bluuebunny/crossref_metadata_2025 huggingface dataset:
Mechanisms underlying abnormalities of immune activation/coagulation in HIV infection
Authors: Lane Clifford
Published: November 2014

Immune activation has been recognized as an important component of the pathogenesis of HIV infection since the first recognition of cases of AIDS in the early 1980s. Early in the AIDS epidemic, patients with HIV infection were noted to have elevated levels of serum immunoglobulins. CD38 expression on CD4+ T cells was shown to be an independent predictor of survival in 1999. The characterization of HIV‐associated immune activation has become progressively sophisticated over the past several years. A consistent finding has been an association of poor clinical outcomes with markers of monocyte activation (IL‐6 and sCD14) and/or coagulation (D‐dimer). These relationships have been shown to exist even in patients with plasma levels of HIV‐1<50 copies/ml. While it is generally accepted that immune activation is related to HIV infection, there is less clarity regarding the pathways that lead to its expression. Among the forces reported to drive HIV‐associated immune activation are innate and adaptive immune responses to HIV and related co‐infections, homeostatic responses to CD4+ T cell depletion and translocation of microbial products across the intestinal wall. Recent work has identified a potential role for “defective” HIV‐1 transcripts in driving immune activation. Studies examining the connections between the adaptive immune system and the coagulation cascade have led to the identification of PAR‐1 as a potential target for therapeutic intervention. Despite the successes experienced with cART, persistent immune activation in association with HIV infection remains a scientific and clinical problem that is yet to be solved.
Efavirenz‐ but not nevirapine‐based antiretroviral therapy decreases exposure to the levonorgestrel released from a sub‐dermal contraceptive implant
Authors: Scarsi Kimberly , Lamorde Mohammed , Darin Kristin , Dilly Penchala Sujan , Else Laura , Nakalema Shadia , Byakika‐Kibwika Pauline , Khoo Saye , Cohn Susan , Merry Concepta , Back David
Published: November 2014

Introduction

Sub‐dermal hormone implants, such as levonorgestrel (LNG), are a safe and desirable form of long‐acting contraception, but their use among HIV‐positive women on antiretroviral therapy (ART) may be compromised given the potential for a cytochrome P450 3A‐mediated drug–drug interaction. Our study aimed to characterize the pharmacokinetics of LNG released from a sub‐dermal implant over six months in HIV‐positive Ugandan women on nevirapine (NVP)‐ or efavirenz (EFV)‐based ART.

Material and Methods

This non‐randomized, parallel group study compared LNG pharmacokinetics between HIV‐positive Ugandan women not yet eligible for ART (control group, n=18) and those on stable NVP‐ (n=20) or EFV‐ (n=20) based ART. The two‐rod (75 mg/rod) LNG sub‐dermal implant was inserted at study enrolment. LNG sampling was obtained pre‐implant and at weeks 1, 4, 12 and 24 post‐insertion. LNG concentrations were analyzed using a validated LC‐MS/MS method, with an assay calibration range of 50–1500 pg/mL. Safety monitoring, including a pregnancy test, was conducted at each study visit.

Results

At enrolment, participants had a mean age of 31 years; CD4+ cell counts were similar between the control, NVP and EFV groups (758, 645 and 568 cells/mm3, respectively; p=0.09); all women in the NVP and EFV groups had an undetectable HIV‐RNA. Women in the control group had a higher baseline body weight (73 kg) compared to those in the NVP (63 kg; p=0.03) or EFV groups (60 kg; p<0.01). By linear regression, weight was a significant predictor of LNG concentrations (1 kg increase in weight=5 pg/mL decrease in LNG, p=0.03). LNG concentrations are reported in the table.

Conclusions

Over a 24‐week period, LNG concentrations were 40–54% lower in women on EFV‐based ART, despite their having a significantly lower body weight, compared to those not on ART. In women on NVP‐based ART, LNG concentrations were 32–39% higher than those observed in the control group, a difference partially explained by body weight. These data confirm a significant drug interaction occurs between the LNG implant and EFV, adding to growing concern for reduced contraceptive efficacy with their combined use. In contrast, these data support use of the LNG implant with NVP‐based ART.
From guidelines to action: implementation opportunities and realities
Authors: El‐Sadr Wafaa
Published: November 2014

The past decade has seen notable progress in confronting the HIV epidemic. By the end of 2013, almost 13 million persons living with HIV had access to antiretroviral therapy (ART) in low‐ and middle‐income countries (LMIC). In addition, progress has also been achieved in terms of HIV prevention with 26 LMIC achieving a 50% decrease in number of new infections including 15 countries in sub‐Saharan Africa. New research findings also offer new efficacious prevention interventions that offer new opportunities for further mitigation of new HIV infections. Such progress has inspired ambitious pronouncements such as achieving “The End of AIDS” or “An AIDS Free Generation.” This progress has also motivated the development of new guidelines aimed to achieving these goals. Implementation of guideline recommendations, however, requires translation of these guidelines into actionable steps and then their successful delivery within established health services. The opportunities offered by new guidelines frequently meet the realities of the frailties of the health system. Achieving current ambitious global targets must confront the specific deficits in the health system that inhibit access and acceptability of programmes as well as hinder achievement of high quality or desired coverage.
Rational allocation of resources available for healthcare: understanding cost effectiveness analyst
Authors: Briggs Andrew
Published: November 2014

Health systems around the world are grappling with the difficult issue of how to allocate scare healthcare resources. Within Europe many different approaches to healthcare resource allocation exist, but it is clear that the formal techniques of cost‐effectiveness analysis are becoming increasingly important. This presentation will first address the fundamental economic principles of scarcity and opportunity cost, before looking at how different European systems are attempting to address the economic challenge of providing healthcare for their population from a limited budget. The presentation will go on to consider general issues in health economic evaluation that are likely important for clinical community focused on HIV treatment: appropriate comparator treatments for defining opportunity cost, patient heterogeneity and the potential for personalized/stratified medicine to control costs and target treatment appropriately.
Enhancing patient self‐management
Authors: Volny‐Anne Alain
Published: November 2014

