bluuebunny/crossref_metadata_2025 huggingface dataset:
Real‐world medication persistence with single versus multiple tablet regimens for HIV‐1 treatment
Authors: Sweet Donna , Song Jinlin , Zhong Yichen , Signorovitch James
Published: November 2014

Introduction

Adherence to antiretroviral (ARV) treatment for HIV‐1 is crucial to achieving optimal clinical outcomes. Simplification of regimens with once‐daily single‐tablet regimens (STRs) can improve adherence compared to multi‐tablet regimens (MTRs). This study compared real‐world persistence (a proxy for treatment effectiveness and adherence) between HIV‐1 infected patients receiving STRs versus MTRs.

Materials and Methods

Adult HIV‐1 infected patients starting their first observed ARV regimen (with at least six prior months of no ARV treatment) were identified in the MarketScan claims database (10/2008–03/2014). Persistence was measured as the time from the index regimen start date to the end of the first 90‐day gap between fills for any ARV in the index regimen, or to the start date of an ARV not in the index regimen. Persistence was described using Kaplan–Meier curves and compared using log‐rank tests, and Cox proportional hazards models adjusted for age, gender, insurance type, region, employment status, Charlson Comorbidity Index, other comorbidities, hospitalizations, emergency room visits and office visits. STRs were further stratified by regimen.

Results

A total of 3257 patients (37%) initiated MTRs, and 5484 (63%) initiated STRs, including 4409 on efavirenz (EFV)/tenofovir (TDF)/emtricitabine (FTC), 484 on rilpivirine (RPV)/TDF/FTC, and 591 on elvitegravir (EVG)/cobicistat (COBI)/TDF/FTC. Median persistence was 45.0 months for STRs versus 15.2 months for MTRs (P<0.001; Figure 1). Median persistence was not reached for RPV/TDF/FTC or EVG/COBI/TDF/FTC; 31 months after RPV/TDF/FTC approval for the treatment of HIV‐1 infection, more than 65% of patients who started on it remained persistent, and 19 months after EVG/COBI/TDF/FTC approval, more than 72% of patients who started on it remained persistent. Compared with MTRs, STRs had an approximately 50% lower hazard of discontinuation (adjusted hazard ratio [HR]=0.54, 95% CI 0.50–0.58). EVG/COBI/TDF/FTC and RPV/TDF/FTC had significantly longer unadjusted and adjusted persistence compared with EFV/TDF/FTC (Figure 2, Table 1).

Conclusions

Among HIV‐1 infected patients, the use of STRs was associated with longer regimen persistence compared with MTRs. Among STRs, EVG/COBI/TDF/FTC and RPV/TDF/FTC were associated with significantly longer persistence than EFV/TDF/FTC.
Patient preferences for characteristics of antiretroviral therapies: results from five European countries
Authors: Gazzard Brian , Ali Shehzad , Muhlbacher Axel , Ghafouri Neda , Maggiolo Franco , Golics Catherine , Nozza Silvia , Jose Fuster Maria , Antela Antonio , Jacques Parienti Jean , Dang Nathalie , Ronot Bregigeon Sylvie , Benzie Andrew , Murray Miranda
Published: November 2014

Introduction

Patient preference to antiretroviral therapy (ART) characteristics should be a key consideration in treatment decisions. ART options exist for people living with HIV (PLWH), however concerns remain related to PLWH satisfaction with current ARTs. The current study examines patient preferences and the strength of preferences for treatment characteristics associated with ART.

Materials and Methods

Patients’ preferences to ART were explored using a discrete choice experiment (DCE). Seven defined treatment characteristics (each with three categories) were identified from a literature review, input from experts, PLWH and physicians. A total of 1582 PLWH from France, Germany, Spain, Italy and the UK were recruited for the study. An adjusted odds ratio <1 signified lower odds of selecting a treatment with this characteristic category, compared to the reference category, independently of other characteristics.

Results

The patient preference analyses showed that participants preferred treatments with a rapid reduction in viral load (OR=0.78; 95% CI 0.74–0.81) and CD4 count (OR=0.86; 95% CI=0.82–0.89). Participants had a strong preference for avoiding diarrhoea (Odds ratio, OR=0.36 95% CI=0.33–0.38) and long term health problems (OR=0.30, 95% CI=0.28–0.32). Convenience related issues related to restrictions on taking drugs because of food or drug interactions were important to avoid (OR=0.80, 95% CI=0.76–0.83 and OR=0.72 95% CI=0.69–0.76 respectively). Participants also had a strong preference to avoid drugs which limited the effectiveness of future treatments (OR=0.70, 95% CI=0.67–0.73).

Conclusions

Avoidance of diarrhoea and long‐term complications were the most important drivers of patient choice. This study, from a large sample of European patients, demonstrates the importance to patients when different aspects of HIV treatment are considered simultaneously.
Comparison of oxidative stress markers in HIV‐infected patients on efavirenz or atazanavir/ritonavir‐based therapy
Authors: Estrada Vicente , Monge Susana , Gómez‐Garre Dulcenombre , Sobrino Paz , Berenguer Juan , Ignacio Bernardino Jose , Santos Jesús , Moreno Zamora Ana , Martínez Esteban , Ramón Blanco Jose
Published: November 2014

Introduction

Chronic low‐grade inflammation and immune activation may persist in HIV patients despite effective antiretroviral therapy (ART). These abnormalities are associated with increased oxidative stress (OS). Bilirubin (BR) may have a beneficial role in counteracting OS. Atazanavir (ATV) inhibits UGT1A1, thus increasing unconjugated BR levels, a distinctive feature of this drug. We compared changes in OS markers in HIV patients on ATV/r versus efavirenz (EFV)‐based first‐line therapies.

