bluuebunny/crossref_metadata_2025 huggingface dataset:
The effects of Maraviroc on liver fibrosis in HIV/HCV co‐infected patients
Authors: Ortega Gonzalez Enrique , Boix Vicente , Garcia Deltoro Miguel , Lopez Aldeguer Jose , Portilla Joaquin , Montero Marta , Ballester Belda Emilio , Abril Vicente , Gutierrez Felix , Minguez Carlos , Galindo Josefa , Benirto Concepcion , Garcia Rodriguez Magdalena , Giner Livia , Rubio Purificacion , Uso Jorge , Llerena Giovanna
Published: November 2014

Introduction

The fibrogenesis analysis in quimeric CCR1 and CCR5 mice revealed that CCR5 mediates its pro‐fibrogenic effects in hepatic cells and promoting stellate cells. The blockage of co‐receptors could preserve the progression of hepatic fibrosis in HIV/HCV co‐infected patients.

Objective

To evaluate the beneficial effects on hepatic fibrosis in HIV/HCV co‐infected patients that are on antiretroviral therapy (ART) with CCR5 co‐receptor antagonists.

Method and materials

A multicentre, retrospective pilot study of the evaluation of hepatic fibrosis at mid‐ and long‐term by non‐invasive methods in a HIV/HCV co‐infected patients cohort in the Valencian Community (Spain) that received ART with a CCR5 co‐receptor antagonist. The cut‐off points of serum marker tests of hepatic fibrosis were: AST to Platelet Ratio Index (APRI)<0.5 (F0–F1); >1.5 F2; >2 Cirrhosis and Forns Index<4.2 excludes fibrosis; >6.9>F2 fibrosis. Inclusion criteria was established for HIV/HCV co‐infected patients on ART with CCR5 co‐receptor antagonists that had no previous history of interferon and ribavirin treatment or those who were null‐responders and received CCR5 co‐receptor antagonist treatment in the previous year. Patients with HBV infection were excluded.

Results

A total of 71 male patients (69%) were reported. A CD4 nadir <100 cells/uL was observed in 42% of patients and 62% (44/71) had a basal CD4 level >350 cells/uL. According to genotypes, 50% were G‐1a, 14% G‐1b, 11% G‐3 and 25% G‐4. The median duration of treatment with Maraviroc (MVC) was the following: 45% took it over a year, 41% over two years and 14% over three years. Before starting treatment with MVC, we observed an initial fibrosis of F0–F1 in 49% of patients, F2–F3 in 24% and F4 in 27%. The medium follow‐up was of 18.45 months. Progression to a higher fibrosis level was observed in five patients, 11 patients improved at least one stage and the others were stable over time. There were 38 patients taking MVC over two years, 27 patients in this group (59.38%) did not modify their fibrosis, 3 patients (11%) progressed and 8 (29.62%) showed regression of liver fibrosis in one stage.

Conclusions

The data above shows a benefit over fibrosis progression with MVC, expressed by fibrosis serum marker tests in HIV/HCV co‐infected patients with CCR5 tropism. The prolong treatment with MVC (over two years) has a better effect on liver fibrosis.
Bladder cancer in HIV‐infected adults: an emerging concern?
Authors: Chawki Sylvain , Ploussard Guillaume , Montlahuc Claire , Verine Jérome , Mongiat‐Artus Pierre , Desgrandchamps François , Molina Jean‐Michel
Published: November 2014

Introduction

As HIV‐infected patients get older more non‐AIDS‐related malignancies are to be seen. Cancer now represents almost one third of all causes of deaths among HIV‐infected patients [1]. Albeit bladder cancer is one of the most common malignancy worldwide [2], only 13 cases of bladder cancer in HIV‐infected patients have been reported in the literature so far [3].

Materials and Methods

We conducted a monocentric study in our hospital. We selected all patients who were previously admitted (from 1998 to 2013) in our hospital with diagnoses of HIV and bladder cancer. The objective was to assess the prevalence and characteristics of bladder cancers in HIV‐infected patients in our hospital.

Results

Based on our administrative HIV database (6353 patients), we found 15 patients (0.2%) with a bladder cancer. Patients’ characteristics are presented in Table 1. Patients were mostly men and heavy smokers. Their median nadir CD4 cell count was below 200 and most had a diagnosis of AIDS. A median time of 14 years was observed in those patients, between the diagnosis of HIV‐infection and the occurrence of bladder cancer, although in patients much younger (median age 56) than those developing bladder cancer without HIV infection (71.1 years) [4]. Haematuria was the most frequent diagnosis circumstance in HIV‐infected patients who had relatively preserved immune function on highly active antiretroviral therapy (HAART). Histopathology showed relatively advanced cancers at diagnosis with a high percentage of non transitional cell carcinoma (TCC) tumor and of TCC with squamous differentiation, suggesting a potential role for human papilloma virus (HPV) co‐infection. Death rate was high in this population.

Conclusions

Bladder cancers in HIV‐infected patients remain rare but occur in relatively young HIV‐infected patients with a low CD4 nadir, presenting with haematuria, most of them being smokers, and have aggressive pathological features that are associated with severe outcomes.
Prevalence of monoclonal gammopathy in HIV patients in 2014
Authors: Genet Philippe , Sutton Laurent , Chaoui Driss , Al Jijakli Ahmad , Gerbe Juliette , Masse Virginie , Wifaq Bouchra
Published: November 2014

Introduction

In non‐HIV patients, Monoclonal Gammopathy of Undetermined Significance (MGUS) is associated with an increased risk of subsequent development of haematologic malignancies, especially multiple myeloma (MM) and it has been recently demonstrated that MM is always preceded by a MGUS phase. A higher prevalence of MGUS and MM has been observed in HIV patients compared to the general population. Nevertheless, it has been shown that MGUS in the context of HIV can disappear with antiretroviral therapy (ART). So, measuring MGUS prevalence in HIV patients in the recent period appears of special interest.