In the context of HIV as a chronic disease, care being delivered with more constrained budgets and being more complex as many patients are ageing, the need for disease self‐management is increasingly recognized. Like in other chronic diseases, HIV care and treatment guidelines increasingly promote the enhancement of health management by patients, within a framework of closer collaboration with their healthcare providers. Therefore, patients progressively become key resources on which health systems should count for efficiency and improvement. Is this a principle or is this reality? We are aware that to count in healthcare, resources must be allocated the necessary support. How does the required support translate into patients’ real lives? Do patient education programmes respond adequately to these needs? Are chronic care models really applicable in contexts where care is not yet sufficiently coordinated, especially with regards to people who are ageing with HIV and the multiple types of care they need? How far should a patient take responsibility for making best of healthcare resources? From the perspective of a person living and ageing with HIV, the role of patients in the management of their own health will be discussed.
Hepatitis C, from screening to treatment, a revolution
Authors: Lacombe Karine
Published: November 2014

Initially associated with blood transfusions and hospital care, the hepatitis C virus (HCV) epidemic has since moved rapidly onwards to intravenous drug users, where it poses a major problem still today. Despite numerous harm reduction programs, such as needle exchange, opiate substitution and controlled shooting galleries, drug addiction remains the number one route of HCV transmission around the world. However, in HIV‐positive patients, the HCV epidemic experienced a major shift in the mid‐90s, with sexual transmission among particularly men who have sex with men (MSM) surfacing as a major route of HCV acquisition. Until recently, therapeutic options in HCV infection had been quite limited, based largely on the use of combined Peg‐interferon and ribavirin, with disappointing results in HIV‐positive patients. With the recent, exciting developments in HCV research, new targets on the virus replication cycle have been discovered. After the release in 2011 of the first direct antiviral agents inhibiting the NS3/4 antiprotease, the development of drugs with newer mode of action, more efficient and with higher tolerance profiles has greatly accelerated. They may greatly change the course of treatment: once daily, highly active and easily‐tolerated regimens, administered for a short period of time with HCV eradication in more than 90% of patients, independently of prior treatment, level of fibrosis and comorbidities such as HIV co‐infection. This definitely has the potential to curb the HCV epidemic towards an HCV cure, provided that advocacy for broad‐access to treatment is successful for those most in need. Their use in resource‐constrained settings may also be the next political challenge for HCV.
Safety and efficacy of ombitasvir – 450/r and dasabuvir and ribavirin in HCV/HIV‐1 co‐infected patients receiving atazanavir or raltegravir ART regimens
Authors: Eron Joseph J , Lalezari Jay , Slim Jihad , Gathe Joseph , Ruane Peter J , Wang Chia , Elion Richard , Blick Gary , Khatri Amit , Hu Yiran B , Gibbons Krystal , Fredrick Linda , Co Melannie , D'Amico Ronald , Da Silva‐Tillmann Barbara , Trinh Roger , Sulkowski Mark S
Published: November 2014

Objective

Whether concomitant HIV antiretroviral therapy (ART) affects the safety and efficacy of interferon‐free HCV therapies or whether HCV treatment may negatively affect HIV control is unclear. We assessed the 3 direct‐acting antiviral (3D) regimen of ombitasvir, ABT‐450 (identified by AbbVie and Enanta; co‐dosed with ritonavir) and dasabuvir with ribavirin (RBV) in HCV/HIV‐1 co‐infected patients with and without cirrhosis, including HCV treatment‐experienced, receiving atazanavir (ATV)‐ or raltegravir (RAL)‐based ART therapy.

Methods

HCV genotype 1‐positive treatment‐naïve or pegIFN/RBV‐experienced patients, with or without Child‐Pugh A cirrhosis, CD4+ count ≥200 cells/mm3 or CD4 + % ≥14%, and plasma HIV‐1 RNA suppressed on stable ART received open‐label 3D + RBV for 12 or 24 weeks. Rates of HCV‐sustained virologic response at post‐treatment weeks 4 and 12 (SVR4 and SVR12, respectively) and bilirubin‐related adverse events (AEs) are reported from post‐hoc analyses for subgroups defined by treatment duration and ART regimen.

Results

The SVR12 rate for patients receiving 12 weeks of 3D + RBV was 93.5% with comparable rates in patients receiving either ATV (93.8%) or RAL therapy (93.3%) (Table 1). The SVR4 rate for the 24‐week arm was 96.9% with a single virologic breakthrough at treatment week 16 in a patient receiving RAL therapy. Patients receiving concomitant ATV had more AEs related to indirect hyperbilirubinemia including ocular icterus, jaundice and grade 3 or 4 elevations in total bilirubin (predominantly indirect). No patient discontinued the study due to AEs, and no serious AEs were reported during or after treatment. No patient had a confirmed plasma HIV‐1 RNA value ≥200 copies/mL during the treatment period.

Conclusions

In this first study to evaluate an IFN‐free regimen in HCV genotype 1‐positive treatment‐naïve and experienced patients with HIV‐1 co‐infection, including those with cirrhosis, high rates of SVR were comparable to those with HCV monoinfection. Indirect hyperbilirubinemia was consistent with the known ABT‐450 inhibition of the OATP1B1 bilirubin transporter, RBV‐related haemolytic anaemia and inhibitory effect of ATV on bilirubin conjugation. The laboratory abnormalities and AEs observed did not negatively affect treatment response or lead to treatment discontinuation.
The cascade of HIV care in Russia, 2011–2013
Authors: Pokrovskaya Anastasia , Popova Anna , Ladnaya Natalia , Yurin Oleg
Published: November 2014

Introduction

The cascade of HIV care is one of the main tools to assess the individual and public health benefits of antiretroviral therapy (ART) and identify barriers of treatment as prevention (TasP) concept realization. We aimed to characterize the changes in engagement of HIV‐positive persons in care in Russia during three years (2011–2013).