Materials and Methods

Cohort of the Spanish Research Network (CoRIS) is a multicentre, open, prospective cohort of HIV‐infected patients naïve to ART at entry and linked to a biobank. We identified hepatitis C virus/hepatitis B virus (HCV/HBV) negative patients who started first‐line ART with either ATV/r or EFV, had a baseline biobank sample and a follow‐up sample after at least nine months of ART while maintaining initial regimen and being virologically suppressed. Lipoprotein‐associated Phospholipase A2 (Lp‐PLA2), Myeloperoxidase (MPO) and Oxidized LDL (OxLDL) were measured in paired samples. Marker values at one year were interpolated from available data. Multiple imputations using chained equations were used to deal with missing values. Change in the OS markers was modelled using multiple linear regressions adjusting for baseline marker values and baseline confounders. Correlations between continuous variables were explored using Pearson's correlation tests.

Results

145 patients (97 EFV; 48 ATV/r) were studied. Mean (SD) baseline values for OS markers in EFV and ATV/r groups were: Lp‐PLA2 [142.2 (72.8) and 150.1 (92.8) ng/mL], MPO [74.3 (48.2) and 93.9 (64.3) µg/L] and OxLDL [76.3 (52.3) and 82.2 (54.4) µg/L]. After adjustment for baseline variables patients on ATV/r had a significant decrease in Lp‐PLA2 (estimated difference −16.3 [CI 95%: −31.4, −1.25; p=0.03]) and a significantly lower increase in OxLDL (estimated difference −21.8 [−38.0, −5.6; p<0.01] relative to those on EFV, whereas no differences in MPO were found. Adjusted changes in BR were significantly higher for the ATV/r group (estimated difference 1.33 [1.03, 1.52; p<0.01]). Changes in BR and changes in OS markers were significantly correlated.

Conclusions

In virologically suppressed patients on stable ART, OS was lower in ATV/r‐based regimens compared to EFV. We hypothesize these changes could be in part attributable to increased BR plasma levels.
Association between lipid genetic and immunological status in chronically HIV‐infected patients
Authors: Echeverría Patricia , Guardiola Montse , González Marta , Carles Vallvé Joan , Puig Jordi , Bonjoch Anna , Clotet Bonaventura , Ribalta Josep , Negredo Eugenia
Published: November 2014

Introduction

Polymorphisms in some host genes have a significant impact on susceptibility to HIV‐1 infection and rate of disease progression [1, 2]. The purpose of the current sub‐study was to find out the relationship between polymorphisms in genes involved in the lipid metabolism and the CD4/CD8 T‐cell counts.

Methods

Sub‐study of a cross‐sectional, observational study conducted in 468 patients with HIV infection attended at the outpatient clinic to investigate individual genetic predisposition to atherogenic dyslipidemia (AD). All patients were genetically characterized and all polymorphisms were in Hardy–Weinberg equilibrium. Thirteen polymorphisms were selected from nine genes: APOA5 (rs662799 and rs3135506); APOC3 (rs5128 and rs4520); LPL (rs328 and rs268); CETP (rs708272); HL (rs1800588); MTP (rs1800591); APOE (rs7412 and rs429358); LRP5 (rs7116604); and VLDLR (rs1454626). Lipid and lipoprotein parameters, CD4 and CD8 T‐cell counts and plasma HIV‐RNA were determinate. The statistical analysis was performed using SPSS statistical software version 19 (SPSS Inc., Chicago, IL, USA).

Results

We studied 468 HIV‐infected patients (men, 77%), with a mean (SD) age of 45.9 (19.7) years. The mean CD4 T‐cell count and nadir CD4 was 547 (459) and 193 (159) cells/µL, respectively; 78.7% of participants were virologically suppressed. Patients carrying rs3135506 in the APOA5 gene presented a 9% increase in circulating TG levels (p=0.002) and 10% decrease in HDLc levels (p=0.005). Such association of APOA5 towards dyslipidemia was accompanied by a 21% decrease of the CD4 T‐cell count (p=0.024) and a 19% increase in CD8 T‐cell count (p=0.002) in carriers of the rare allele in the APOA5 rs662799 polymorphism adjusted by age and gender. Patients carrying the rare allele in rs5128 (APOC3) had a 16% decrease in circulating CD4 T cells (p=0.029); patients carrying rs1800591 (MTP) had a 29% decrease in CD4 T cells and 14% decrease in CD8 T cells (p=0.018 and p=0.008, respectively); patients carrying the rare allele rs1800588 in HL had a 11% increase in CD4 T cells (p=0.043); and carriers of the rs145626 in the VLDLR gene had 10% decrease in CD4 circulating T cells (p=0.013).

Conclusion

Variants in genes involved in the development of AD may also influence the immunological host–virus equilibrium in chronically HIV‐infected subjects [2, 3].
The impact of tenofovir disoproxil fumarate on kidney function: four‐year data from the HIV‐infected outpatient cohort
Authors: Monteiro Nadine , Branco Margarida , Peres Susana , Borges Fernando , Mansinho Kamal
Published: November 2014

Introduction

With improvements in survival and disease progression in the era of combined antiretroviral therapy, complications such as kidney disease are becoming increasingly prevalent in HIV‐infected patients. Tenofovir disoproxil fumarate (TDF) has been associated with nephrotoxicity, including decline in glomerular filtration rate, proximal tubular damage and acute kidney injury.

Objective

Characterize kidney safety of TDF‐containing antiretroviral treatment (ART) regimens in HIV‐infected patients.

Methods

Non‐controlled, observational, retrospective study was based on the clinical files registry of HIV patients who started TDF between January and December 2008. We assessed outpatients followed at a single Portuguese center. Demographic, clinical, virological and immunological data at baseline were collected. Serum creatinine, estimated glomerular filtration rate (eGFR) and creatinine clearance (CrCL) were assessed at baseline, after six months and every year up to four years. CrCL and eGFR were calculated by Cockroft–Gault and Modification of Diet in Renal Disease equations, respectively.