Materials and Methods

From January to June 2014, in each out‐patient seen in our unit, a serum protein electrophoresis was performed.

Results

A total of 393 patients were screened. Eight patients with HIV2 and one patient with HIV1+HIV2 infection were excluded. Finally, 383 patients (173 female, 210 male) with HIV1 infection were analyzed. Characteristics of patients were as follows: median age 42.2 years (19.1–79.1), hepatitis B virus (HBV) and/or hepatitis C virus (HCV) co‐infection 47 (18.8%), median CD4 610 (2–1758), CD8 793 (113–4010), presence of a past AIDS event for 88 patients (23%). Median time with HIV infection was 11 years (0–30). Three hundred fifty‐nine patients (93.7%) were on ART for a median duration of 105 months (0–287). For 320 patients (83.6%), viral load was below 50 viral copies/ml. Twelve cases of MGUS (3.1%) were observed: IgG Kappa (five cases), IgG Lambda (five cases), biclonal with two IgG Kappa (one case) and in one case, three monoclonal immunoglobulins were observed (IgG Kappa×2+IgG Lambda). The monoclonal immunoglobulin's level was low and below 1 g/l in all cases except two (2.1 and 11.6 g/l). No factor was found to be predictive of the presence of MGUS in particular age, CD4, HBV/HCV co‐infection, viral load or ART.

Conclusions

In the context of modern ART, the prevalence of MGUS remains above those observed in the general population. Even if the level of monoclonal spike observed in our cohort is generally low, an excess risk of subsequent development of MM could be present. Nevertheless, a prospective follow‐up of HIV patients with MGUS is necessary to determine this risk.
Prevalence of anal human papillomavirus infection and cytologic abnormalities among HIV‐infected and HIV‐uninfected men who have sex with men
Authors: Latini Alessandra , Gabriella Dona Maria , Ronchetti Livia , Giglio Amalia , Moretto Domenico , Colafigli Manuela , Laquintana Valentina , Frasca Mirko , Zaccarelli Mauro , Antinori Andrea , Cristaudo Antonio , Giuliani Massimo
Published: November 2014

Introduction

Human papillomavirus (HPV) is responsible for 85% of anal cancers. Recently, anal cancer incidence has been increasing, particularly in men who have sex with men (MSM). Cytology may be a useful tool for the detection of anal precancerous lesions. We assessed the prevalence and determinants of anal HPV infection and cytologic abnormalities among HIV‐infected and ‐uninfected MSM.

Materials and Methods

MSM ≥18‐year‐old attending an STI clinic in Rome (Italy) were enrolled. Anal cytologic samples were collected in PreservCyt (Hologic) using a Dacron swab. The Linear Array HPV Genotyping Test (Roche Diagnostics) was used for the detection and genotyping of 37 mucosal HPV types. Liquid‐based cytological slides were obtained using a ThinPrep2000 processor (Hologic). The morphology of the anal pap‐test was classified following the Bethesda 2001 guidelines.

Results

We enrolled 180 HIV‐infected (median age 41 years, IQR 33–47) and 438 HIV‐uninfected MSM (median age 32 years, IQR: 27–39). Most of the individuals were Caucasian (92.2% and 97.0%, respectively). HPV prevalence, both overall (93.3% vs 72.4%, p<.001) and by high‐risk (HR) HPV types (80.5% vs 56.0%, p<.001), was significantly higher among HIV‐infected than HIV‐uninfected individuals. HPV‐multiple infections were evidenced in 48.2% of the HIV‐uninfected and 76.1% of the HIV‐infected MSM (p<.001). HPV16 was the most prevalent genotype in both groups (23.3% in HIV‐positive and 17.6% in HIV‐negative MSM). HPV6 and 84 were the most frequent low‐risk types in both cohorts. Anal cytologic abnormalities were found in a significantly higher proportion of HIV‐infected MSM (46.1% vs 27.9%, p<.001). H‐SILs (high‐grade squamous intraepithelial lesions) were exclusively observed among the HIV‐infected individuals, although at a low prevalence (1.2%).

Conclusions

A high prevalence of anal HPV infection and cytologic abnormalities was evidenced in both populations. Nonetheless, HIV‐infected MSM showed a significantly higher rate of HPV infection and abnormal cytology, confirming that HIV‐1 infection poses a significant risk for anal HPV infection as well as for anal cellular abnormalities. Screening for anal cancer, which is currently the most frequent non‐AIDS‐defining cancer in HIV‐positive MSM, should be considered for this population. Moreover, vaccination strategies for the prevention of HPV infection should be taken into account.
Pregnancy outcomes in women growing up with perinatally acquired HIV in the United Kingdom and Ireland
Authors: Byrne Laura , Thorne Claire , Foster Caroline , Tookey Pat
Published: November 2014

Introduction

In the United Kingdom and Ireland more than 40% of individuals living with perinatally acquired HIV are now aged >16. Globally, increasing numbers of women with perinatally acquired HIV are becoming pregnant, but data on fertility and pregnancy outcomes is scarce. We present pregnancy outcome data for this emerging cohort.

Methods

Pregnancies in diagnosed HIV‐infected women in the United Kingdom and Ireland, and children diagnosed with HIV, are reported to the National Study of HIV in Pregnancy and Childhood. We analyzed data on pregnancies in women diagnosed aged ≤13 with perinatally acquired HIV, reported by June 2014.

