell counts 200 cells/mm3 (62–82%); however, no substantial differences in response were seen across the BMS‐663068 and ATV/r arms in either sub‐group. Mean changes in CD4+ T‐cell counts from BL were similar across all arms regardless of gender, age and BL CD4+ T‐cell count.

Conclusion

Virologic response rates were similar across the BMS‐663068 and ATV/r arms in TE subjects, regardless of BL demographic characteristics (gender, race, age), BL HIV‐1 RNA, or BL CD4+ T‐cell count. Mean increases in CD4+ T‐cell counts across the BMS‐663068 arms were consistent with ATV/r, regardless of gender, age and BL CD4+ T‐cell count. These results support continued development of BMS‐663068.

Note

Previously submitted at IDWeek, Philadelphia, PA, 8 October 2014.
Safety profile of HIV‐1 attachment inhibitor prodrug BMS‐663068 in antiretroviral‐experienced subjects: week 24 analysis
Authors: Lalezari Jacob , Latiff Gulam H , Brinson Cynthia , Echevarria Juan , Treviño‐Pérez Sandra , Bogner Johannes R , Stock David , Joshi Samit R , Hanna George J , Lataillade Max
Published: November 2014

Introduction

BMS‐663068 is a prodrug of BMS‐626529, an attachment inhibitor that binds directly to HIV‐1 gp120, preventing initial viral attachment and entry into the host CD4+ T‐cell. AI438011 is an ongoing, Phase IIb, randomized, active‐controlled trial investigating the safety, efficacy and dose–response of BMS‐663068 vs. atazanavir/ritonavir (ATV/r) in treatment‐experienced (TE), HIV‐1‐positive subjects. At Week 24, response rates across the BMS‐663068 arms were consistent with ATV/r.

Materials and Methods

Antiretroviral TE subjects (exposure to ≥1 antiretroviral for ≥1 week) with susceptibility to all study drugs (including BMS‐626529 IC50 100 nM) were randomized equally to four BMS‐663068 arms (400 or 800 mg, BID; 600 or 1200 mg, QD) and a control arm (ATV/r 300/100 mg QD), with tenofovir disoproxil fumarate (TDF) + raltegravir (RAL). The complete safety profile through Week 24 is reported.

Results

In total, 251 subjects were treated (BMS‐663068, 200; ATV/r, 51). No BMS‐663068‐related adverse events (AEs) led to discontinuation. Grade 2–4 drug‐related AEs occurred in 17/200 (8.5%) subjects across the BMS‐633068 arms; however, these events were mostly single instances and no dose‐relationship was seen. Similarly, no noticeable trend for Grade 3–4 laboratory abnormalities was seen and Grade 3–4 hematologic changes and liver chemistry elevations were uncommon (neutropenia, 2.5%; AST/ALT elevations, 1% (n=196)). In the ATV/r arm, Grade 2–4 drug‐related AEs occurred in 14/51 (27.5%) subjects and were mostly secondary to gastrointestinal and/or hepatobiliary disorders. Serious adverse events (SAEs) occurred in 13/200 (6.5%) and 5/51 (9.8%) subjects receiving BMS‐663068 and ATV/r, respectively; most were secondary to infections and none were related to study drugs. The most common AE reported for BMS‐663068 was headache (28/200, 14%), occurring in 5/51 (10%) subjects in the ATV/r arm; in the BMS‐663068 arms, this was not dose‐related. There were no deaths.

Conclusions

BMS‐663068 was generally well tolerated across all arms, with no related SAEs or AEs leading to discontinuation and no dose‐related safety signals. There were no trends for Grade 2–4 AEs or clinical laboratory abnormalities. These results support continued development of BMS‐663068.

Note

Previously submitted at IDWeek, Philadelphia, PA, 8 October 2014.
Rates of cardiovascular events and deaths are associated with advanced stages of HIV‐infection: results of the HIV HEART study 7, 5 year follow‐up
Authors: Esser Stefan , Eisele Lewin , Schwarz Birte , Schulze Christina , Holzendorf Volker , Brockmeyer Nobert H , Hower Martin , Kwirant Friedhelm , Rudolph Roland , Neumann Till , Reinsch Nico
Published: November 2014

Introduction

Cardiovascular diseases are increasing in aging HIV‐positive patients (HIV+). Impact of traditional cardiovascular risk factors, HIV‐specific parameters and antiretroviral therapy (ART) on the incidence of cardiovascular events (CVE) and on the mortality rate are investigated in different HIV+ cohorts.

Methods

The HIV HEART (HIVH) study is an ongoing prospective observational cohort study in the German Ruhr area to assess the frequency and clinical course of cardiac disorders in 1481 HIV+ by standardized non‐invasive cardiovascular screening. CVE were defined as diagnosed or documented myocardial infarction, coronary heart disease, arterial coronary intervention, stent implantation, bypass operation and stroke.