Results

A total of 176 patients (71.6% males) with a mean age of 43 years were enrolled. Ninety‐six (52%) were ART‐naive patients at TDF initiation. At baseline 12.5% had hypertension, 4% diabetes, 25% chronic hepatitis C and 9% chronic hepatitis B infections; 58% had normal renal function (eGFR ≥90 ml/min/1.73 m2), 36% had mild (eGFR 60‐89 ml/min/1.73 m2) renal dysfunction and 2.3% had moderate (eGFR 30‐59 ml/min/1.73 m2) renal dysfunction at initiation of TDF. Eighty‐three (47%) patients were on protease inhibitors and the remaining on NNRTIs containing regimens. During 48 months follow‐up, 5% experienced moderate renal dysfunction and 1.7% severe renal dysfunction. Twenty‐one (12%) patients met the definition criteria of rapid decline of renal function (annual decline of eGFR ≥3 ml/min/1.73 m2 in two consecutive years). The development of kidney events was associated with age above 50 years, presence of comorbidities and advanced stage HIV infection (p>0.05 in univariate analysis).

Conclusions

These data reveal a favourable renal safety profile of TDF, during a four‐year follow‐up. Screening for kidney disease markers, regular follow‐up and control and prevention of risk factors for renal failure are crucial for adequate management of HIV‐infected patients.
Relationship between body mass index and bone mineral density in HIV‐infected patients referred for DXA
Authors: Pinnetti Carmela , Federico Lupi , Lorenzini Patrizia , Domenico Chiappetta , Rita Bellagamba , Laura Loiacono , Zaccarelli Mauro , Cicalini Stefania , Libertone Raffaella , Giannetti Alberto , Mosti Silvia , Busi Rizzi Elisa , Antinori Andrea , Ammassari Adriana
Published: November 2014

Introduction

Reduced bone mass density (BMD) is a frequent observation in HIV‐infected persons. Relationship between body mass index (BMI), weight, height and BMD was reported for many populations. In particular, BMI has been found to be inversely related to the risk of osteoporosis.

Methods

This is a cross‐sectional, monocentric study where all HIV‐infected patients referred to first DXA scan in clinical routine during 2010–2013 were included. Osteopenia and osteoporosis were defined by T‐ score <−1 and <−2.5, respectively. Patients were categorized according to WHO BMI classification: underweight <18.5 kg/m2; normal weight 18.5–24.9 kg/m2; over weight 25–29.9 kg/m2; obese >30 kg/m2. Statistical analysis was carried using logistic regression.

Results

A total of 918 patients were included: median age 49 years (IQR, 44–55); 59.4% male; 93% Caucasian. Median anthrometric characteristics were: 68 kg (IQR, 59–78); 1.7 m (IQR, 1.6–1.75); 23.5 kg/m2 (IQR, 21.4–26.2). Underweight was found in 5%, normal weight in 61%, overweight in 26% and obesity in 8% of patients. According to T‐scores, 110 (11.2%) patients were osteoporotic and 502 (54.7%) had osteopenia. In the femoral neck area, the prevalence of osteoporosis was slightly lower (5.7%) than lumbar spine site (9.2%). Agreements between sites of T‐scores for the diagnosis of osteoporosis were 26 and 172 and 346 for osteopenia and normal BMD values, respectively. T‐scores at femoral neck or lumbar spine positively correlated with BMI (p<0.001) (Figure 1). Among predictors of osteopenia/osteoporosis, univariable analysis showed: older age (p<0.0001); lower weight (p<0.0001); increasing height (p<0.002). Patients underweight had a higher risk of osteopenia (p=0.02) as well as of osteoporosis (p=0.003). Patients with BMI above normal had a reduced risk of low BMD (osteopenia p<0.0001; osteoporosis p<0.03). Controlling for calendar year, gender, ethnicity, and age, BMI was confirmed as risk factor if below normal (AdjOR of osteopenia 2.42 [95% CI 1.16–5.07] p=0.02; AdjOR of osteoporosis 3.22 [95% CI 1.60–6.49] p=0.001).

Conclusions

Our findings indicate that almost 66% of HIV‐infected patients have subnormal bone mass. Further, as in other patient populations, in the HIV infection also low BMI is an important risk factor for osteopenia/osteoporosis. This finding highlights the compelling need for standardized screening actions, particularly in patients weighting below normal.
Proton 1H‐ and Phosphorus 31P‐MR spectroscopy (MRS) in asymptomatic HIV‐positive patients
Authors: Schuettfort Gundolf , Hattingen Elke , Pilatus Ulrich , Stephan Christoph , Wolf Timo , Goepel Siri , Haberl Annette , Blasel Stella , Zanella Freidhelm , Brodt Hans‐Reinhard , Bickel Markus
Published: November 2014

Introduction

HIV infection is accompanied by a variety of neurological disorders. Depression of cell‐mediated immunity is followed by the development of central nervous system opportunistic infections/tumours, and frequently by the occurrence of the AIDS dementia complex (ADC). However, the pathophysiology of the emergence of neuro‐AIDS is still unknown. Despite the development of cognitive impairments, the early diagnosis, objectification and quantification of the existence and extent of this impairment during infection are difficult to recognize in each individual case. To support the early diagnosis of ADC, there is a need for additional, non‐invasive diagnostic methods. In this study, it is of interest to answer the clinically relevant question of whether magnetic resonance spectroscopy can detect changes in the cerebral metabolism of asymptomatic HIV‐positive patients and is possibly suitable for the early diagnosis and prevention of HIV encephalopathy.