Results

A total of 759 females born before 2001, diagnosed with perinatally acquired HIV aged ≤13 years, and in care in the UK and Ireland have been reported. Forty‐four of these (6%) have had at least one pregnancy reported, with nineteen 2nd and four 3rd/4th pregnancies. Women's year of birth ranged from 1985 to 1996; 60% of women were UK/Irish‐born and 39% African‐born. Twenty one percent were diagnosed at <2 years, 39% at 2–7 and 41% at 8–13 years. Nine pregnancies were conceived in 2005–07, 22 in 2008–10 and 36 in 2011–13. Median age at conception of first pregnancy was 19 years. CD4 count was >500 cells/µL in 36% of first pregnancies, 350–499 in 15% and <350 in 49%. Women were on antiretroviral therapy (ART) at conception in 71% of pregnancies. There were 51 singleton live births, 2 miscarriages, 9 terminations and 5 continuing to term. In 17 live births to women not on ART at conception, median gestational age at start of ART was 17 weeks (range 3–29). HIV viral load was <50 copies/mL near delivery in 64% of live births, 51–1000 in 31% and >1000 in 5%. Forty four percent of live births were delivered by elective caesarean section (CS), 27% by emergency CS, 27% by planned vaginal delivery and with one unplanned vaginal delivery. Of 29 live births with viral load <50, 31% were delivered by elective CS, 17% by emergency CS and 52% by vaginal delivery. Fifteen percent of infants were delivered at 32–36 weeks gestation, and 2% at 30 weeks; 16% weighed 1.5–2.5 kg and 16% weighed <1.5 kg. Among 38 of the 51 infants where infection status is already reported, one is perinatally infected.

Conclusions

Currently at least 6% of perinatally infected women in care in the UK and Ireland have experienced one or more pregnancies. Linking paediatric, pregnancy and second generation data will enable further monitoring of pregnancy outcomes in this newly emerging population.
Morbidity and mortality in HIV‐exposed under‐five children in a rural Malawi setting: a cohort study
Authors: Divala Oscar , Michelo Charles , Ngwira Bagrey
Published: November 2014

Introduction

Paediatric HIV infection significantly contributes to child morbidity and mortality in southern Africa. In Malawi as in most countries in the region, care of HIV‐exposed children is constrained by the lack of area‐specific information on their risk to dying and morbidity. This research estimates and compares morbidity and mortality events between HIV‐exposed and ‐unexposed under‐five children in a rural Malawian setting.

Methods

Data for children under the age of five collected from January 2009 to June 2011 at a demographic and health site in Karonga district of northern Malawi were analyzed. Morbidity and mortality rates among HIV‐exposed and ‐unexposed children were calculated and compared using Kaplan‐Meier survival analysis and Cox proportional hazard regression.

Results

Overall (n=7,929) cohort data of under‐five children born in a demographic and health site represented 12380.8 person years of observation (PYO) of which 3.1% were contributed by HIV‐exposed infants. Females accounted for half of the sample, and the overall mean age was 18.4 months (SD 13.4) with older children in the HIV–unexposed group. All‐cause morbidity rate was 337.6/1000 PYO (95% CI 327.5/1000–348.0/1000) and HIV‐exposed children morbidity rate was 1.34 times higher (p<0.001) compared to HIV‐unexposed children. integrated management of childhood illness (IMCI) pneumonia was the most common diagnosis (39.3%) in this cohort. Child mortality rate was 16.6/1000 PYO (95% CI 14.5–19.1) from 206 deaths. HIV‐exposed children had 4.5 times higher (p<0.001) mortality rate compared to the HIV‐unexposed children. Higher mortality rates were observed in children under one year (129.2/1000 PYO) compared to older age groups.

Conclusion

HIV exposure at birth has a greater impact on child morbidity and mortality especially in the first year of life. This underscores the need for targeted and synergetic interventions that included focused prevention of mother‐to‐child transmission (PMTCT) which could reduce HIV transmission to children in their infancy in this setting.
The spectrum of HIV mother‐to‐child transmission risk
Authors: Reliquet Veronique , Winer Norbert , Chereau Natacha , Launay Elise , Lamberet Aurore , Andre‐Garnier Elisabeth , Raffi Francois , Brunet Cecile
Published: November 2014

Introduction

With the implementation of combined antiretroviral therapy (cART) and prevention of mother‐to‐child transmission (MTCT) we observed dramatic decreases in rates of perinatal MTCT of HIV, 0.3% in France in women with plasma viral load (pVL) <50 c/mL at delivery. We describe a case of MTCT which occurred despite virologic suppression of the mother at delivery, the first case in our centre since 2002.

Description of the case

A 26‐year‐old black woman, Guinea‐native, living in France since 2007, was diagnosed with HIV‐1 CRF02 in 2008 and lost to follow‐up since November 2012 after second delivery (2 female born in March 2009 and October 2012, uninfected). Third pregnancy began in July 2013 and baseline characteristics in September were as follows: week 13 of gestational age (GA), CDC stage A, CD4 317/mm3, pVL 4.89 log c/mL. cART with abacavir/lamivudine and atazanavir/ritonavir 300/100 mg daily (qd) was introduced. VL decreased to 2.4 log c/mL in 4 weeks and CD4 increased to 456/mm3. In December, at week 22 of GA, viral rebound at 4.14 log c/mL due to sub‐optimal maternal adherence was observed. After counselling, pVL decreased to 1.69 log c/mL in March 2014, at week 35 of GA and 1.3 log c/mL at delivery. As pVL was <400 c/mL at week 36 of GA, vaginal delivery with IV zidovudine was decided. However, because of poor/uncertain maternal adherence to cART, the neonate was treated with a combination of 2 drugs (lamivudine‐nevirapine) with the 4‐week zidovudine regimen, until the result of delivery pVL. This combination was stopped at day 2 when maternal delivery pVL (22 c/mL) was received and standard oral zidovudine prophylaxis was continued. Infant was tested for HIV infection at baseline (day 3) and found to be HIV‐infected (HIV‐RNA 60 c/mL) attesting in‐utero HIV transmission. On day 15, zidovudine prophylaxis was discontinued and treatment for HIV infection initiated with standard cART according to the French Paediatric Antiretroviral Guidelines.