Methods

We defined seven steps in the cascade of care framework: HIV infected (estimation data), HIV diagnosed, linked to HIV care, retained in HIV care, need ART, on ART and viral suppressed (VL < 1000 copies/mL during 12 month ART). Information was extracted from the Federal AIDS Centre database and from the national monitoring forms of Rospotrebnadzor from the beginning of 2011 to 31 December 2013.

Results

Nearly 668,032 HIV‐diagnosed Russian residents were alive by the end of 2013, which consisted 49% of the estimated 1,363,330 people living with HIV. Among the alive HIV‐diagnosed patients, 516,403 (77%) were linked to care and 481,783 (72%) were retained. Of 163,822 (25% of HIV diagnosed) patients who were eligible for ART, 156,858 (96%) were on treatment while 127,054 (81%) had viral suppression. However, only 19% of HIV‐diagnosed patients achieved viral suppression which is necessary to prevent viral transmission. We noted substantial improvements over time in the proportion of individuals on ART. The proportion of patients who received ART increased from 24% in 2011 to 34% in 2013. The most significant leakages of patients during three years were on steps: “HIV infected → HIV diagnosed” (loss −55% in 2011, −53% in 2012, and −51% in 2013), “HIV diagnosed → Linked to care” (−23% yearly) and “Retained in care → Need ART” (−76%, −70%, and −66%, respectively).

Conclusion

The stages of HIV diagnosis and estimation of ART eligibility were the most vulnerable to leakage. Encouraging HIV testing and earlier ART initiation are needed to maximize the effects of TasP interventions and to contain the spread of HIV in Russia.
CD4 cell count and the risk of infective and non‐infective serious non‐AIDS events in HIV‐positive persons seen for care in Italy
Authors: Madeddu Giordano , D'Arminio Monforte Antonella , Girardi Enrico , Di Biagio Antonio , Lo Caputo Sergio , Piolini Roberta , Marchetti Giulia , Pellizzer Giampietro , Giacometti Andrea , Galli Laura , Antinori Andrea , Cozzi Lepri Alessandro ,   on behalf of the ICONA Foundation Study
Published: November 2014

Introduction

Serious non‐AIDS events (SNAE) are frequent in HIV patients receiving cART. Current CD4 count was shown to be more strongly associated with infective compared to not‐infective SNAE and unable to predict cardiovascular events. We investigated the relationship between baseline and current CD4 count and the risk of both infective and non‐infective SNAE in HIV‐positive patients according to current ART use.

Methods

We included all HIV‐positive persons enrolled in the ICONA Foundation Study cohort who had at least one follow‐up visit. SNAE were grouped in infective (pneumonia, sepsis, endocarditis and meningitis) and non‐infective (malignancies, chronic kidney disease, cardiovascular events, hepatic events and pancreatitis) aetiology. Incidence of these event groups were calculated overall and according to baseline and current CD4 count (grouped as 0–200, 201–350, 351–500, 501–750, and >750 cells/mm3). Participants’ follow‐up accrued from the date of enrolment (baseline) to a diagnosis of SNAE or their last visit. An event was defined the first time one of the considered SNAE occurred so that each person contributed a single event. A Poisson regression model for each of the two endpoints was used.

Results

A total of 10,822 patients were included (25.3% females, 38.2% heterosexuals) and 26.6% had hepatitis co‐infections. Median age was 36 (IQR 31–42) years. Overall, 423 not‐infective and 385 infective SNAE were included. The most frequent non‐infective SNAE were malignancies (n=202) and the most frequent infective SNAE were pneumonia (n=289). Crude rates of non‐infective SNAE were 0.78, 1.08 and 0.80/100 PYFU, and those of infective SNAE were 1.00, 0.51 and 0.66/100 PYFU in ART naive, currently off and currently on ART patients, respectively. Higher current CD4 count was associated with reduced risk of both infective and non‐infective SNAE in naives and in patients on ART (Table 1). The association was less strong in the group which suspended ART (for non‐infective SNAE the p value for interaction between current log‐CD4 and ART‐status, p=0.004). Conversely, we found no association between baseline CD4 count and risk of non‐infective SNAE in people treated with ART (p value for interaction = 0.0001). When CVD were considered separately, there was no association with CD4 count (not shown).

Conclusions

Our findings show that, differently from ART naive, in ART‐treated patients, non‐infective SNAE are predicted by current but not by baseline CD4, suggesting that immune restoration is crucial to prevent these events.
Cenicriviroc blocks HIV entry but does not lead to redistribution of HIV into extracellular space like maraviroc
Authors: Kramer Victor , Hassounah Said , Colby‐Germinario Susan , Mesplède Thibault , Lefebvre Eric , Wainberg Mark
Published: November 2014

Introduction

Cenicriviroc (CVC), a once‐daily, dual CCR5/CCR2 co‐receptor antagonist, has completed Phase 2b development. CVC demonstrated favourable safety and similar efficacy compared with efavirenz (EFV) in Study 202 (NCT01338883); an ex vivo sub‐analysis evaluated treatment effects on HIV entry, measured by intracellular HIV DNA declines, in subjects with virologic success at Week 24. In addition, in vitro assays determined and compared the extent of any cell‐free virion redistribution that CVC or maraviroc (MVC) may cause.