Methods

A group of 13 asymptomatic, HIV‐positive patients with combined antiretroviral therapy (cART) and 13 healthy controls were examined with 2D 1H‐MRS and 3D 31P‐MRS at 3T. The patients were treated with cART for at least 12 months. Changes in the absolute concentrations of phosphorylated metabolites (ATP), N‐acetyl‐aspartate, creatine, myo‐Isonitol, glutamate/glutamine and choline‐containing compounds were compared with that of control subjects.

Results

Asymptomatic HIV‐positive patients had significantly lower N‐acetyl‐aspartate in the white matter in a frontal and parietal target region. The other evaluated metabolites in the 1H MRS showed no significant difference between the HIV‐positive patients and healthy controls. The 31P‐MRS detected significant elevated values regarding the choline‐containing compounds PEth, GPE and PCho.

Conclusions

This spectroscopic study revealed a significantly lower N‐acetyl‐aspartate in the white matter in a frontal and parietal cerebral target region in asymptomatic, HIV‐positive patients as an early sign of neuronal disintegration. The 31P‐MRS detected significant elevated values regarding the choline‐containing compounds PEth, GPE and PCho as an early sign of gliosis. Furthermore we could show that with the use of 1H‐MRS and 31P‐MRS cerebral metabolites can be reliably detected and measured in HIV‐positive patients. The 1H‐MRS and 31P‐MRS is therefore suited as a diagnostic tool for early cerebral metabolic changes in HIV‐positive patients.
The effect of dolutegravir on the pharmacokinetics of metformin in healthy subjects
Authors: Zong Jian , Borland Julie , Jerva Fred , Wynne Brian , Choukour Mike , Song Ivy
Published: November 2014

Introduction

Dolutegravir (DTG) is an HIV integrase strand transfer inhibitor approved for use in combination with other antiretrovirals for the treatment of HIV‐infection in adults and adolescents. Metformin is a drug frequently used in diabetic HIV‐infected patients, which requires titration to optimize dosing. In vitro, DTG inhibits organic cation transporter 2 (OCT2) and multidrug and toxin extrusion transporter 1 (MATE 1) which are known to be involved in the disposition of metformin. The objective of this study was to assess the drug interaction between DTG and metformin.

Materials and Methods

This was an open‐label, parallel‐group, three‐period crossover study in healthy adult subjects. Eligible subjects were enrolled into one of the two treatment cohorts (15 subjects/cohort). Subjects received metformin 500 mg q12h for 5 days in Period 1; metformin 500 mg q12h plus DTG 50 mg q24h (Cohort 1) or 50 mg q12h (Cohort 2) for 7 days in Period 2; and metformin 500 mg q12h for 10 days in Period 3. There were no washout periods between treatments. All doses of study drug were taken with a moderate‐fat meal. Serial plasma PK samples and safety assessments were obtained throughout the study. Non‐compartmental PK analysis was performed and geometric least squares (GLS) mean ratios and 90% confidence intervals (CI) were generated by the mixed effect model for within‐subject treatment comparisons for each cohort.

Results

Fourteen and thirteen subjects completed study in Cohort 1 and Cohort 2, respectively. Plasma exposures of metformin were significantly increased when co‐administered with DTG (Table 1).

There were no apparent changes in metformin half‐life and tmax. Increased metformin plasma exposure returned to normal levels observed in Period 1 after DTG was discontinued in Period 3. No Grade 3 or 4 adverse events (AEs), deaths or serious AEs were reported during the study. Most frequently reported drug‐related AEs were headache (9), loose stools (8), and nausea (7). All AEs were mild or Grade 1 with the exception of one Grade 2 headache.

Conclusions

Co‐administration of DTG and metformin was well tolerated, yet significantly increased metformin plasma exposure; effects were DTG dose dependent. Though metformin has a wide therapeutic index and alone is not associated with hypoglycemia, close monitoring is recommended when co‐administering metformin and DTG. Dose adjustments of metformin may be considered.
Simulation of the impact of rifampicin on darunavir/ritonavir PK and dose adjustment strategies in HIV‐infected patients: a population PK approach
Authors: Dickinson Laura , Winston Alan , Boffito Marta , Khoo Saye , Back David , Siccardi Marco
Published: November 2014

Introduction

Treatment of HIV/TB co‐infection is challenging due to high drug–drug interaction potential between antiretrovirals and rifamycins, such as rifampicin (RIF). The PK interaction between darunavir/ritonavir (DRV/RTV) and RIF has not been studied. Utilizing other protease inhibitor data, population PK modelling and simulation was applied to assess the impact of RIF on DRV/RTV PK and generate alternative dosing strategies to aid future clinical trial design.

Materials and Methods

A previously developed model describing DRV/RTV PK including data from three studies in HIV patients was used [n=51, 7 female, DRV/RTV 800/100 mg (n=32) or 900/100 mg once daily (qd; n=19) [1]. The PK interaction between DRV/RTV and RIF was assumed to mimic that observed in HIV‐infected, TB negative patients receiving lopinavir (LPV)/RTV (n=21) [2]. Simulations of DRV/RTV 800/100 mg qd (n=1000) were performed (‐RIF). The model was adapted to increase the typical value of apparent oral clearance (CL/F) by 71% and 36% and decrease relative bioavailability (F) by 20% and 45% for DRV and RTV, respectively [2]; 1000 simulations were generated (+RIF). Dose adjustments of DRV/RTV 1200/200 mg qd, 800/100 mg and 1200/150 mg twice daily (bid) were simulated to overcome the interaction. DRV trough (Ctrough) for each dosing scenario was compared to the reference (‐RIF) by GMR (90% CI).

Results

DRV and RTV were described by a 1 and 2‐compartment model, respectively. A maximum effect model, with RTV inhibiting DRV CL/F, best described the relationship between the drugs. Compared to the reference (‐RIF), simulated DRV Ctrough was 70%, 46% and 20% lower for 800/100 mg qd, 1200/200 mg qd and 800/100 mg bid all +RIF, respectively. Ctrough was 38% higher with 1200/150 mg bid +RIF (Table 1).