Conclusions

The risk of HIV acquisition is low in infants born to women who receive standard cART during pregnancy and labour and achieve undetectable VL at delivery. However, transmission remains a hazard, with possibility of in‐utero infection during episodes of non‐adherence, and the risk of a possible MTCT has to be mentioned to all pregnant women.
Overall and cause‐specific mortality in HIV‐positive subjects compared to the general population
Authors: Alejos Belen , Hernando Victoria , López‐Aldeguer Jose , Segura Ferrán , Antonio Oteo José , Rubio Rafael , Sanvisens Arantza , Sobrino Paz , del Amo Julia , Coris Cohort
Published: November 2014

Introduction

Emerging non‐AIDS related causes of death have been observed in HIV‐positive subjects in industrialized countries. We aimed to analyze overall and cause‐specific excess of mortality of HIV‐positive patients compared to the general population and to assess the effect of prognostic factors.

Material and Methods

We used generalized linear models with Poisson error structure to estimate overall and cause‐specific excess of mortality in HIV‐positive patients from 2004 to 2012 in the cohort of the Spanish Network of HIV Research (CoRIS), compared to Spanish general population and to assess the impact of multiple risk factors. We investigated differences between short‐term and long‐term risk factors effects on excess of mortality. Multiple Imputation by Chained Equations was used to deal with missing data.

Results

In 9162 patients there were 363 deaths, 16.0% were non‐AIDS malignancies, 10.5% liver and 0.3% cardiovascular related. Excess mortality was 1.20 deaths per 100 person years (py) for all‐cause mortality, 0.16 for liver, 0.10 for non‐AIDS malignancies and 0.03 for cardiovascular. Short‐term (first‐year follow‐up) excess Hazard Ratio (eHR) for global mortality for baseline AIDS was 4.27 (95% CI 3.06–6.01) and 1.47 (95% CI 0.95–2.27) for HCV coinfection; long‐term (subsequent follow‐up) eHR for baseline AIDS was 0.88 (95% CI 0.58–1.35) and 4.48 (95% CI 2.71–7.42) for HCV coinfection. Lower CD4 count and higher viral load at entry, lower education, being male and over 50 years were predictors for overall excess mortality. Excess of liver mortality was higher in patients with CD4 counts at entry below 200 cells compared to those above 350 (eHR: 6.49, 95% CI 1.21–34.84) and in HCV‐coinfected patients (eHR: 3.85, 95% CI 0.85– 17.37), although it was borderline significant. Patients over 50 years old (eHR: 5.55, 95%CI 2.4–12.85) and HCV coinfected (eHR: 5.81, 95% CI 2.6–13) showed a higher risk of non‐AIDS malignancies mortality excess. Excess of cardiovascular mortality was related with HCV coinfection (eHR: 6.68, 95% CI 1.25–35.73).

Conclusions

Our results show overall, liver, non‐AIDS malignancies and cardiovascular excess of mortality associated with being HIV‐positive, despite improvements in HIV disease management and antiretroviral therapies. Differential short‐term and long‐term effect of AIDS before entry and HCV coinfection was found for overall mortality.
Burden of subclinical heart and lung disease detected on thoracic CT scans of HIV patients on HAART
Authors: Zona Stefano , Santoro Antonella , Besutti Giulia , Ligabue Guido , Mussini Cristina , Raggi Paolo , Leipsic Jonathon , Sin Don D. , Guaraldi Giovanni
Published: November 2014

Introduction

The aim was to determine the prevalence of lung and heart abnormalities on thoracic CT scans in HIV‐infected patients who were treated with antiretroviral therapy (ART).

Material and Methods

Thoracic CT scans of 903 patients infected with HIV (mean age 48±7 yrs, 29% females) were reviewed by three radiologists by consensus. Patients were phenotyped according to smoking status, pack years and years since cessation for ex‐smokers. Individuals known to have active lung or heart disease at the time of CT scanning were excluded. Multimorbidity lung and heart disease (MLHD) was defined by the presence of >2 lung or heart abnormalities on the CT scan.

Results

Prevalence of lung abnormalities were: 326 patients (36.1%) with emphysema, 271 (30.0%) with bronchiolitis, 44 (4.9%) with non‐calcified lung nodules, 568 (63%) with significant bronchial wall thickening, 150 (16.7%) with bronchiectasis, 9 (1%) with interstitial lung disease. Overall, 445 patients (49.3%) had >2 lung abnormalities. Imaging findings suggestive of prior myocardial infarction (MI) were found in 1.4% (13 patients); 26.6% (240 patients) had CAC scores of 1 to 100, and 9.8% (89 patients) had CAC>100. 13.6% (123 patients) of the patients had CAC>100 and/or previous MI. MLHD was present in 484 patients (53.6%) and among 78 patients (16%) who never smoked. Table 1 describes CT findings according to pack year and stop smoking groups vs never smokers.

MLHD increased proportional to cumulative smoking history (p for trend <0.001) and decreased in proportion to the number of years since smoking cessation (p for trend=0.017). Independent predictors for MLHD were: age (OR=1.07, CI 1.05–1.10), sex (OR=1.59, CI 1.15–2.19), current smoking (OR=1.76, CI 1.08–2.89), and pack‐years history of smoking (OR=1.03, CI 1.02–1.05). In patients who never smoked, nadir CD4<200 was significantly associated with MLHD after adjustment for age and sex (OR=1.98, CI 1.98–3.63).