Results

1481 HIV+ subjects (mean age: 49.3±10.7 years (y), female: 15.6%) were included. 130 CVE and 90 deaths were documented until the end of 7, 5 year follow‐up of HIVH. Mean duration of the HIV‐infection was 12.9±6.8 y. HIV+ were treated with ART on average for 8.6±6.8 y. According to the CDC classification of the HIV‐infection, HIV+ were distributed over the clinical categories (A:34.6%; B:31.4% and C:33.9%) while more than the half had an advanced immunodeficiency (I:8.3%; II:41.1%; III:50.7%). Advanced clinical and immunological stages were significantly (p<0.001) associated with higher incidences of deaths (A:16.7%; B:26.7%; C:56.7% and I:6.7%; II:27.7%; III:65.6%) and CVE (A:17.7%; B:33.1%; C:49.2% and I:3.1%; II:32.3%; III:64.6%) but not with the duration of HIV‐infection (per y: Hazard ratio (HR): 0.91 [0.88–0.94]) and ART (per y: HR: 0.81 [0.79–0.84]) adjusted for age. The proportion of deceased HIV+ with HIV‐RNA ≥50 copies/mL and lower CD4‐cell counts at their last visit is significantly higher compared with living HIV+ without CVE (HIV‐RNA ≥50 copies/mL: 25.6% vs 14.7%). Median CD4‐cells: 286.5 cells/µL (IQR: 168.8–482.8) versus 574 cells/µL (IQR: 406–786). 96.1% of the living HIV+ with CVE had HIV‐RNA<50 copies/mL and median CD4‐cells 542.5 cells/µL (IQR: 370–793.5).

Conclusions

Advanced clinical and immunological stages of HIV‐infection, but not the duration of ART, were associated with higher incidences of CVE and deaths in the HIVH cohort. These observations support an earlier initiation of ART in HIV+. Special cardiovascular risk calculations for HIV+ should consider immunological and clinical categories of the HIV‐infection.
Cardiovascular markers of inflammation and serum lipid levels in HIV‐infected patients with undetectable viraemia
Authors: Viskovic Klaudija , Zidovec‐Lepej Snjezana , Gorenec Lana , Grgic Ivana , Lukas Davorka , Zekan Sime , Dragobratovic Anja , Begovac Josip
Published: November 2014

Introduction

Successfully treated HIV‐infected patients may still have an increased risk for cardiovascular morbidity and mortality, which might be related not only to traditional risks, but also to inflammation and dyslipidemia induced by HIV and/or antiretroviral therapy [1, 2]. We examined the relationship of serum lipid levels with plasma biomarkers of inflammation using a composite inflammatory burden score (IBS) from the following seven markers of inflammation: CD40L, tPA, MCP‐1, IL‐8, IL‐6, hCRP and P‐selectin.

Materials and Methods

Subjects were selected among consecutive HIV‐infected males ≥18 years of age with an undetectable viral load (<50 copies/mL of HIV1‐RNA), seen at the University Hospital for Infectious Diseases, Zagreb, Croatia, in the period from January 2012 to March 2013. Plasma inflammatory biomarkers (CD40L, tPA, MCP‐1, IL‐8, IL‐6, hCRP and P‐selectin, quantified by bead‐based cytometry) >75th percentile were considered elevated and an IBS was constructed as the presence of zero, one, two, or three or more elevated biomarkers. Correlations between the IBS and lipid parameters were examined using Spearman's Rho and by ordered logistic regression proportional odds model to estimate the odds of more elevated (>75th percentile) biomarkers.

Results

181 male patients were included into the study, the median age was 46.7 (Q1–Q3, 39.9–55.0) years and the median current CD4 cell count was 553.0 (Q1–Q3, 389–729) per microliter. The patients were mainly treated with two nucleoside reverse transcriptase inhibitor (NRTI) plus one non‐NRTI (NNRTI) (N=100, 60.8%) or two NRTI plus lopinavir (N=50, 27.6%). There was a significant correlation between the IBS and serum cholesterol (Rho=0.23, 95% CI, 0.09–0.37), triglycerides (Rho=0.30, 95% CI, 0.16–0.42) and cholesterol/HDL‐cholesterol ratio (Rho=0.25, 95% CI 0.11–0.38). In the multivariable model a one unit increase in cholesterol/HDL‐cholesterol ratio was associated with a 1.72‐fold (95% CI, 1.27–2.33) increased odds of having a greater IBS. One unit increase (mmol/L) of cholesterol and triglycerides was associated with a 1.41‐fold (95% CI, 1.13–1.76) and 1.37‐fold (95% CI, 1.18–1.60) increased odds of having a greater IBS, respectively.

Conclusions

Our study suggests that in virologically suppressed patients there is a significant association between markers of inflammation and serum levels of cholesterol and triglycerides as well as the cholesterol/HDL‐cholesterol ratio.
Prevalence and concordance of high cardiovascular disease scores in HIV/AIDS patients from Croatia and Serbia with four international algorithms
Authors: Begovac Josip , Dragovic Gordana , Viskovic Klaudija , Kusic Jovana , Perovic Mihanovic Marta , Lukas Davorka , Jevtovic Djordje
Published: November 2014

Introduction

We evaluated cardiovascular risks in HIV‐infected patients from Croatia and Serbia and the eligibility for statin therapy as recommended by the 2013 American College of Cardiology/American Heart Association (ACC/AHA) guidelines, European AIDS Clinical Society (EACS) Guidelines and European Society of Cardiology and the European Atherosclerosis Society (ESC/EAS) guidelines for cardiovascular disease (CVD) prevention [1–3].

Materials and Methods

A cross‐sectional analysis of consecutive patients between 40 and 79 years old who had received antiretroviral therapy for at least 12 months was performed.