Conclusions

Modelling and simulation was used to investigate the theoretical impact of RIF on DRV/RTV PK. Based on simulations, 800/100 mg and 1200/150 mg both bid could largely overcome the impact of the interaction. However, the risk of increased RTV‐related side effects and higher pill burden should be considered. In vitro work is ongoing to develop a physiologically based model characterizing the interaction and informing simulations.
HIV test: which is your best? A National survey on testing preferences among MSM in Italy
Authors: Mattioli Sandro , Maria Corbelli Giulio , Pieralli Stefano , Degli Esposti Michele
Published: November 2014

Introduction

HIV testing opportunities in Italy are frequently limited to the hospital setting. Experiences in other countries show that offering HIV testing in other facilities could improve HIV testing uptake.

Methods

An internet‐based survey was conducted between March 10 and April 3, 2014.

Results

A total number of 348 questionnaires were collected. Responders were 88% male. Most represented age groups were 25–34 (35%) and 35–44 (25%). Most of the responders identify themselves as homosexual (81%) or bisexual (9%). Half of responders had an HIV test within 2 years (56%) while 18% never tested for HIV. Among all responders, 61% had more than 2 sexual partners in the past year. Reported condom use in the past year was: always 39%, always but once 11%, sometimes 27%, never 14%. Most known places to have an HIV test is the hospital (95%), STI clinic (58%) and chemical analysis laboratory (54%); most used places are hospital (73%), STI clinic (30%), laboratory (22%) while 5 responders reported having had a self‐test at home. Preferred places where to have an HIV test is self‐testing at home (53%), hospital (36%), pharmacy (32%) and headquarter of an organization (31%). Most known testing method is draw blood from vein (97%), which is also most used (80%) but the least preferred (31%) while saliva (65%) and finger prick (56%) are the preferred choices. Most responders know that physicians (84%) and nurses (77%) are those who perform HIV tests and most of them had an HIV test with them (60% and 65% respectively). Physicians are the preferred operators (54%) followed by self‐testing (46%), nurses (46%) and peer‐volunteers (39%). The ideal HIV test should be: reliable (86%), with no medical prescription (75%), free (63%), rapid (55%), with no personal information collected (45%), with the opportunity to speak with a peer‐counsellor (36%).

Conclusions

Changing HIV testing policies in Italy is urgently needed in order to grant a better access to the service: waiting for the results and bureaucratic obligations represent the major barriers to be removed. Home‐testing and community‐based testing seem to be among the best ways to offer new opportunities though they may require a change in the legal, social and cultural context to be implemented and home testing will not allow any kind of support for newly diagnosed people.
Reducing turnaround time for laboratory test results does not improve retention of stable HIV‐infected adults on POV program: experience from Uganda
Authors: Maselle Edna , Muhanguzi Asaph , Muhumuza Simon , Nansubuga Jeniffer , Nawavvu Cecilia , Namusobya Jeniffer , Kamya Moses R , Semitala Fred C
Published: November 2014

Introduction

HIV/ AIDS clinics in resource limited settings (RLS) face increasing numbers of patients and workforce shortage [1, 2]. To address these challenges, efficient models of care like pharmacy only visits (POV) and nurse only visits (NOV) are recommended [3]. The Makerere University Joint AIDS Program (MJAP), a PEPFAR funded program providing care to over 42,000 HIV infected adults has implemented the POV model since 2009. In this model, stable patients on antiretroviral therapy (ART) with adherence to ART >95% and Karnofsky score >90% are reviewed by a doctor every four months but visit pharmacy for ART re‐fills every two months. A study conducted in August 2011 showed low retention on the POV program with symptomatic diseases, pending CD4 count, complete blood count results, and poor adherence to ART as the major reasons for the non‐retention in the POV program. To improve retention on POV, the TAT (Turnaround Time) for laboratory results (the main reason for non‐retention in the previous study) was reduced from one month to one week. In August 2012, the study was repeated to assess the effect of reducing TAT on improving retention one year after patients were placed on POV.

Materials and Methods

A cohort analysis of data from patients in August 2011 and in August 2012 on POV was done. We compared retention of POV before and after reducing the TAT for laboratory results.

Results

Retention on POV was 12.0% (95% CI 9.50–14.7) among 619 patients in 2011, (70% Females), mean age was 33 years, Standard Deviation (SD) 8.5 compared to 11.1% (95% CI 9.15–13.4) among 888 patients (70% Females), mean age 38.3 years, SD 8.9 in 2012 (p=0.59). The main reasons for non‐retention on the POV program in 2012 were poor adherence to ART (23%) and missed clinic appointments (14%).

Conclusions

Reducing TAT for laboratory test results did not improve retention of stable HIV‐infected adults on POV in our clinic. Strategies for improving adherence to ART and keeping clinic appointments need to be employed to balance workload and management of patients without compromising quality of care, patients’ clinical, immunological and adherence outcome.
Haemophagocytic syndrome and elevated EBV load as initial manifestation of Hodgkin lymphoma in a HIV patient: case report and review of the literature
Authors: Sculier Delphine , Doco‐Lecompte Thanh , Rougemont Mathieu , Calmy Alexandra
Published: November 2014

Introduction

In HIV patients, haemophagocytic syndrome (HPS) may occur in the presence of cancer, concomitant viral infection, HIV primo‐infection or at the initiation of highly active antiretroviral therapy (HAART). Hodgkin lymphoma remains a rare cause of HPS. We describe a case of HPS with very high Epstein Barr virus (EBV) load in a HIV patient as initial manifestation of Hodgkin lymphoma.