Methods

Ex vivo: intracellular DNA (frozen PBMCs) from 30 subjects with virologic success at Week 24 (10, 13 and 7 subjects on CVC 100 mg, CVC 200 mg and EFV, respectively). Early (strong‐stop) and late (full‐length) reverse transcript levels were measured by qPCR. In vitro: PM‐1 cells were infected with CCR5‐tropic HIV‐1 BaL in the presence or absence of inhibitory concentrations of CVC (20 nM), MVC (50 nM) or controls. P24 and viral load levels were measured by ELISA and qRT‐PCR after 4 hours.

Results

Ex vivo analysis showed full‐length HIV DNA declines were similar across all groups (CVC 100 mg, CVC 200 mg and EFV) at Week 24. Strong‐stop HIV DNA declines (a marker of HIV entry) at Week 24 were pronounced for both CVC arms (CVC 100 mg, 51% decline; CVC 200 mg, 37% decline) compared to no decline for the EFV arm. In vitro experiments revealed that CVC‐treated cells had lower levels of supernatant P24 at 4 hours versus baseline (0 hrs: 506 ng/mL; 4 hrs: 192 ng/mL), but P24 levels remained constant for MVC‐treated cells after 4 hours (0 hrs: 506 ng/mL; 4 hrs: 520 ng/mL). Viral load levels for CVC‐treated cells remained stable after 4 hours (0 hrs: 1.19×1010 copies/mL; 4 hrs: 1.26×1010 copies/mL). MVC‐treated cells exhibited a slight increase in viral load after 4 hours (0 hrs: 1.19×1010 copies/mL; 4 hrs: 1.67×1010 copies/mL).

Conclusions

Ex vivo analysis confirmed that CVC treatment blocks HIV entry (strong‐stop HIV DNA declines), while in vitro analysis showed that CVC‐treated cells do not repel virus back into the extracellular space, as seen with MVC. Experiments are underway to determine whether or not interactions between CVC and HIV at the binding site may explain these unanticipated findings.
Factors associated with the continuum of care of HIV‐infected patients in Belgium
Authors: Van Beckhoven Dominique , Lacor Patrick , Moutschen Michel , Piérard Denis , Sasse André , Vaira Dolorès , Van den Wijngaert Sigi , Vandercam Bernard , Van Ranst Marc , Van Wijngaerden Eric , Vandekerckhove Linos , Verhofstede Chris , Verbrugge Ruth , Demeester Rémy , De Wit Stéphane , Florence Eric , Fransen Katrien , Delforge Marie‐Luce , Goffard Jean‐Christophe , Goubau Patrick ,   BREACH
Published: November 2014

Introduction

We studied factors associated with the continuum of HIV care in Belgium.

Methods

Data of the national registration of new HIV diagnosis and of the national cohort of HIV‐infected patients in care were combined to obtain estimates of and factors related with proportions of HIV‐infected patients in each step of the continuum of care from diagnosis to suppressed viral load (VL). Factors associated with ignorance of HIV seropositivity were analyzed among patients co‐infected with HIV and STI in the Belgian STI sentinel surveillance network. Associated factors were identified by multivariate logistic regression.

Results

Among 4038 individuals diagnosed with HIV between 2007 and 2010, 90.3% were linked to care. Of 11684 patients in care in 2010, 90.8% were retained in care up to the following year, 88.3% of those were on ART, of whom 95.3% had suppressed VL (<500 cp/ml) (Figure 1). In multivariate analyses, factors associated with ignoring HIV+ status were being younger (p<0.001), being heterosexual compared to MSM, and of a region of origin other than Belgium, Sub‐Saharan Africa and Europe. Non‐Belgian regions of origin were associated with lower entry and retention in care (p<0.001 for both). Preoperative HIV testing was associated with lower entry in care (p=0.003). MSM had a higher retention in care (p<0.001), whilst IDU had lower retention (p=0.004). Low CD4 at first clinical contact and clinical reasons for HIV testing were independently associated with being on ART (p<0.001 for both); whilst prenatal HIV diagnosis was associated with lower proportion on ART (p=0.016) and lower proportion with suppressed VL among those on ART (p=0.005). Older age was associated with both being on ART and having suppressed VL among those on ART (p=0.007 and p<0.001 respectively), independently of time since HIV diagnosis (Table 1).

Conclusions

Regions of origin and risk groups (MSM/heterosexual/IDU) are the main factors associated with ignorance of HIV seropositivity, entry and retention in care, but once the HIV patient is retained in care, no effect of these factors on the proportions on ART and with suppressed VL are observed. The association of prenatal HIV diagnosis and proportions on ART and with suppressed VL could be biased by transitory CD4 disturbances during pregnancy and ART discontinuation after pregnancy. The higher probabilities of older patients to be on ART and have suppressed VL once retained in care could be influenced by factors not studied here like comorbidities, adherence or duration on ART.
No difference in persistence to treatment with atazanavir or darunavir in HIV patients in a real‐world setting
Authors: Farr Amanda M , Johnston Stephen S , Ritchings Corey , Brouillette Matthew , Rosenblatt Lisa
Published: November 2014

Introduction

There is a lack of data comparing the protease inhibitors (PIs) atazanavir (ATV) and darunavir (DRV) in a real‐world setting. This study compared persistence (time to switch/discontinuation) to therapy between ATV‐treated and DRV‐treated patients with human immunodeficiency virus (HIV).