Results

Of 254 (132 from Croatia and 122 from Serbia) persons included in the study, 76% were male; median age was 49 years. Up to 51.6% of persons had a high CVD risk. The prevalence of current smoking was 42.9%, hypertension 31.5% and hypercholesterolaemia (>6.2 mmol/L) 35.4%. Statins would be recommended to 21.3% (95% CI, 16.3% to 27.4%) of persons by the EACS, 25.6% (95% CI, 20.2% to 31.9%) by ESC/EAS and 37.9% (95% CI, 31.6 to 44.6%) by the ACC/AHA guidelines. A high 5‐year data collection on adverse effects of anti‐HIV drugs study risk score (>5%) had a moderate agreement with the high (≥20%) 10‐year CVD Framingham risk score (kappa=0.47) and high (≥5%) 10‐year European systematic coronary risk evaluation score algorithm (kappa=0.47), and substantial agreement with the elevated (≥7.5%) 10‐year Pooled Cohort Atherosclerotic CVD risk equation score (kappa=0.63).

Conclusion

We found a high prevalence of CVD risks in patients from Croatia and Serbia. The ACC/AHA guideline would recommend statins more often than ESC/EAS and EACS guidelines.
Lipid‐lowering agents for dyslipidemia in patients who were infected with HIV in Taoyuan, Taiwan
Authors: Cheng Shu‐Hsing , Cheng Chien‐Yu , Sun Na‐Lee
Published: November 2014

Introduction

There is no doubt that highly active antiretroviral therapy (ART) has decreased the total mortality of HIV‐infected populations drastically, and HIV has become a chronic and manageable condition. However, complications after long‐term treatment of ART tarnished the great efforts. We aimed to study the effects of add‐on lipid‐lowering agents on ART for patients who developed hyperlipidemia after HIV treatment. The risk factors for failure to normalize lipid profile were analyzed.

Materials and Methods

HIV‐infected patients who visited outpatient clinics of Taoyuan General Hospital between July 2013 and January 2014 were retrospectively reviewed. Subjects who needed the management of dyslipidemia were enrolled. Total cholesterol (TC), triglyceride (TG), high‐density lipoprotein (HDL) and low‐density lipoprotein (LDL) were regularly followed up for at least 6 months. ART modification and add‐on lipid‐lowering agents for dyslipidemia were analyzed.

Results

There were 926 HIV‐infected patients undertaking ART in the hospital during the study period. Among them, 23.2% of patients undergoing lopinavir‐based regimen, 8.4% efavirenz‐based regimen, 4.2% darunavir‐based regimen, 3.3% nevirapine‐based regimen, 2.4% raltegravir‐based regimen and 2.3% atazanavir‐based regimen developed dyslipidemia. There were 76 patients (8.2%) who needed management of dyslipidemia (Table 1). Among them, 97% received lipid‐lowering agents, and 17% switched to lipid‐friendly ART (atazanavir, boosted atazanavir, boosted darunavir, nevirapine or raltegravir) despite statins or fibrates used. Mean values (mg/dL) of TC/ TG/LDL were, respectively, 279/422/139 before enrolment, 209/270/114 at 4–12 weeks and 206/250/121 at 48 weeks (p<0.05 for baseline compared to 4–12 weeks and 1 year, respectively). No obvious changes in HDL were noted. In Cox proportional hazard model, patients who received lopinavir (adjusted hazard ratio [aHR], 0.293; 95% confidence interval [CI], 0.110–0.784; p=0.015) or efavirenz (aHR, 0.185; 95% CI, 0.072–0.447; p=0.005) were less likely to achieve normalization of TC (<200 mg/dL) and TG (<200 mg/dL). Modification of ART (aHR, 1.807; 95% CI, 0.828–3.944; p=0.137) did not change the outcome (Figure 1).

Conclusions

Efavirenz and lopinavir were independent factors for the persistence of dyslipidemia despite adding lipid‐lowering agents. ART associated with a favourable lipid profile would be considered in the modern era, and this certainly leaves the question of cost versus benefit.
Estimation of the true incidence of lactic acidosis within the Lighthouse Clinic cohort, and the likely magnitude of missed diagnoses in the region
Authors: Speight Colin , Gabriel Layout , Phiri Sam , Tweya Hannock , Sutherland Rebecca
Published: November 2014

Introduction

Lactic acidosis is one of the most serious side effects associated with ART, most commonly associated with stavudine. Clinical features are non‐specific and specialist laboratory capabilities are essential to confirm the diagnosis, making under‐diagnosis likely in resource‐constrained settings. Lighthouse Trust is a tertiary referral ART centre with over 23,500 patients on ART. The adjacent University of North Carolina Project laboratory, also serving Kamuzu Central Hospital, has been the only site processing lactate tests in Central Zone for many years. Our objective was to quantify the true incidence within our cohort, and estimate the likely degree of historical missed diagnoses from less central ART clinics.

Methods

All high lactate results between June 2010 and June 2013 were treated as cases, and cross referenced with the Lighthouse database. Patients transferring in to Lighthouse within one month prior to diagnosis were assumed to have been referred due to their lactic acidosis, and moved to the Central Zone cohort to avoid referral bias. Routinely collected quarterly ART cohort data for both Lighthouse and the entire Central Zone were analyzed.

Results

Over the three‐year period, from within the Lighthouse cohort, there were 138 cases: 74% were female, median duration on ART was 14 months (IQR 10–26), and 98.5% were attributable to stavudine (only two cases to zidovudine). Over this period, the average number of patients taking stavudine at Lighthouse was 10,960 (3,600 on zidovudine). For the whole Central Zone (minus Lighthouse patients) there were 61,000 on stavudine (4,830 on zidovudine), yet only 124 cases of lactic acidosis were apparently diagnosed from within this cohort.