Materials and Methods

A 29‐year‐old HIV positive man, successfully treated with HAART with an undetectable viral load and CD4 cells count of 438/µl, was admitted for high fever of unknown origin. Laboratory results showed a pancytopenia with haemoglobin at 82 g/l, lymphocyte count at 0.36G/l and platelets count at 47G/l; a highly elevated ferritine >7500 µg/l; increased lactate dehydrogenase at 885U/l and soluble IL2 receptor (CD25) >60 ng/ml. EBV load was measured and confirmed at 2,600,000 copies/ml. A PET‐CT imaging showed diffuse elevated metabolic activity in the bone marrow and in two lesions in the spleen without lymphadenopathy. Bone marrow and liver biopsies revealed images of haemophagocytosis and lymphocyte depleted Hodgkin lymphoma. Treatment consisted in etoposid, steroids, and R‐ABVD (rituximab, doxorubicin, bleomycin, vinblastine, dacarbazine) chemotherapy. The patient completed six cycles of chemotherapy. We reviewed the literature in PubMed with the following keywords: HPS, HIV, EBV, Hodgkin lymphoma.

Results

We identified four publications and two reviews reporting cases of HPS associated with Hodgkin lymphoma in HIV patients with either a positive EBV load either the presence of encoded EBV RNA in tumour cells. Twenty‐two cases (including one pediatric case) were described. Among adults, mostly men, the median age was <50 years and immune suppression was marked with a median CD4 cell count<100 cells/µl, even in patients receiving HAART. When measured, EBV load in the serum was high. Prognosis was poor with a high mortality despite adequate treatment consisting in steroids and chemotherapy, with or without etoposide (Table 1).

Conclusions

Our case report and the review of literature suggest that physicians should be aware of the association between EBV infection/reactivation and Hodgkin lymphoma as a cause of HPS in HIV patients, even if successfully treated with HAART. The pathogenesis of these three interrelated conditions (viral infection, oncogenesis and immunologic reaction) remains unclear.
The absolute lymphocyte count accurately estimates CD4 counts in HIV‐infected adults with virologic suppression and immune reconstitution
Authors: Young Barnaby , Lye David , Tek Ng Oon , Sin Leo Yee
Published: November 2014

Introduction

The clinical value of monitoring CD4 counts in immune reconstituted, virologically suppressed HIV‐infected patients is limited. We investigated if absolute lymphocyte counts (ALC) from an automated blood counting machine could accurately estimate CD4 counts.

Materials and Methods

CD4 counts, ALC and HIV viral load (VL) were extracted from an electronic laboratory database for all patients in HIV care at the Communicable Diseases Centre, Tan Tock Seng Hospital, Singapore (2008–13). Virologic suppression was defined as consecutive HIV VLs <400 days apart, <200 copies/mL. CD4 counts and same day ALCs were collected during virologic suppression from the first CD4> 300 cells/mm3. CD4 counts were estimated using the CD4% from the first value >300 and an ALC 181–540 days later.

Results

A total of 1215 periods of virologic suppression were identified from 1183 patients, with 2227 paired CD4‐ALCs available for analysis. 98.3% of CD4 estimates were within 50% of the actual value. 83.3% within 25% and 40.5% within 10%. The error pattern was approximately symmetrically distributed around a mean of −6.5%, but significant peaked and with mild positive skew (kurtosis 4.45, skewness 1.07). Causes for these errors were explored. Variability between lymphocyte counts measured by ALC and flow cytometry did not follow an apparent pattern, and contributed to 32% of the total error (median absolute error 5.5%, IQR 2.6–9.3). The CD4% estimate was significantly lower than the actual value (t‐test, p<0.0001). The magnitude of this difference was greater for lower values, and above 25%, there was no significant difference. Precision of the CD4 estimate was similar as baseline CD4% increased, however accuracy improved significantly: from a median 16% underestimation to 0% as baseline CD4% increased from 12 to 30. Above a CD4% baseline of 25, estimates of CD4 were within 25% of the actual value 90.2% of the time with a median 2% underestimation. A robust (bisqaure) linear regression model was developed to correct for the rise in CD4% with time, when baseline was 14–24 (coefficients: intercept=3.30, CD4=0.939). This improved accuracy from 82.0% to 85.4%, and median error from 11% underestimation to 1% (p<0.0001). Adding time since baseline CD4% into the model increased complexity without significantly improving accuracy.

Conclusion

In virologically suppressed hosts with CD4 ≥300 cells/mm3 and percentage ≥14, CD4 counts can be predicted with 85–90% confidence to within 25% of the actual value using the ALC.
Intermittent viraemia and immune reconstitution in patients with more than 10–15 years of antiretroviral therapy: baseline values still matter
Authors: Erdbeer Gesa , Sabranski Michael , Sonntag Ina , Stoehr Albrecht , Horst Heinz‐A , Plettenberg Andreas , Schewe Knud , Unger Stefan , Stellbrink Hans‐J , Fenske Stefan , Hoffmann Christian
Published: November 2014

Introduction

Data on patients with long‐term exposure to ART is scarce because controlled studies usually do not follow up patients for more than five to seven years. We were interested whether baseline parameters such as CD4 T‐cell nadir or pre‐treatment viraemia do have an impact on ART success after more than a decade of treatment.

Methods

ELBE is a cross‐sectional study on adult HIV+ patients presenting consecutively with viral suppression (<50 HIV RNA copies/mL) and with ART exposure of at least five years. In this sub‐analysis, all patients with more than 10 years of ART exposure were evaluated for immune reconstitution and for intermittent transient viraemia (50–1000 copies/mL, defined as “blips”) during the last five years.