Materials and Methods

Retrospective, observational cohort study using US insurance claims for commercially and Medicaid‐insured patients. Patients were aged ≥18 years and initiated an ATV‐ or DRV‐based regimen boosted with ritonavir between 7/1/2006 and 3/31/2013, with ≥6 months of continuous enrolment prior to and ≥3 months of continuous enrolment following initiation; patients were required to have ≥1 inpatient or outpatient medical claim with an ICD‐9‐CM diagnosis code for HIV during that time period of enrolment. Patients with no claims for antiretroviral therapy (ART) any time prior to initiation were considered to be ART‐naïve. Time to switch/discontinuation was defined as the number of days from initiation of the regimen until earliest of: (1) a ≥30‐day continuous gap in therapy in ATV or DRV; (2) a prescription claim for an ART agent that was not part of the initial regimen (with the exception of changes in concomitant nucleoside reverse transcriptase inhibitors or the addition of integrase inhibitors); (3) censoring at a ≥30‐day continuous gap in therapy in ritonavir; (4) censoring at disenrolment from insurance benefits or (5) censoring at the study end date (9/30/2013 in the commercial data and 12/31/2013 in the Medicaid data). Time to switch/discontinuation was compared using incidence rates and multivariable Cox proportional hazards models adjusted for calendar time, patient demographics and clinical characteristics.

Results

Table 1 displays the study results and cohort sample sizes. Mean ages across the cohorts were 41–42 years. The proportions of patients who were ART‐naïve were 58–59% among the ATV/r cohorts and 53–55% among the DRV/r cohorts. There were no significant differences in the adjusted hazards of switch/discontinuation between the cohorts.

Conclusions

The incidence of switch/discontinuation was higher among Medicaid patients (who may be socioeconomically disadvantaged) than Commercial patients. There were no significant differences in persistence (time to switch/discontinuation) with the initiated PI among HIV patients who initiated an ATV‐based regimen versus a DRV‐based regimen.
Cerebrospinal‐fluid exposure of efavirenz and its major metabolites when dosed at 400 and 600 mg once daily; a randomized controlled trial
Authors: Winston Alan , Puls Rebekah , CSF Sub‐study group Encore
Published: November 2014

Introduction

The optimal penetration of antiretroviral agents into central nervous system (CNS) may be a balance between providing adequate drug exposure to inhibit HIV‐replication whilst avoiding concentrations associated with toxicities.

Methods

Cerebrospinal‐fluid (CSF) exposure of efavirenz and metabolites 7‐hydroxy (7OH‐) and 8OH‐efavirenz were assessed after at least 12 weeks of antiretroviral therapy in HIV‐infected subjects randomized to commence antiretroviral regimens containing efavirenz at either 400 mg or 600 mg once daily. Clinical, pharmacokinetic and pharmacogenomic factors associated with CSF efavirenz and its metabolite concentrations were assessed.

Results

Of 28 subjects who completed all study procedures (14/14 on efavirenz 400 mg/600 mg), CSF HIV RNA was below 20 copies/mL in all at the time of examination. Concentrations of efavirenz and 7OH‐efavirenz in the CSF were slightly lower when dosed at 400 mg versus 600 mg, although this was not statistically significant. A different trend was observed regarding 8OH‐efavirenz concentrations where CSF exposure was slightly increased in the 400 mg efavirenz arm (see Table 1). Efavirenz concentration in the CSF was above 0.51 ng/mL (proposed CSF IC50 for WT virus) in all subjects and 8OH‐efavirenz concentration in the CSF was above 3.3 ng/mL (a proposed toxicity threshold, reference) in 11/14 and 7/14 subjects randomized to the 400 mg and 600 mg doses of efavirenz, respectively. Whilst CSF efavirenz concentration was significantly associated with plasma concentration (P<0.001) and CYP2B6 genotype (CSF efavirenz GG to GT/TT GM ratio 0.56, 90% CI 0.42–0.74), CSF 8OH‐efavirenz concentration was not (P=0.242 for association with plasma concentration and CSF 8OH‐efavirenz GG to GT/TT GM ratio 1.52, 90% CI 0.97–2.36). Lastly, CSF 8OH‐efavirenz concentration was associated with efavirenz symptom questionnaire results at one year (Spearman's correlation 0.13, P=0.05).

Conclusions

With both doses of efavirenz studied, CSF concentrations were considered adequate to inhibit HIV‐replication, although concentrations of 8OH‐efavirenz were greater than that reportedly associated with neuronal toxicity. CSF exposure of 8OH‐efavirenz was not dependent on plasma exposure and we postulate may be subject to saturable pharmacokinetic effects.
Epi‐aortic lesions, pathologic FMD, endothelial activation and inflammatory markers in advanced naïve HIV‐infected patients starting ART therapy
Authors: Bellacosa Chiara , Maggi Paolo , Volpe Anna , Altizio Sergio , Ladisa Nicoletta , Cicalini Silvia , Viglietti Rosaria , Chirianni Antonio , Bellazzi Lara , Zanaboni Domenico , Maserati Renato , Martinelli Canio , Corsi Paola , Sofia Silvia , Celesia Maurizio , Sozio Ferdinando , Abbrescia Nicola , Angarano Gioacchino
Published: November 2014

Introduction

PREVALEAT II (PREmature VAscular LEsions and Antiretroviral Therapy II) is an ongoing multicenter, longitudinal cohort study aimed to the evaluation of cardiovascular (CV) risk in advanced HIV‐infected antiretroviral (ARV) naïve patients starting their first antiretroviral therapy (ART).

Patients and methods

All consecutive naïve patients with CD4 cell count<200/mL starting any PI/r‐based or NNRTI‐based + 2 NRTIs regimen from January 2010 to January 2013 in the participant centres were enrolled. At baseline and after 3 (T1), 6 (T2) and 12 (T3) months patients were subjected to epi‐aortic vessels ultrasonography and brachial artery flow mediated dilation (FMD). Viral load, CD4+ cell count, serum lipid values, serum glucose, endothelial activation (ICAM‐1 and VCAM‐1) and inflammatory markers (IL‐6 and hsCRP) values were recorded at the same time. Data about independent risk factors for HIV infection and CV disease are taken at time 0. We enrolled 94 patients: 81% males, 87% caucasians, 40% smokers, 8.2% HCV co‐infected and 3.5% with lipodystrophy; 33% of them were homosexuals, 12% drug addicts; 23% were AIDS at presentation. Statistical data analysis has been conducted by the χ2 nonparametric method.