Conclusions

MLHD is common in HIV‐infected individuals even in non‐smokers. Reduced CD4 count (hence severity of HIV infection) may be an important risk factor for chronic lung and heart disease. Thoracic CT scans may provide an excellent screening tool to detect MLHD in HIV‐infected patients.
Transmitted antiretroviral drug resistance mutations in newly diagnosed HIV‐1 positive patients in Turkey
Authors: Sayan Murat , Sargýn Fatma , Inan Dilara , Yýldýz Sevgi Dilek , Kocagül Celikbas Aysel , Yasar Kadriye , Kaptan Figen , Sayýn Kutlu Selda , Tasdelen Fýsgýn Nuriye , Inci Ayse , Ceran Nurgül , Karaoðlan Ýlkay , Cagatay Atahan , Kemal Celen Mustafa , Tekin Koruk Suda , Ceylan Bahadýr , Yýldýrmak Taner , Akalýn Halis , Korten Volkan , Willke Ayse
Published: November 2014

Introduction

The objective of this study was to determine the transmitted drug resistance mutations (TDRMs) in newly diagnosed HIV‐1 positive patients in Turkey.

Materials and Methods

The study was carried out between 2009 and 2014 and antiretroviral naïve 774 HIV‐1 infected patients from 19 Infectious Diseases and Clinical Microbiology Departments in Turkey were included; gender: 664 (86%) male, median age: 37 (range; 1–77), median CD4+T‐cell: 360 (range; 1–1320) count/mm3, median HIV‐RNA load: 2.10+E6 (range; 4.2+E2–7.41+E8) IU/mL. HIV‐1 drug resistance mutations were detected by population based sequencing of the reverse transcriptase (codon 41–238) and protease (codon 1–99) domains of pol gene of HIV‐1, and analyzed according to the criteria by the World Health Organization 2009 list of surveillance drug resistance mutations [1].

Results

The patients had TDRMs to NRTIs (K65R, M184V), NNRTIs (K101E, K103N/S, G190A/E/S, Y181I/C, Y188H/L) and PIs (M46L, I54V, L76V, V82L/T, N83D, I84V, L90M). The prevalence of overall TDRMs was 6.7% (52/774). Resistance mutations were found to be 0.7% (6/774), 4.1% (32/774) and 2.1% (17/774) to NRTIs, NNRTIs and PIs drug groups, respectively. Three patients had NRTIs+NNRTs resistance mutations (M184V+K103N) as multi‐class drug resistance. However, thymidine analogue resistance mutations (TAMs) determined two distinct genotypic profiles in the HIV‐1 reverse transcriptase: TAM1: M41L, L210W and T215Y, and TAM2: D67N, K70R, K219E/Q, and T215F. The prevalence of TAM1 and TAM2 were 7.7% (60/774) and 4.3% (34/774), respectively.

Conclusions

The TDRMs prevalence of antiretroviral naïve HIV‐1 infected patients may be suggested current situation of Turkey. These long‐term and large‐scale results show that the resistance testing must be an integral part of the management of HIV infection in Turkey.
Long‐term efficacy and safety of E/C/F/TDF vs EFV/FTC/TDF and ATV+RTV+FTC/TDF in HIV‐1‐infected treatment‐naïve subjects ≥50 years
Authors: Gazzard Brian , Marie Girard Pierre , Di Perri Giovanni , Gallant Joel , Towner William , Rogatto Felipe , Demorin Jennifer , McColl Damian , Liu Hui , Rhee Martin , Szwarcberg Javier , Piontkowsky David
Published: November 2014

Introduction

In high‐income countries, ≥30% of HIV‐infected patients are ≥50 years (yrs) old (UNAIDS 2013). In two phases, three clinical trials (Studies 102 and 103) elvitegravir/cobicistat/emtricitabine/tenofovir DF (E/C/F/TDF; STB) had non‐inferior efficacy and favourable safety vs efavirenz/emtricitabine/tenofovir DF (EFV/FTC/TDF; ATR) or ritonavir‐boosted atazanavir (ATV+RTV)+FTC/TDF (TVD) in HIV‐infected, treatment‐naïve subjects at Week 144. The efficacy and safety of STB in subjects < or ≥50 yrs is described.

Materials and Methods

Post hoc analysis of efficacy, tolerability and safety in subjects < or ≥50 yrs at Week 144.

Results

Subjects ≥50 yrs in Study 102: STB: 14% (49/348), ATR: 16% (56/352); in Study 103: STB: 14% (48/353), ATV+RTV+TVD: 14% (48/355). Efficacy, safety and tolerability by age and study endpoint are shown in Table 1. Regardless of age, STB had robust efficacy at Week 144 with similar virologic outcomes vs ATR or ATV+RTV+TVD. Discontinuations (DC) due to AE on STB were similar to the comparators, most occurred by Week 48. Median changes in eGFR on STB were similar by age; DC with renal PRT was rare [STB: 4 (0.6%); ATV: 3 (0.8%); ATR: 0], 2 and 1 in ≥50 yrs old strata, respectively.

Conclusions

STB compared to ATR or ATV+RTV+TVD, is an efficacious, well‐tolerated and safe regimen for HIV‐1‐infected, treatment‐naïve subjects<or≥50 yrs of age.
An observational comparison of first‐line combination antiretroviral treatment (cART) with 2NRTI and ATV/r or DRV/r in HIV‐infected patients in Italy
Authors: Cozzi‐Lepri Alessandro , Antinori Andrea , Bonora Stefano , Cingolani Antonella , Cassola Giovanni , Angarano Gioacchino , Vullo Vincenzo , Mussini Cristina , Gori Andrea , Maggiolo Franco , Castagna Antonella ,   Antonella d'Arminio Monforte on behalf of the ICONA Foundation Study
Published: November 2014

Introduction

In a recent clinical trial (ACTG 5257), no difference in viral failure (VF) of a first‐line cART containing atazanavir/r (ATV/r) or darunavir/r (DRV/r) was found [1]. For the endpoint of discontinuation due to intolerance, the regimen with DRV/r was superior to that of ATV/r (49% of the stops of ATV/r were attributed to jaundice or hyperbilirubinemia). These and other intolerances to ATV/r remain a concern for clinicians.