Results

From a total of 894 patients included in the three participating ELBE centres, 524 patients had an ART exposure of at least 10 years and had been treated continuously during the last 5 years. Of these, 33.4% had at least one “blip” while 63.5% did not show any transient viraemia of more than 50 copies/mL. Patients with at least one blip had a higher pre‐treatment viraemia compared to patients without blips (5.30 versus 5.06 log copies/mL, p=0.0003). In patients with a pre‐treatment viraemia of more than 100,000, 50,000–100,000 and less than 50,000 copies/mL, the proportions of patients with blips during the last five years were 39.5%, 30.5% and 21.8% (p=0.007), respectively. The history of an AIDS‐defining illness or the CD4 T‐cell nadir was not associated with a higher frequency of blips. However, CD4 T‐cell nadir was a strong predictor for current CD4 T‐cell counts. In patient groups with a CD4 T‐cell nadir of 0–99, 100–199, 200–349, 350+ cells/µL, the median current CD4 T cells were 571, 667, 710 and 890 cells/µL, respectively. These differences remained significant when the analysis was restricted to patients with more than 15 years of ART exposure (n=268).

Conclusions

In this large group of positively selected HIV+ patients with long‐term exposure to ART of at least 10–15 years, high pre‐treatment viraemia was still associated with a higher frequency of intermittent transient viraemia (“blip”). A low CD4 T‐cell nadir remained associated with a lower CD4 cell recovery. The clinical implications of these findings remain to be evaluated.
The effect of tenofovir on renal function in HIV‐positive pregnant women
Authors: Flanagan Stuart , Barnes Lynne , Anderson Jane , Barber Tristan
Published: November 2014

Introduction

Tenofovir is a commonly used component of antiretroviral therapy (ART) to reduce vertical transmission of HIV. Although systematic review of tenofovir use in pregnancy concluded it to be low risk for foetal abnormalities [1], data is limited on its impact on renal function in pregnant women. A recent South African study [2] concluded that renal dysfunction in HIV‐infected pregnant women is significantly less common than in other HIV‐infected adults, however there is currently no UK data. We aimed to investigate the effect of tenofovir on renal function in HIV‐1 positive pregnant women in a UK clinic.

Methods

We retrospectively analyzed data on renal function in pregnancy from a cohort of women attending a busy inner city London antenatal clinic. All women were screened for renal function throughout pregnancy via serum creatinine and estimated glomerular filtration rate (eGFR) calculated using modification of diet in renal disease (MDRD) and corrected for ethnicity.

Results

Ninety‐seven HIV‐1 positive women were registered at Homerton Hospital antenatal service of a total of 105 pregnancies between January 2010 and September 2013. Tenofovir was prescribed in 71/105 pregnancies (67.6%). Of the 71 pregnancies, 41 were prescribed tenofovir pre‐conception (57.7%). Of the pregnant women who started tenofovir in pregnancy, 21/31 (67.7%) were initiated before week 24 of pregnancy, in line with British HIV association (BHIVA) guidelines [3]. There was no deterioration in median serum creatinine or decline in eGFR in women prescribed tenofovir during pregnancy. At six weeks after delivery, in the 42 women who continued tenofovir therapy and had eGFR measured, one woman had eGFR=60, all others eGFR >90 (Table 1).

Conclusions

Consistent with current guidelines and experience, this study shows tenofovir did not cause decline in renal function in pregnancy in our cohort of HIV‐1 positive women, whether started during pre‐conception or during pregnancy. More evidence should be prospectively collected looking at effects of tenofovir on other measures of tubular renal function in pregnancy such as proteinuria and protein‐creatinine ratio.
Lp‐PLA2 levels in HIV‐infected patients
Authors: Díaz‐Pollán Beatriz , Estrada Vicente , Fuentes‐Ferrer Manuel , Gómez‐Garré Dulcenombre , San Román‐Montero Jesús
Published: November 2014

Introduction

HIV‐infected patients show an increased risk of cardiovascular disease (CVD). In the general population, lipoprotein‐associated phospholipase A2 (Lp‐PLA2) appears to be an independent predictor of CVD. We aimed to study associations between Lp‐PLA2 plasma levels and other risk factors for CVD in HIV patients.

Materials and Methods

A cross‐sectional, comparative study of two series of cases (HIV patients, n=116 and age‐matched non‐HIV healthy controls, n=113) was conducted. Eighty‐seven percent HIV patients on antiretroviral therapy (ART), 72.4% with HIV‐1 viral load <50 cop/mL. Inflammatory biomarkers (CRP, Lp‐PLA2) and internal carotid intima‐media thickness (IMT) were measured and CVD risk (Framingham and SCORE algorithms) was calculated. Univariate and multivariable associations between these variables were performed.

Results

HIV patients presented higher Lp‐PLA2 levels [276.81 ng/mL (209.71–356.58)] than uninfected healthy controls [220.80 ng/mL (172.70–256.90)], p≤0.01. In univariate analysis of the global sample, only cigarette smoking was associated with higher Lp‐PLA2 levels, p≤0.001. In HIV group, female and smoker patients showed higher Lp‐PLA2 levels, p≤0.05. No significant association was found between Lp‐PLA2 levels and another CVD risk factors, carotid IMT, Framingham and SCORE algorithms, ART, HIV‐1 viral load neither and CD4+ T lymphocyte count. In multivariate analysis, cigarette smoking remained significantly associated with Lp‐PLA2 levels [β=64.8 (95% CI 10.8–118.9) ng/mL, p=0.020].

Conclusions

HIV‐infected patients present higher Lp‐PLA2 levels than healthy controls, and in this population, tobacco smoking is significantly associated with increased Lp‐PLA2 levels. Smoking cessation should be a priority in CVD prevention in HIV‐infected patients.
Liver fibrosis is associated with cognitive impairment in HIV‐positive patients
Authors: Ciccarelli Nicoletta , Fabbiani Massimiliano , Grima Pierfrancesco , Limiti Silio , Fanti Iuri , Mondi Annalisa , Gagliardini Roberta , D'Avino Alessandro , Borghetti Alberto , Cauda Roberto , Di Giambenedetto Simona
Published: November 2014

Introduction

The aim of our study was to investigate the potential relationship between liver fibrosis (LF) and cognitive performance in HIV+ patients.