Conclusions

Although cases may, of course, also have been missed at Lighthouse, as a tertiary referral centre the rate observed is likely to be closer to the true incidence. Over the three years, with 138 cases from the 10,960 patients taking stavudine at Lighthouse, it is likely that somewhere in the region of 700 additional cases occurred amongst the 61,000 patients elsewhere in the Central Zone. This equates to somewhere in the region of 550 missed diagnoses or 80% of all cases. Given that the clinical sequelae of undiagnosed lactic acidosis are either death or at best ART default, this provides further vindication for the decision to phase out stavudine in Malawi.
Lipohypertrophy and metabolic disorders in HIV patients on antiretroviral therapy: a systematic multidisciplinary clinical approach
Authors: Sculier Delphine , Toutous‐Trellu Laurence , Verolet Charlotte , Matthes Nicolas , Lecompte Thanh , Calmy Alexandra
Published: November 2014

Introduction

Morphological and metabolic complications in HIV patients on antiretroviral therapy remain a challenge. While new cases of lipoatrophy (LA) disappear, irreducible central lipohypertrophy (LH) and metabolic complications require highly specialized management. We described a day hospital dedicated to lipodystrophy (LD) and metabolic disorders in HIV patients on treatment in Geneva, Switzerland, with a focus on LH.

Materials and Methods

The “Groupe Lipo & Metabolism” is a multidisciplinary consultation where patients undergo a standard evaluation including questionnaire, physical examination, dual‐energy x‐ray absorptiometry (DEXA) and L5‐level CT scans, blood tests and consultations with various specialists. Based on prospectively maintained data, we describe clinical, biological and radiological characteristics of patients ≥18 years who attended the consultation between 2008 and 2013. We defined LH by CT scan, the gold standard method, as abdominal visceral adipose tissue (VAT) ≥130 cm2, value associated with increased risk of cardiovascular event.

Results

A total of 195 patients attended the consultation during study period. Reasons for referral included LH in 28.3%, LA in 25% and mixed syndrome in 15.5% of cases. Metabolic disorders accounted for 19% of referrals with or without LD features. Among patients with a CT scan performed (n=183), 46 (25%) had LH with a VAT ≥130 cm2. In this population, mean age was 49.1 years and 53.6% were male. HIV viral load was <50 cp/ml in 87% of patients. Mean body mass index was 24.6 kg/m2. Mean waist to hip ratio (WHR) was 0.98 for males and 0.89 for females. A total of 9.8%, 29.5% and 35% of patients had abnormal levels of total cholesterol (≥6.5 mmol/L), triglycerides (≥2.0 mmol/L) and HDL cholesterol (≤1.0 mmol/L), respectively. Mean fasting glycaemia was 5.7 mmol/L and HbA1c was >6% in 10.5% of patients. Vitamin‐D level was <75 nmol/L in 70.7% of patients. Respectively 31.2% and 12.1% of patients had osteopenia and osteoporosis on the spine and 44.8% and 6.6% on the hip neck. Factors associated with a VAT≥130 cm2 included male gender (OR 3.7 [95% CI 1.7–8.2] p<0.001), triglycerides ≥2 mmol/L (OR 2.6 [95% CI 1.3–5.4] P<0.01) and increase in BMI category (OR 1.8 [95% CI 1.2–2.8] p<0.01).

Conclusions

Lipohypertrophy is a prevalent feature of fat redistribution among HIV patients on treatment. Risk factors for LH include male gender, dyslipidemia and overweight. Glucose impairment and bone disorders are also common. A multidisciplinary approach is important to identify and promptly address these disorders.

Acknowledgments

The “Groupe Lipo & Metabolism” team.
Nephrolithiasis and renal failure among patients exposed to atazanavir, other PIs and PI‐free regimens
Authors: Nkhoma Ella , Kumar Monica , Hines Patricia , Moorthy Vidya , Klauck Isabelle , Villasis Keever Angelina
Published: November 2014

Introduction

Recent single‐site studies and case reports have linked atazanavir (ATV) with the occurrence of nephrolithiasis. The purpose of this study was to estimate and compare the incidence rate of nephrolithiasis and to characterize the occurrence of subsequent renal failure among patients on ATV, other protease inhibitors (PIs) and PI‐free regimens using real world data.

Materials and Methods

This was a retrospective cohort analysis using claims data from a US commercial and a US public health insurance database (Medicaid) spanning 2003–2011 and 2006–2011, respectively. We identified adult HIV patients who were prescribed ATV, other PIs or PI‐free regimens with at least 6 months of continuous enrolment prior to the index claim. Nephrolithiasis was defined as an inpatient or outpatient ICD‐9 diagnosis code for nephrolithiasis or an associated condition, plus an imaging/corrective procedure code. Renal failure was also identified using diagnosis codes among patients experiencing nephrolithiasis. Hazard ratios were estimated using propensity score (PS) adjusted Cox regression, crude and adjusted for demographics, baseline comorbidities and comedications.

Results

A total of 14,477 patients (ATV: 4,150; other PIs: 4,153; PI‐free: 6,174) were identified in the commercial database: 83% male and 20% age ≥50 years. In the Medicaid database, 9,104 patients (ATV: 3,460; other PIs: 3,117; PI‐free: 2,527) were identified: 53% male and 25% age ≥50 years. There were significant baseline differences in demographics, comorbidities and concomitant medications among the three cohorts. In adjusted analyses, ATV use was not significantly associated with nephrolithiasis when compared to other PIs. When ATV was compared to PI‐free regimens, a positive association was observed in the commercial insurance but not the Medicaid database. In both databases, previous history of nephrolithiasis was the strongest predictor of nephrolithiasis in the ATV/PI‐free regimens contrast, but not the ATV/other PIs contrast. For the renal failure outcomes, there were insufficient cases across all cohorts to conduct crude or adjusted analyses (see Table 1).