Results

In Table 1 it is reported the percentage of patients with pathologic values, moreover, at T3, 60.46% showed undetectable viraemia and 69.77% had CD4 + > 200.

Conclusions

Our data evidence at baseline has a relevant deterioration of CV conditions in terms of ultrasonographic data, FMD, inflammation and cytokine markers among advanced naïves. During follow‐up epi‐aortic lesions tend to worsen but not significantly, percentage of pathologic FMD remains stable. Regarding markers of endothelial activation ICAM‐1 significantly worsens during the period of observation; also VCAM‐1 has a trend towards the worsening while not significantly. Conversely, a significant improvement was observed for the markers of inflammation D‐dimers and high sensitivity C‐reactive protein (hsCRP). IL‐6 improved but not significantly. Serum lipid profile shows an increase of HDLc and total cholesterol, but not of LDLc. In conclusion, after a twelve‐month follow‐up period, CV risk of the patients remains high. ARV therapy seems in fact to improve only non‐specific and poor sensitive inflammation biomarkers and HDLc; markers of endothelial activations tend to worsen, intima‐media ultrasonography and FMD do not show relevant modifications. Further data are warranted to better understand the role of the different ARV regimens.
Randomized, crossover, double‐blind, placebo‐controlled trial to assess the lipid lowering effect of co‐formulated TDF/FTC
Authors: Ramón Santos José , Saumoy María , Curran Adrian , Bravo Isabel , Navarro Jordi , Estany Carla , Podzamczer Daniel , Ribera Esteban , Negredo Eugenia , Clotet Bonaventura , Paredes Roger
Published: November 2014

Introduction

Previous studies have described improvements on lipid parameters when switching from other antiretroviral drugs to tenofovir (TDF) and impairments in lipid profile when discontinuing TDF. [1–3] It is unknown, however, if TDF has an intrinsic lipid‐lowering effect or such findings are due to the addition or removal of other offending agents or other reasons.

Materials and Methods

This was a randomized, crossover, double‐blind, placebo‐controlled clinical trial (NCT 01458977). Subjects with HIV‐1 RNA <50 copies/mL during at least 6 months on stable DRV/r (800/100 mg QD) or LPV/r (400/100 mg BID) monotherapy, with confirmed fasting total cholesterol ≥200 or LDL‐cholesterol ≥130 mg/dL and not taking lipid‐lowering drugs were randomized to (A) adding TDF/FTCduring 12 weeks followed by 24 weeks without TDF/FTC, or (B) continuing without TDF/FTC for 12 weeks, adding TDF/FTC for 12 weeks and then withdrawing TDF/FTC for 12 additional weeks. Randomization was stratified by DRV/r or LPV/r use at study entry. All subjects received a specific dietary counselling. Primary endpoints were changes in median fasting total, LDL and HDL‐cholesterol 12 weeks after TDF/FTC addition. Analyses were performed by ITT.

Results

46 subjects with a median age of 43 (40–48) years were enrolled in the study: 70% were male, 56% received DRV/r and 44% LPV/r. One subject withdrew the study voluntarily at week 4 and another one interrupted due to diarrhoea at week 24. Treatment with TDF/FTC decreased total, LDL and HDL‐cholesterol from 235.9 to 204.9 (p<0.001), 154.7 to 127.6 (p<0.001) and 50.3 to 44.5 mg/dL (p<0.001), respectively. In comparison, total, LDL and HDL‐cholesterol levels remained stable during placebo exposure. Week 12 total cholesterol (p<0.001), LDL‐cholesterol (p<0.001) and HDL‐cholesterol (p=0.011) levels were significantly lower in TDF/FTC versus placebo. Treatment with TDF/FTC reduced the fraction of subjects with abnormal fasting total‐cholesterol (≥200 mg/dL) from 86.7% to 56.8% (p=0.001) and LDL‐cholesterol (≥130 mg/dL) from 87.8% to 43.9% (p<0.001), which was not observed with placebo. There were no virological failures, and CD4 and triglyceride levels remained stable regardless of exposure.

Conclusion

Coformulated TDF/FTC has an intrinsic lipid‐lowering effect, likely attributable to TDF.
Higher rates of metabolic syndrome among women taking zidovudine as compared to tenofovir in rural Africa: preliminary data from the CART‐1 study
Authors: Labhardt Niklaus Daniel , Cheleboi Molisana , Faturyiele Olatunbosun , Motlatsi Mokete M , Pfeiffer Karolin , Ismael Lejone Thabo , Cerutti Bernard , Muser Jürgen , Shankar Gupta Ravi , Lynen Lutgarde , Hatz Christoph
Published: November 2014

Introduction

Due to its side effects stavudine (D4T) has been replaced by zidovudine (AZT) and tenofovir (TDF) in most low‐ and middle‐income countries (LMICs). In 2014 about 38% of adult first‐line regimens contain AZT and 62% TDF [1]. Whereas the unfavourable metabolic outcomes of D4T in comparison to TDF have been described extensively, studies from LMICs comparing metabolic profiles between patients on AZT and TDF are scarce. Given the high number of patients in LMICs still taking AZT, data on their metabolic profile are needed. We present rates of metabolic syndrome (MS) in adult patients taking either AZT‐ or TDF‐containing first‐line, non‐nucleoside reverse transcriptase (NNRTI)‐based regimens.