Materials and Methods

We performed a cross‐sectional cohort study by consecutively enrolling HIV+ patients during routine outpatient visits at two clinical centres in Italy. Subjects with decompensated liver disease were excluded. All subjects underwent a comprehensive neuropsychological battery exploring memory, attention, psychomotor speed and language; cognitive impairment was defined as at least two abnormal [1.5 SD below the mean for appropriate norms] cognitive domains. LF was explored by calculating FIB4 index; in a subgroup of patients, LF was also assessed by transient elastography. Factors associated with cognitive impairment were investigated by logistic regression models.

Results

A total of 413 patients [77% males, median age 46 (IQR 39–52), 17% with past AIDS‐defining events, 19% past IDU, 3% with diabetes, 94% on cART, 90% with HIV RNA <50 copies/mL, 18% co‐infected with HCV] were enrolled. Seventeen patients (4%) had FIB4 >3.25 and 14/129 (3%) had liver stiffness >14KPa. Forty‐seven patients (11%) were diagnosed with cognitive impairment. At multivariate analyses patients with FIB4 >1.45 showed a higher risk of cognitive impairment in comparison with those with lower values (OR 2.19, 95% CI 1.02–4.72; p=0.044) after adjusting for education (OR 0.79, 95% CI 0.71–0.88; p<0.001), past IDU (OR 1.69, 95% CI 0.67–4.23; p=0.264), diabetes (OR 2.35, 95% CI 0.62–8.86; p=0.207), HIV RNA <50 copies/mL (OR 0.47, 95% CI 0.19–1.14; p=0.095) and HCV co‐infection (OR 0.88, 95% CI 0.33–2.39; p=0.807). Analyzing any single cognitive domain, a higher risk of abnormal psychomotor speed was associated with fibroscan score >14KPa in comparison with fibroscan score <7KPa (OR 285.07; 95% CI 2.42–33574.06; p=0.020) after adjusting for education (OR 0.54, 95% CI 0.31–0.92; p=0.024), age (for 10 years increase) (OR 2.03, 95% CI 0.55–7.53; p=0.288), past IDU (OR 4.43, 95% CI 0.35–7.57; p=0.526), HIV RNA <50 copies/mL (OR 0.01, 95% CI 0.00–0.18; p=0.003), HIV history (for 1 year increase) (OR 0.96, 95% CI 0.83–1.12; p=0.641), CD4 cells count at nadir (OR 1.10, 95% CI 0.56–2.16; p=0.779), and HCV co‐infection (OR 0.06; 95% CI 0.00–1.93; p=0.113).

Conclusions

In HIV‐infected patients higher LF, estimated through non‐invasive methods, is associated to a higher risk of cognitive impairment.
Viral escape in the CNS with multidrug‐resistant HIV‐1
Authors: Béguelin Charles , Vázquez Miriam , Bertschi Manuel , Yerly Sabine , de Jong Denise , Rauch Andri , Cusini Alexia
Published: November 2014

Introduction

HIV‐1 viral escape in the cerebrospinal fluid (CSF) despite viral suppression in plasma is rare [1,2]. We describe the case of a 50‐year‐old HIV‐1 infected patient who was diagnosed with HIV‐1 in 1995. Antiretroviral therapy (ART) was started in 1998 with a CD4 T cell count of 71 cells/ìL and HIV‐viremia of 46,000 copies/mL. ART with zidovudine (AZT), lamivudine (3TC) and efavirenz achieved full viral suppression. After the patient had interrupted ART for two years, treatment was re‐introduced with tenofovir (TDF), emtricitabin (FTC) and ritonavir boosted atazanavir (ATVr). This regimen suppressed HIV‐1 in plasma for nine years and CD4 cells stabilized around 600 cells/ìL. Since July 2013, the patient complained about severe gait ataxia and decreased concentration.

Materials and Methods

Additionally to a neurological examination, two lumbar punctures, a cerebral MRI and a neuropsycological test were performed. HIV‐1 viral load in plasma and in CSF was quantified using Cobas TaqMan HIV‐1 version 2.0 (Cobas Ampliprep, Roche diagnostic, Basel, Switzerland) with a detection limit of 20 copies/mL. Drug resistance mutations in HIV‐1 reverse transcriptase and protease were evaluated using bulk sequencing.

Results

The CSF in January 2014 showed a pleocytosis with 75 cells/ìL (100% mononuclear) and 1,184 HIV‐1 RNA copies/mL, while HIV‐1 in plasma was below 20 copies/mL. The resistance testing of the CSF‐HIV‐1 RNA showed two NRTI resistance‐associated mutations (M184V and K65R) and one NNRTI resistance‐associated mutation (K103N). The cerebral MRI showed increased signal on T2‐weighted images in the subcortical and periventricular white matter, in the basal ganglia and thalamus. Four months after ART intensification with AZT, 3TC, boosted darunavir and raltegravir, the pleocytosis in CSF cell count normalized to 1 cell/ìL and HIV viral load was suppressed. The neurological symptoms improved; however, equilibrium disturbances and impaired memory persisted. The neuro‐psychological evaluation confirmed neurocognitive impairments in executive functions, attention, working and nonverbal memory, speed of information processing, visuospatial abilities and motor skills.

Conclusions

HIV‐1 infected patients with neurological complaints prompt further investigations of the CSF including measurement of HIV viral load and genotypic resistance testing since isolated replication of HIV with drug resistant variants can rarely occur despite viral suppression in plasma. Optimizing ART by using drugs with improved CNS penetration may achieve viral suppression in CSF with improvement of neurological symptoms.