Conclusions

In this analysis of two large real world databases, we did not find evidence of an increased risk of nephrolithiasis among patients on ATV compared to other PIs. However, when ATV was compared to PI‐free regimens, the results differed across the two databases, requiring further study. Additionally, renal failure following nephrolithiasis was infrequent and not significantly different across the three cohorts.
Prevalence and European AIDS Clinical Society (EACS) criteria evaluation for proximal renal tubular dysfunction diagnosis in patients under antiretroviral therapy in routine setting
Authors: Pitisci Lorenzo , Demeester Rémy , Legrand Jean‐Claude
Published: November 2014

Introduction

Tenofovir (TDF) is an antiretroviral drug often used in combination regimen in HIV‐positive patients. Adverse effects affecting kidneys consist in an increase or a new onset proteinuria, a decrease of glomerular filtration rate (GFR), and/or a proximal renal tubular dysfunction (PRTD) that rarely leads to Fanconi's syndrome. EACS guidelines propose to screen PRTD in patients with chronic renal insufficiency, with a sudden decrease of eGFR, with hypophosphataemia (if non‐renal causes such as vitamin D deficiency are excluded) and with a new onset proteinuria. We aim to evaluate the prevalence of PRTD by comparing the group of patients under TDF to the group free of TDF, in our cohort of 300 patients. We also aim to evaluate the accuracy of EACS criteria for screening PRTD in routine settings and to assess the utility of urinary samples in PRTD diagnosis.

Materials and Methods

During two consecutive years, we collected annually blood and urine samples at the same time in our outpatient clinic. We assessed kidney function, plasma levels and fractional excretion of phosphate, uric acid, potassium, plasma glucose and proteinuria. PRTD was defined by the presence of at least two out of the five following criteria: fractional excretion (FE) of phosphate >20% (or >10% when serum phosphate <0.8 mmol/L), non‐diabetic glycosuria (positive urine glucose with plasma glucose <70 mg/dL), renal tubular acidosis (urinary pH >5.5 and serum bicarbonate <21 mmol/L), uric acid FE >10% or potassium FE >10%. After the first year, patients with TDF regimen who were diagnosed with PRTD were shifted to TDF‐free regimen and included again in the study.

Results

For PRTD (first line), they are expressed in number of diagnoses/total number of patients in this group. The second line resumes the number of PRTD diagnose patients who should have been screened according to EACS criteria.

Conclusions

PRTD screening according to EACS criteria is not sufficient to diagnose every case, especially minor PRTD, mainly because the prevalence is low and its diagnosis remains difficult in routine settings. We recommend performing a urine test including proteinuria every year for patients undergoing TDF treatment. The next step will be to follow PRTD patients to evaluate the time laps until full recovery after TDF shift.
Prevalence of osteoporosis and predictors of low BMD in a cohort of HIV‐1‐infected patients in Rome: features of a population at high risk
Authors: D'Avino Alessandro , Lassandro Annapia , Lamonica Silvia , Piccoli Benedetta , Fabbiani Massimiliano , Mondi Annalisa , Gagliardini Roberta , Borghetti Alberto , Fanti Iuri , Pallavicini Federico , Cauda Roberto , Di Giambenedetto Simona
Published: November 2014

Introduction

Ageing of HIV‐infected patients led to an increasing rate of osteopenia and osteoporosis. The cause is multifactorial, including virus activity, drug toxicity and host factors. The aim of our analysis is to quantify this issue according to our department experience and to evaluate predictors of low BMD.

Materials and Methods

HIV‐1‐infected patients, on stable HAART, were consecutively enrolled in this cross‐sectional study and underwent DEXA. We analyzed the prevalence and evaluated predictors of low BMD in our population.

Results

We collected data from 208 patients, 148 of whom were male, with 49 years median age (IQR 24.1–68.3). About 39% of patients were heterosexuals, 33.7 MSM and 12.5% were IDU, 40.4% were smokers. Caucasians were 93.3%, and 13.9% were co‐infected with HCV virus. Around 6.7% of patients were on their first HAART regimen and all of them started TDF. Their median time of HAART exposure was 1.17 years (IQR 0.8–1.6). Conversely, median time of HAART exposure of multi‐experienced patients was 8.5 years (IQR 3.1–12.0). We stratified DEXA results for patients on first‐line regimen versus multi‐experienced one. We found that 42.9% of patients on first‐line HAART had low BMD of lumbar spine and 7.1% had osteoporosis. Regarding the multi‐experienced group of patients, lumbar spine osteopenia was observed in 36.6% of patients and 15.5% of them had osteoporosis. Median age of patients with low BMD of lumbar spine was 45.6 (IQR 24.1–68.3) for patients on first‐line regimen and 49.8 years for multi‐experienced (IQR 44.2–54.0) regimen. We found similar data for BMD of hip, but no patients in the first group had hip osteoporosis. We also analyzed predictors of low BMD in our population. MSM patients showed a 3.4‐fold higher risk to have osteoporosis of lumbar spine (OR 3.41, CI 1,105–9,269, p=0.03). As expected, we found that non‐Caucasian patients had 13.5‐fold higher risk to have osteoporosis of the hip (OR 13.52, CI 1.5–122.7, p=0.02). Exposure to HAART was also evaluated, but no predictors were found.