Materials and Methods

Data derived from a cross‐sectional multi‐disease screening conducted in ten facilities in two rural districts of Lesotho, Southern Africa [2]. Patients were eligible if aged ≥25 years and on NNRTI‐containing first‐line ART ≥6 months. The MS definition for Africa of the International Diabetes Federation was applied [3]. Assessed potential predictors for MS were age, time on ART, virologic suppression, body‐mass index (BMI), alcohol consumption, wealth quintile, NNRTI (nevirapine (NVP) or Efavirenz (EFV)), history of previous D4T exposure and ART‐backbone (AZT or TDF). Statistical analyses – stratified for sex – comprised univariate logistic regression for each predictor variable with subsequent construction of a multivariate model including all predictors with an association to MS at a significance level<0.1 in univariate analysis.

Results

Out of 1026 patients, 660 (64.3%) were female. MS prevalence was 9.8% (95% CI 6.9–13.4) in men and 22.9% (19.7–26.3) in women. In women, aged ≥35 years, AZT‐backbone, NVP‐base, BMI ≥25kg/m2 and taking ART for ≥4.5 years were associated with MS in univariate analysis. In the multivariate model only AZT (adjusted odds‐ratio: 2.2, 95% CI 1.4–3.6; p=0.001) and BMI ≥25kg/m2 (9.8; 2.8–34.1, p<0.001) were associated with MS. For men, age, higher wealth quintile, history of D4T exposure and BMI were associated with MS in univariate analysis. In the multivariate model only a BMI ≥25kg/m2 was associated with MS (8.9; 3.8–20.9, p<0.001).

Conclusions

In rural Lesotho, Southern Africa, the use of AZT instead of TDF among women who are on ART for ≥6 months predisposes to the development of metabolic syndrome. Given that, still 38% of first‐line regimens in LMIC contain AZT, this finding needs to be verified in other settings in Sub‐Saharan Africa.
Investigating presentations and outcomes of a joint HIV–renal clinic
Authors: Scott Jake , Williams Deborah
Published: November 2014

Introduction

HIV patients are at risk of renal dysfunction directly from HIV, indirectly from chronic inflammation as well as from antiretroviral drug toxicity. In particular, tenofovir (TDF) has been associated with proximal renal tubular dysfunction. A joint HIV–renal clinic was set up in 2009 to facilitate a timely review and minimize additional follow‐up appointments. Brighton has a cohort of 2,150 HIV patients, 90% are on ARVs with 910/1,935 (47.0%) on regimens including TDF. This study aims to investigate the utility of this clinic and describe renal disease in this cohort.

Materials and Methods

Notes of patients scheduled for assessment at the clinic between 2012 and 2014 were reviewed. Demographics, HIV history, number of visits, reason for referral and outcome information were collected.

Results

Sixty‐five patients, median age 51 years (28–88) and median duration of HIV 163 months (20–335), were reviewed. Forty‐two were taking TDF for a mean of 55.8 months (9–122). Forty‐two patients were reviewed once with a median number of visits of 1 (1–4).

Of those on TDF with proteinuria, 5 (13.2%) had TDF toxicity diagnosed and were discontinued at once, 27 continued with close monitoring with a further 7 subsequently discontinuing; total discontinued were 12 (32%). Overall, blood pressure control was the commonest intervention, 23/65 (35.4%), with 8/12 (66.7%) in the non‐TDF proteinuria group. Four (6%) patients underwent renal biopsy (2 focal segmental glomerulosclerosis, 1 IgA nephropathy and 1 glomerulonephritis and granuloma). In 4 (6%) creatinine rise was attributed to NSAIDs, creatine or protein supplements usage.

Conclusions

TDF toxicity was the commonest reason for referral but only a minority (13.2%) needed to discontinue immediately. Optimizing BP control was the most frequent outcome suggesting this is an underappreciated cause for renal dysfunction amongst HIV physicians, as were other causes such as creatine and protein supplement usage. Running a “one‐stop‐shop” clinic supports continuation of tenofovir in patients with proteinuria, and supports the diagnosis and management of poorly controlled hypertension and streamlines the management of these patients.
No association between vitamin D deficiency and parathyroid hormone, bone density and bone turnover in a large cohort of HIV‐infected men on tenofovir
Authors: Samarawickrama Amanda , Jose Sophie , Sabin Caroline , Walker‐Bone Karen , Fisher Martin , Gilleece Yvonne
Published: November 2014

Introduction

Combination antiretroviral therapy (cART) may affect vitamin D [25(OH)D], parathyroid hormone (PTH), bone mineral density (BMD) and bone turnover (BT). Reduced BMD and secondary hyperparathyroidism have been reported with tenofovir (TDF). We investigated the associations between TDF and bone markers, especially in 25(OH)D‐deficient patients.

Materials and Methods

In a single‐centre longitudinal study investigating BMD in HIV‐positive men, serum 25(OH)D, calcium, phosphate, PTH and alkaline phosphatase (ALP) were measured. Lumbar spine, non‐dominant total hip and non‐dominant femoral neck BMD (g/cm2) were measured using dual‐energy X‐ray absorptiometry. BT was assessed by serum type 1 procollagen (P1NP) and carboxy‐terminal collagen cross‐links (CTX). Mann–Whitney U tests compared serum markers and BT, and t‐tests compared BMD according to TDF in all and 25(OH)D‐deficient patients.