Methods

Participants in the ICONA Foundation Study who started cART with 2NRTI+ ATV/r or DRV/r while ART‐naïve were included. Several endpoints were evaluated: confirmed VF>200 copies/mL after six months of therapy, discontinuation of DRV/r or ATV/r for any reasons or because of intolerance/toxicity (as reported by the treating physician) and the combined endpoint of VF or stop. Survival analysis with Kaplan–Meier curves and Cox regression model stratified by clinical site was used. Patients' follow‐up accrued from cART initiation to the date of the event or to the date of last available visit/viral load.

Results

894 patients starting 2NRTI+ATV/r and 686 2NRTI+DRV/r when ART‐naïve on average in 2011 (IQR: 2010–2012) were studied. Most common NRTIs used were FTC/TDF (84%) and ABC/3TC (12%). Median age was 40 years, 22% females, 44% heterosexuals. Patients starting ATV/r were more likely to be hepatitis B/C infected (2% and 14% vs 1% and 9%, p=0.001), they started one year earlier (2011 vs 2012, p=0.001), were more likely to be enrolled in sites located in the north of Italy (63% vs 54%, p=0.04), started cART less promptly after HIV diagnosis (5 vs 2 months, p=0.02) and less likely to have started TDF/FTC (83% vs 85%, p=0.02). By two years of cART, 9.8% (95% CI 7.6–12.0) of those starting ATV/r experienced discontinuation due to intolerance/toxicity vs 6.5% in DRV/r group (95% CI 4.2–8.8, p=0.04). After controlling for several potential confounders (age, gender, nation of birth, mode of HIV transmission, hepatitis co‐infection status, AIDS diagnosis, nucleoside pair started, baseline CD4 count and viral load and year of starting cART) the relative hazard (RH) for ATV/r vs DRV/r was 2.01 (95% CI 1.23, 3.28, p=0.005). There were no statistical differences detected for any of the other outcomes.

Conclusions

Although unmeasured confounding cannot be ruled out, our results seem to be consistent with those of the ACTG 5257. When all cause discontinuations were considered, or the composite endpoint of treatment failure, there was no difference between ATV/r‐ and DRV/r‐based regimens.
Gag drug resistance mutations in HIV‐1 subtype C patients, failing a protease inhibitor inclusive treatment regimen, with detectable lopinavir levels
Authors: Kelly Pillay Sameshnee , Singh Urisha , Singh Avashna , Gordon Michelle , Ndungu Thumbi
Published: November 2014

The development of antiretroviral (ARV) drugs and their use in human immunodeficiency virus type 1 (HIV‐1) has led to the effective control of HIV replication in infected patients. However the emergence of resistant HIV‐1 strains still remains a problem. Literature has shown that mutations may accumulate in the protease (PR) and gag regions of HIV‐1 patients who fail therapy with protease inhibitor (PI) drugs [1, 2]. Gag mutations have also been found to play an important role in the evolution of PI resistance [2]. Despite this, the standard genotypic drug‐resistance test examines mutations in the reverse transcriptase (RT) and PR region of HIV‐1 and not gag [3]. This study investigated the frequency of gag drug resistance mutations in the absence of major PI mutations in HIV‐1 subtype C patients, failing a PI inclusive treatment regimen. Sixty‐eight samples were retrieved from patients that were classified as second line treatment failures as they had a viral load greater than 1000 copies\mL, as well as detectable lopinavir (LPV) levels. The gag and protease region of these patients were genotyped. Mutations in the gag and protease region were assessed using the REga Db sequencing tool and the CPR programme on the Stanford University HIV drug resistance database. The mean LPV level of these samples was 11.66 µg/mL. 69.11% (n=46) of the patients have no major PI mutations in protease. The following mutations that are associated with PI exposure were present in the data set: G62R (n=6), H219Q (n=11), S737T (n=8), I389T (n=8) and Q474L (n=7). Predictably, mutations that are associated with PI resistance were found, which are generally located in the p7/p1 and p1/p6 cleavage site. These mutations are K436R (n=4), I437V (n=1), L449P (n=5), R452K (n=4) and P453L\T (n=9). These results contribute to the knowledge of resistance mutations in gag and their impact on PI resistance.
Long term effectiveness of once‐daily unboosted atazanavir plus abacavir/lamivudine as a switch strategy in subjects with virological suppression
Authors: Llibre Josep M , Cozzi‐Lepri Alessandro , Antonio Valencia La Rosa Jorge , Pedersen Court , Ristola Matti , Losso Marcelo , Mocroft Amanda , Mitsura Victor M. , Ormaasen Vidar , Maltez Fernando , Beniowski Marek , Paredes Roger ,   on behalf of Eurosida in Eurocoord
Published: November 2014

Background

Use of unboosted atazanavir (ATV400) is approved in the US but not in Europe [1]. Due to pharmacokinetic interactions it should not be used with tenofovir but can be used with abacavir/lamivudine (ABC/3TC) [1, 2,3]. Effectiveness data of ATV400+ABC/3TC as a switch strategy in clinical routine however are scant.

Methods

We evaluated treatment outcomes of ATV400+ABC/3TC in pre‐treated subjects in the EuroSIDA cohort with undetectable HIV‐1 RNA, and previous ABC experience or assumed previous HLA B57*01 testing. We performed a time to loss of virologic response (TLOVR below 50 c/mL) and a snapshot analysis at 48, 96 and 144 weeks. Virological failure (VF) was defined as a confirmed plasma HIV‐1 RNA >50 c/mL.