Conclusions

Our data confirm how osteoporosis is highly prevalent and occurs earlier in HIV‐infected patients. Antiretrovirals play a crucial role. In our experience loss of BMD can occur within a year of treatment, when almost half of our patients starting TDF had a low BMD. MSM patients have a higher risk to develop spine osteoporosis and non‐Caucasian patients are more likely to have hip osteoporosis. We remark the importance of BMD assessment for HIV‐infected patients especially during their first months of treatment.
Co‐administration of ritonavir‐boosted protease inhibitors and rate of tenofovir discontinuation in clinical practice
Authors: Costarelli Silvia , Cozzi‐Lepri Alessandro , Lapadula Giuseppe , Bonora Stefano , Madeddu Giordano , Maggiolo Franco , Antinori Andrea , Gori Andrea , D'Arminio‐Monforte Antonella
Published: November 2014

Introduction

In clinical trials, toxicity leading to discontinuation of tenofovir (TDF) is a rare occurrence (3% by two years)[1, 2]; however, in clinical practice it seems to be higher. Previous studies suggested that TDF toxicity is higher when it is co‐administered with ritonavir‐boosted protease inhibitors (PI/r)[3, 4]. The aim of this study is to assess the rate of TDF discontinuations in clinical practice and to explore associated factors.

Methods

All previously antiretroviral‐naïve patients initiating a TDF‐containing regimen were selected from the ICONA cohort, unless they were positive for hepatitis B. The primary outcome was TDF discontinuation (>30 days) regardless of the reason, the secondary was TDF discontinuation due to toxicity. All analyses were repeated for the isolated stop of TDF (no stop of associated drugs). The main reason for discontinuation as reported by the treating physicians was used to classify stops. Kaplan–Meier (KM) analysis and Cox proportional hazards model were used.

Results

A total of 3,303 naïve patients were enrolled: 674 (20.4%) were female, the median age was 38 years (32–45), 55% were on PI/r‐based regimen and 45% on NNRTI; 80% of calculated estimated glomerular filtration rates (eGFR) were >90 ml/min. The probability of discontinuation of TDF regardless of the reason was 10% (95% CI 8–11) at two years, 20% by eight years. The causes of discontinuation were: toxicity (33%), failure (10%), non‐adherence (21%), simplification (16%) and other/unknown causes (20%). The five‐year KM estimates in the PI/r vs. not PI/r groups were 23% vs. 10%, respectively (log‐rank p=0.0001), for the outcome of stopping regardless of the reason, and 8% vs. 4% (p=0.18) for discontinuation due to toxicity. In a multivariable Cox model, PI/r use and lower body weight were associated with increased risk of discontinuing TDF regardless of the reason; lower eGFR at baseline was associated with TDF discontinuation for toxicity and PI/r use was associated with isolated stop of TDF (Figure). No differences in rates of TDF discontinuations between PIs were found.

Conclusion

In our cohort, the observed frequency of TDF discontinuations was low although higher than estimated in clinical trials (10% by two years). Co‐administration of TDF with PI/r was associated with an increased rate of TDF discontinuations. This finding should guide further investigations of the mechanism that may have led to discontinuation of TDF in patients using PI/r.
Efficacy and safety of etravirine‐containing regimens in a large cohort of HIV/HCV coinfected patients according to liver fibrosis
Authors: Luis Casado Jose , Mena Alvaro , Bañón Sara , Moreno Ana , Castro Angeles , Perez‐Elías María J , Pedreira JD , Moreno Santiago
Published: November 2014

Introduction

Etravirine has become an alternative in HIV/HCV coinfected patients because of safety and lack of interactions with anti‐HCV drugs. The aim of this study was to establish the risk of liver toxicity in HIV/HCV coinfected patients receiving etravirine in the clinical setting, according to the degree of liver fibrosis and different accompanying drugs.

Material and Methods

Cohort study of 211 patients initiating etravirine as part of their antiretroviral regimen. HCV coinfection was defined as a positive RNA‐HCV, whereas baseline liver fibrosis was assessed by transient elastography at baseline. Hepatotoxicity was defined as an increased AST/ALT, 5‐fold higher over upper, normal limits for patients with normal baseline values, or 3.5‐fold if altered at baseline.

Results

HCV coinfection was observed in 145 patients (69%) with a longer time of HIV infection and time on HAART than mono‐infected patients, and a lower nadir (182 vs 227 cells/mL; p=0.02) and baseline CD4+ count (446 vs 552 cells/mL; p=0.02). Etravirine was used with two nucleoside analogues in 62%, with boosted darunavir in 17%, with raltegravir in 10%, and with darunavir plus raltegravir or maraviroc in 10% of patients without differences according to HCV serostatus. Transient elastography in 117 patients performed at etravirine initiation (median, 33 days) showed fibrosis 1 and fibrosis 4 in 37% and 24% of cases, and median stiffness value was 8.25 kPa (3.5–69). During an accumulated follow‐up of 449.3 patient‐years (median, 611 days), only one coinfected patient with fibrosis 4 (stiffness value, 50.1 kPa), receiving a rescue regimen including darunavir/r plus maraviroc plus two nucleoside analogues, developed a grade 3‐4 of liver toxicity (0.5%). There were no other episodes of liver toxicity, as defined, and only 6 (3%) and 9 patients (4%) had a grade 1 and 2 of toxicity, respectively, in most cases related to HCV coinfection (6 and 6 cases). Moreover, HCV coinfection or advanced fibrosis was not associated to a higher risk of etravirine discontinuation (26% vs 21%; p=0.27, log‐rank test) or virologic failure (9% vs 11%, p=0.56). CD4+ cell count increase was lower in HCV patients (+23 vs +86 at 6 month; p=0.02).