Results

A total of 422 men were recruited: mean age 47 (SD 9.8) years, 94% white ethnicity, 93% MSM, diagnosed HIV positive for median 9.6 (IQR 5.0,15.5) years, median CD4 547 (IQR 411,696) cells/µL, HIV RNA <40 copies/mL in 87% (96% of those on cART). 25(OH)D (nmol/L) was normal (>75), insufficient (50–75), deficient (25–50) and severely deficient (<25) in 14%, 29%, 50% and 7%, respectively. Of 381 men on cART, 77% were currently on TDF. TDF was not associated with median calcium (p=0.69) or phosphate (p=0.52), but patients had higher (but normal) median ALP [81 (IQR 69,103) vs. 73 (IQR 60,89) IU/L, p=0.005) compared to non‐TDF cART. There was no difference in the association between vitamin D and PTH according to whether someone currently was (r=0.11, p=0.06, Figure 1) or was not using TDF (r=0.12, p=0.29, Figure 1). TDF was also not associated with PTH, BMD or BT in either all patients on cART (Table 1a) or in patients with 25(OH)D deficiency (Table 1b).

Conclusions

In this largely TDF‐experienced cohort of HIV‐positive men, there was no association between TDF and 25(OH)D deficiency, hyperparathyroidism, reduced BMD or increased BT, although patients on TDF had higher but normal ALP. We found no evidence to support additional monitoring of bone markers in patients on TDF regardless of 25(OH)D status.
Safety of darunavir/ritonavir (DRV/r) in HIV‐1‐infected DRV/r‐experienced and ‐naïve patients: analysis of data in the real‐world setting in Italy
Authors: Antinori Andrea , Borderi Marco , Cauda Roberto , Bini Teresa , Chirianni Antonio , Squillace Nicola , Mancusi Daniela , Termini Roberta
Published: November 2014

Introduction

This descriptive, non‐interventional study on HIV‐1‐infected patients treated with DRV/r in the usual clinical setting, with a single‐arm prospective observational design, collected data on utilization of darunavir/ritonavir (DRV/r) under the conditions described in marketing authorization in usual clinical practice in Italy to evaluate efficacy and safety of DRV/r‐based antiretroviral (ARV) treatment. This analysis focussed on the safety profile of DRV/r in HIV‐1 infected patients.

Materials and Methods

Data were analyzed from four cohorts of HIV‐1‐infected patients treated with DRV/r in the real‐world setting, including an ARV‐naïve‐DRV/r‐naïve cohort (Cohort 1), an ARV‐experienced‐DRV/r‐naïve cohort (Cohort 2) and two ARV‐DRV/r‐experienced cohorts (Cohorts 3 and 4), one of which (Cohort 3) was from the DRV/r Early Access Program. The objective of this analysis was to examine the safety data obtained in these four cohorts in patients enrolled from June 2009 to November 2011 and observed until December 2012 or DRV/r discontinuation.

Results

Safety data from 875 patients were analyzed. DRV/r‐based treatment was well tolerated, with 36.2% of patients reporting ≥1 adverse event (AE) and very few discontinuations due to study drug‐related AEs (3.0% overall). The most frequent AEs were diarrhoea (2.7%), reduced bone density (2.6%) and hypercholesterolaemia (2.1%) (Table 1). Regarding metabolic parameters, levels of liver enzymes alanine aminotransferase (ALT) and aspartate aminotransferase (AST) remained stable from baseline to the last study visit (LSV) in DRV‐experienced patients and decreased in DRV‐naïve patients. Blood glucose concentrations remained stable in all cohorts. Serum triglyceride and cholesterol concentrations remained stable in DRV‐experienced patients but increased in naïve patients, yet were still within normal range.

Conclusions

In HIV‐1‐infected patients treated with DRV/r in these settings, the tolerability profile was favourable and similar to (or better than) that reported in controlled clinical trials. These data confirm DRV/r to be a safe treatment choice in DRV/r‐experienced and naïve patients.
Sex differences in apolipoprotein A1 and nevirapine‐induced toxicity
Authors: Marinho Aline , Dias Clara , Antunes Alexandra , Caixas Umbelina , Branco Teresa , Marques Matilde , Monteiro Emília , Pereira Sofia
Published: November 2014

Nevirapine (NVP) is associated with severe liver and skin toxicity through sulfotransferase (SULT) bioactivation of the phase I metabolite 12‐hydroxy‐NVP [1–3]. The female sex, a well‐known risk factor for NVP‐induced toxicity, is associated with higher SULT expression [4] and lower plasma levels of 12‐hydroxy‐NVP [3]. Interestingly, apolipoprotein A1 (ApoA1) increases SULT2B1 activity and ApoA1 synthesis is increased by NVP [5, 6]. Herein, we explore the effect of ApoA1 levels on NVP metabolism and liver function. The study protocol was firstly approved by the hospitals’ Ethics Committees. All included individuals were HIV‐infected patients treated with NVP for at least one month. The plasma concentrations of NVP and its phase I metabolites were quantified by HPLC [7]. ApoA1 levels were assessed by an immunoturbidimetric assay. Forty‐nine HIV‐infected patients on NVP were included (53% men, 59% Caucasian). NVP plasma levels were correlated with HDL‐cholesterol (Spearman r=0.2631; p=0.0441) and ApoA1 (Spearman r=0.3907; p=0.0115). Women had higher ApoA1 levels than men (Student's t Test; p=0.0051). In both sexes, 12‐hydroxy‐NVP levels were negatively correlated with ApoA1 (male: Spearman r=−0.3810; p=0.0499 female: Spearman r=−0.5944; p=0.0415). In men, ApoA1 was positively correlated with aspartate aminotransferase (AST, Spearman r=0.5507; p=0.0413), while in women ApoA1 was associated (Spearman r=0.6408; p=0.0056) with alanine aminotransferase (ALT). These results show sex differences in NVP‐induced ApoA1 synthesis. The higher ApoA1 levels in women might stabilize SULT2B1 [6]. This would explain the lower levels of 12‐hydroxy‐NVP [3] and the higher hepatotoxicity found in women, due to increased sulfonation of this metabolite. These data support a role for ApoA1 in the sex dimorphic mechanism leading to NVP‐induced toxicity.