Results

We included 258 subjects: 176 (68%) male, median age 46 (IQR 41, 53) y, 225 (87.2%) white, hepatitis virus co‐infection 36%, median baseline CD4 at switch 540 cells (360, 700), time with VL≤ 50 c/mL 45 (24, 69) months. The median calendar year of switching was 2008 (2006, 2010). The 3rd drug in previous regimen was ATV/r in 70 (27.1%), other PI/r in 25 (9.7%), and other 163 (63.2%); 85 (32.9%) had previously failed with a PI. The virological response at 48/96/144 weeks was, respectively, 89.5 [95% CI 85.1, 92.9]/88 [83.4, 91.7]/86.3% [81.6, 90.4] (TLOVR, composite endpoint failure or stop for any reason) and the risk of VF was 8.3/7.6/7.6%. In the snapshot analysis HIV‐RNA was below 50 c/mL in 72.5/65.9/51.6%, respectively, and >50 c/mL in 6.6/5.4/4.3%. Only 0.8/1.9/3.5% discontinued due to adverse events. There was a high rate of discontinuations due to other reasons or with VL missing in window. In a multivariate adjusted analysis, we observed an association between VF and nadir CD4 count (RH 0.60 [0.39, 0.93] per 100 cells higher), time with VL≤50 c/mL (RH 0.89 [0.81, 0.98] per 6 months longer) and previous failure with a PI (3.04 [1.36, 6.80]). There was no association with gender, age, hepatitis virus co‐infection, CD4 count at time of switching or third drug used in the previous regimen.

Conclusions

A switch to ATV400+ABC/3TC in selected subjects with HIV‐RNA below 50 c/mL is associated with relatively low rates of VF and discontinuation due to adverse events. Use might be considered in those with long‐term suppression and without prior PI failure. Larger cohorts are required to further define the appropriate selection criteria.
Bone mineral density improvement after 48 weeks of switch to maraviroc+darunavir/ritonavir 300/800/100 mg QD, preliminary results of GUSTA study
Authors: Bianco Claudia , Rossetti Barbara , Gagliardini Roberta , Lamonica Silvia , Fanti Luri , Lombardi Francesca , Cauda Roberto , Di Giambenedetto Simona , De Luca Andrea
Published: November 2014

Introduction

Low bone mineral density (BMD) and osteoporosis are prevalent in HIV‐infected patients and were associated with HIV infection and tenofovir‐containing ART.

Materials and Methods

The GUSTA study (GUided Simplification with Tropism Assay) is a two‐arm, prospective, multicenter, 1:1 randomized controlled trial designed to demonstrate the non‐inferiority of therapeutic switch to maraviroc+darunavir/ritonavir (MVC+DRV/r) 300/800/100 mg QD against the continuation of previous triple cART in patients with stable virological suppression. Enrolment criteria include HIV1‐RNA <50 copies/mL for >6 months, R5 tropism and CD4>200 cells/µL for >3 months. Dual energy X‐ray absorptiometry scans of proximal femur and lumbar spine were performed at baseline and week 48. Bone composition was evaluated using L2‐L4 lumbar column and proximal femoral BMD, T‐score and the Z‐score. At the same timepoints, plasma bone metabolism biomarkers were measured. Linear regression was used to compare means of differences between arms. The association between BMD changes and the baseline variables was assessed by linear regression.

Results

27 patients were included, 13 from study group and 14 from control group, 74.1% were males, 44.4% heterosexuals, 81.5% Caucasian, median age was 47 years (IQR 41–53), time from HIV diagnosis 13.4 years (9–19), CD4 553/µL (406–739), nadir CD4 201/µL (76–283). At baseline, median ART duration was 10.5 years (5.7–15.3), the majority of patients (70.4%) was on tenofovir, 63% was on a PI‐based regimen and 14,8% on an NNRTI‐based regimen. Mean proximal femur BMD from baseline increased over 48 weeks by 2.06% (SD 2.24) in the study arm and decreased by −2.77% (SD 4.63) in control arm (p=0.003). The change over 48 weeks in proximal femur T‐score was significantly different between the study (+0.11, SD 0.22) and control arm (−1.14, SD 0.27, p=0.016). Also the changes in total alkalin phosphatase (−20 U/L vs −1.5, p=0.003) was significant between the two groups. After adjusting for time from HIV diagnosis and years of ART, study group was the only factor associated to higher mean percentage change from baseline femoral BMD (MVC+DRV/r +4.83, p=0.044).

Conclusions

The study demonstrated a significant improvement in femoral BMD and T‐score after treatment simplification with MVC+DRV/r.
The importance of viral blips and duration of therapy initiated in primary infection in maintaining viral control after stopping cART
Authors: Fidler Sarah , Olson Ashley , Fox Julie , Phillips Andrew , Morrison Charles , Thornhill John , Bucher Heiner , Muga Roberto , Porter Kholoud
Published: November 2014

Introduction

After achieving undetectable HIV‐RNA on cART, on cessation, HIV‐RNA rebounds to pre‐treatment values for the majority due to the presence of an inaccessible viral reservoir. There is some evidence that cART during primary HIV infection (PHI) limits the reservoir size, optimizing the chance of maintaining viral control off cART. Data are required to predict possible viral controllers for treatment interruption following cART. This analysis aims to investigate the effect of cART duration and the rate of viral blips while on cART initiated in PHI, and other factors on maintaining viral control for those stopping cART.

Material and Methods

Using CASCADE data on HIV seroconverters, we characterized virologic blip (viral suppression on cART followed by a single HIV‐RNA above a blip threshold and a subsequent measure below the threshold without cART change) rates for those starting cART within six months of seroconversion (SC). Using Cox models, we examined the effect of the following factors on time to virologic rebound (HIV‐RNA>1000) after cART stop: cART duration, severity/rate of blips on cART, time from SC to cART start, cART class, SC year, SC age, CD4 at cART start/stop, sex and HIV risk group.