Conclusions

Etravirine is safe in HIV/HCV coinfected patients, even in presence of moderate and advanced liver fibrosis and as part of different antiretroviral regimens.
Cerebral volumes, neuronal integrity and brain inflammation measured by MRI in patients receiving PI monotherapy or triple therapy
Authors: Pérez Valero Ignacio , Gonzalez Baeza Alicia , Antonio Hernandez‐Tamames Juan , Monge Susana , Arnalich Francisco , Ramon Arribas Jose
Published: November 2014

Introduction

Penetration of protease inhibitors (PI) in the central nervous system (CNS) is limited. Therefore, there are concerns about the capacity of PI monotherapy (MT) to control HIV in CNS and preserve brain integrity.

Methods

Exploratory case‐control study designed to compare neuronal integrity and brain inflammation in HIV‐suppressed patients (>2 years) with and without neurocognitive impairment (NI), treated with MT or triple therapy (TT), 3‐Tesla cerebral magnetic resonance image (MRI) and spectroscopy (MRS) were used to evaluate neuronal integrity (volume of cerebral structures and MRS levels of N‐acetyl‐aspartate (NAA)) and brain inflammation (MRS levels of myo‐inositol (MI) and choline (CHO)). MRS biomarkers were measured in 4 voxels located in basal ganglia, frontal (2) and parietal lobes. A comprehensive battery of tests (14 tests ‐ 7 domains) was used to diagnose neurocognitive impairment [1].

Results

We included 18 neurocognitively impaired patients (MT: 10, TT: 8) and 21 without NI (MT: 9; TT: 12, Table 1). Subset of patients with NI: cerebral volumes and MRS biomarkers were mostly similar between MT and TT with exception of the right cingulate nucleolus volume (MT: 8854±1851 vs TT: 10482±1107 mm3; p<0.04), CHO levels in basal ganglia (MT: 0.44±0.05 vs TT: 0.37±0.03 MMOL/L; p<0.01) and the NAA levels in parietal lobe (MT: 1.49±0.12 vs 1.70±0.13 MMOL/L; p<0.01). Subset of patients without NI: cerebral volumes and MRS biomarkers were mostly similar between MT and TT with exception of MI levels in frontal lobe (MT: 1.20±0.36 vs 0.81±0.25 MMOL/L; p=0.01).

Conclusions

We did not find significant differences in cerebral volumes or MRS biomarkers in most areas of the brain. However, we found higher levels of inflammation and neuronal damage in some brain areas of patients who received MT. This observation has to be taken into caution while we could not adjust our results by potential confounders. Further investigation is needed to confirm these preliminary results.
Quality of life of people living with HIV, preliminary results from IANUA (Investigation on Antiretroviral Therapy) study
Authors: Venturini Alberto , Giannini Barbara , Montefiori Marcello , Di Biagio Antonio , Mazzarello Giovanni , Cenderello Giovanni , Giacomini Mauro , Merlano Caterina , Orcamo Patrizia , Setti Maurizio , Viscoli Claudio , Cassola Giovanni
Published: November 2014

Introduction

The introduction of combined antiretroviral treatment (cART) has reduced HIV‐associated morbidity and mortality, and changed the patients’ perspective of life. As a result, Health Related Quality of Life (HRQOL) has become a crucial clinical issue.

Objective

Assessment of HRQOL in a sample of Italian patients from IANUA study. Investigate correlation between CD4 cell counts, viral load and changes in HRQOL.

Materials and Methods

EQ‐5D‐3L self‐reported questionnaire has been used in the evaluation of HRQOL. It assesses five dimensions: “mobility,” “self care,” “usual activities,” “pain/discomfort” and “anxiety/depression.” Each dimension has three levels: no problems, some problems and extreme problems. In addition, it includes a Visual Analogue Scale (VAS) where one's own health “today” is rated from 0 “worst imaginable health” to 100 “best imaginable health.” The respondents provide information on marital status, education, employment/unemployment, other treatments used in addition to HAART (1,2,3,4,5 or more) and number of hospitalizations due to HIV/AIDS.

Results

684 patients completed the questionnaire: 231 females and 453 males. The mean age of the sample was 51 years (range 21–78). The mean VAS score was 69.9. 558 patients (81.5%) reported no problems in mobility. 642 patients (93.5%) had no problems in self care. 423 patients (61.8%) had no pain/discomfort while 219 had some problems. 326 patients (46.1%) had some problems in anxiety/depression.

Conclusions

The analysis of self‐reported questionnaires indicates that HRQOL in our sample group is not deeply affected by HIV/AIDS. The dimensions that are affected in the least are “mobility” and “self care” while the major problem is “anxiety/depression” with half of the sample reporting moderate or high level.
Potential implications of CYP3A4, CYP3A5 and MDR‐1 genetic variants on the efficacy of Lopinavir/Ritonavir (LPV/r) monotherapy in HIV‐1 patients
Authors: Berno Giulia , Zaccarelli Mauro , Gori Caterina , Tempestilli Massimo , Pucci Luigia , Antinori Andrea , Perno Carlo Federico , Paolo Pucillo Leopoldo , D'Arrigo Roberta
Published: November 2014

Introduction

Several genetic single nucleotide polymorphisms (SNPs) in biotransformation enzymes (CYP3A4, CYP3A5) or transporter proteins (multidrug resistance MDR1 gene product, P‐gp) are involved in PI metabolism so that PI pharmacokinetics is characterized by a large inter‐individual variability. The aim of this study was: (i) to develop an in‐house PCR/direct sequencing, based on DNA purification of full‐length CYP3A4 and CYP3A5 genes (SNPs) and MDR1 C3435T variant; (ii) to investigate association of CYP3A4 and CYP3A5 reported or unreported genetic polymorphisms and MDR1‐C3435T (CC homozygote, CT heterozygote, TT homozygote) with clinical outcome of HIV‐1 infected subjects treated with PI.

Methods

Overall, 39 HIV‐1 infected patients receiving boosted Lopinavir (LPV/r) monotherapy after virological suppression were genotyped and analyzed through PCR and direct sequencing of full‐length CYP3A4 and CYP3A5 gene sequences [1] and MDR1 gene (C3435T). CD4+T‐cell counts and plasma viral load were analyzed before and after LPV/r initiation; LPV/r therapeutic drug monitoring (TDM) was determined at 12‐hours.

Results

LPV/r TDM (ng/ml) did not show significant differences among CYP3A4 or CYP3A5 SNPs, although a mean lower level of LPV/r was associated with detection of several SNPs: CYP3A5*3 rs776746; CYP3A5 rs28365088, CYP3A5 rs15524, CYP3A4 rs2687116, and a not already described polymorphism CYP3A4 nt20338. In follow‐up analysis, <90% adherence was the main factor associated with virological failure of LPV/r monotherapy (83.3% of failure vs 34.4%, p<0.001 at log‐rank test). Adjusting for adherence, the detection of a single CYP3A5*3 rs776746 and CYP3A5 rs15524 SNPs was associated with higher probability of LPV/r monotherapy failure (p<0.01), and in general, detection of any CYP3A5 SNP was associated with failure (26.2% vs 58.3%, p=0.067). No‐association with detection of any CYP3A4 SNPs was found. MDR1 TT variants showed significant lower frequency of treatment failure (0.0% vs 47.7%, p=0.026), since non‐TT homozygote patient failed LPV/r monotherapy.

Conclusions

Efficacy of PI monotherapy is strongly dependent from patient adherence, but, in adherent patients, genetic factors, such as CYP3A5 and MDR1‐C3435T gene variants, may affect the response to treatment, though their role, as well of other genetic variants, need further investigation.
Efficacy, safety, and lack of interactions with the use of raltegravir in HIV‐infected patients undergoing antineoplastic chemotherapy
Authors: Bañón Sara , Machuca Isabel , Araujo Susana , Moreno Ana , Perez‐Elías María J , Moreno Santiago , Casado Jose Luis
Published: November 2014

Introduction

Concomitant use of combination antiretroviral regimen (cART) and cancer chemotherapy is difficult due to complex interactions and increased toxicity. Raltegravir could be an adequate option through its favourable drug‐drug interaction profile.

Methods

Prospective longitudinal study of HIV patients with cancer, AIDS related or not, undergoing chemotherapy. Patients without resistance or previous failure were switched or initiated raltegravir plus two nucleoside analogues. Plasma trough levels of raltegravir were measured.

Results

Overall, 28 patients receiving a raltegravir‐based regimen (4 naive) with tenofovir‐emtricitabine (18 cases) or abacavir‐lamivudine (10 cases) were included. Mean age was 46.2 years (IQR, 39–52.7), and 79% were male. Median time of HIV was 201.7 months, CD4+ nadir was 268 cells/mm3, and 75% had previous AIDS. At the diagnosis of neoplasia, 17 were on protease inhibitors and 4 with efavirenz. Ten patients had a non‐HIV‐related cancer (three breast, two pancreatic, one Ewing sarcoma, one myeloblastic leukemia, one melanoma, one parotid adenocarcinoma, one lung), and 18 had an HIV‐related cancer (nine non‐Hodgkin lymphoma, seven Hodgkin disease, two anal). Overall, 43% of patients received more than one line of chemotherapy, including antimetabolites in 12 patients (5‐FU, capecitabine, methotrexate, gemcitabine), alkylating agents in 12 cases (ciclophosphamide, iphosphamide), vinca alkaloids in 20 patients (vincristine, vinblastine, vindesine), antitumor antibiotics in 16 cases (adriamycin), cisplatin o carboplatin in six and monoclonal antibodies in six patients (rituximab, trastuzumab, cetuximab). Six patients modified the doses of antineoplastic agents due to toxicity (four neutropenia), not related to raltegravir. During a median follow up of 12.7 patients‐year in concomitant therapy, there was only 1 case of virological failure and no patient discontinued raltegravir. Plasma concentrations of raltegravir in eight patients showed a median concentration of 143 ng/mL (79–455). Four patients (14%) died during the study, not related to AIDS progression. Raltegravir was continued after chemotherapy in all the cases.

Conclusions

A raltegravir‐based therapy is safe and effective in HIV patients undergoing antineoplastic chemotherapy, regardless of the type of tumour, and type and duration of chemotherapy. Pharmacokinetic data show adequate raltegravir levels.