Results

The 660 individuals initiating cART in PHI were mostly male (91%), seroconverting between 1995 and 2012, with a median (IQR) age of 34 (29, 41) years mostly infected through sex between men (73%). Median cART duration was 14.8 (7.0, 31.7) months initiated at a median 1.9 (0.5, 3.9) months post SC. 13 (11, 16), 9 (7, 11), 6 (5, 9) and 7 (6, 10)% of individuals experienced blips >50, 100, 200 and 400 copies/mL, respectively. Of those who experienced blips, most (77–90%, depending on blip threshold) experienced just one. Among 250 individuals with undetectable HIV‐RNA at cART stop, median time to rebound was 1.6 (0.30, 5.8) months. Time on cART was the only factor independently associated with control after stopping, HR for rebound=0.91 (0.86, 0.98) per extra six months spent on cART, HR for ever blipping >400 copies/mL while on cART=0.88 (0.40, 1.93).

Conclusions

Blips occur in about 10% of individuals who initiate cART in PHI, most of who experience only one blip, but was not predictive of subsequent virologic rebound. Increasing time spent on cART initiated in PHI could increase time of virological suppression after cART stop.
Effect of hyperbilirubinaemia on neurocognitive, renal, bone and cardiovascular markers in HIV infection treated with boosted protease inhibitors
Authors: Barber Tristan J , Moyle Graeme , Hill Andrew , Jagjit Singh Gurmit , Boffito Marta , Nelson Mark
Published: November 2014

Introduction

Use of some protease inhibitors (PI) is associated with unconjugated hyperbilirubinaemia (HBR), due to inhibition of UGT1A1. As observed in Gilbert's syndrome, HBR may have antioxidant and anti‐inflammatory effects. Inflammation may be relevant to neurocognitive (NC) impairment, cardiovascular, renal and bone co‐morbidities in HIV infection. This study aimed to analyse correlations between antiretroviral associated HBR and NC impairment as well as renal, bone and cardiovascular parameters.

Material and Methods

This cross‐sectional study included 101 HIV‐1‐infected individuals stable (>6 months) on antiretroviral regimens including tenofovir/emtricitabine or abacavir/lamivudine plus a ritonavir‐boosted PI. Patients with >grade 2 HBR were compared to patients with normal bilirubin on NC data collected using CogState. An overall composite score was calculated for each subject. Two‐tail P‐values were calculated using the Mann‐Whitney U test. We measured the following parameters in all participants: Bone – Calcaneal Stiffness Index (CSI), blood bone markers, calculated FRAX score; CV – vascular endothelial function markers (iCAM, vCAM), lipid fractions and sub fractions (Total, HDL and LDL cholesterol, triglycerides, ApoB), Carotid Intimal Thickness (CIT), Pulse Wave Velocity (PWV), glucose and insulin for calculation of HOMA‐IR, IL‐6, d‐dimer, uric acid, and hsCRP; Renal – urea and electrolytes (U&E), urinary protein/creatinine ratio (uPCR), urinary retinal binding protein (RBP)/creatinine ratio.

Results

Forty‐three participants had normal bilirubin (NBR) levels and 35 had high bilirubin (HBR; >2.5 times upper limit); the remaining 23 patients had intermediate bilirubin levels or violated the protocol. The mean age of participants was 48 years; 93% were male and 84% Caucasian. Mostly no significant differences were seen in any of the markers when comparing the NBR and HBR groups. Two component tests of the CogState were seen to be different – visual learning and memory (OCL) and working memory (ONB) (Table 1).

VCAM1 and FRAX scores were noted to be different between the two groups, but the latter had a worse outcome in the HBR group.

Conclusions

The numbers seen here were not felt to be large enough to draw clear conclusions around clinical significance. In the context of overall cognitive screening, the individual test differences were also not felt to be clinically significant. Clearly there are some early signs here of differences that may be worth investigating further in a larger, prospective study.
Dominant drug targets suppress the emergence of antiviral resistance
Authors: Tanner Elizabeth J , Liu Hong-mei , Oberste M Steven , Pallansch Mark , Collett Marc S , Kirkegaard Karla
Published: November 2014

The emergence of drug resistance can defeat the successful treatment of pathogens that display high mutation rates, as exemplified by RNA viruses. Here we detail a new paradigm in which a single compound directed against a ‘dominant drug target’ suppresses the emergence of naturally occurring drug-resistant variants in mice and cultured cells. All new drug-resistant viruses arise during intracellular replication and initially express their phenotypes in the presence of drug-susceptible genomes. For the targets of most anti-viral compounds, the presence of these drug-susceptible viral genomes does not prevent the selection of drug resistance. Here we show that, for an inhibitor of the function of oligomeric capsid proteins of poliovirus, the expression of drug-susceptible genomes causes chimeric oligomers to form, thus rendering the drug-susceptible genomes dominant. The use of dominant drug targets should suppress drug resistance whenever multiple genomes arise in the same cell and express products in a common milieu.
Pulse‐Chase Analysis for Studying Protein Synthesis and Maturation
Authors: Fritzsche Susanne , Springer Sebastian
Published: November 2014

Pulse‐chase analysis is a well‐established and highly adaptable tool for studying the life cycle of endogenous proteins, including their synthesis, folding, subunit assembly, intracellular transport, post‐translational processing, and degradation. This unit describes the performance and analysis of a radiolabel pulse‐chase experiment for following the folding and cell surface trafficking of a trimeric murine MHC class I glycoprotein. In particular, the unit focuses on the precise timing of pulse‐chase experiments to evaluate early/short‐time events in protein maturation in both suspended and strictly adherent cell lines. The advantages and limitations of radiolabel pulse‐chase experiments are discussed, and a comprehensive section for troubleshooting is provided. Further, ways to quantitatively represent pulse‐chase results are described, and feasible interpretations on protein maturation are suggested. The protocols can be adapted to investigate a variety of proteins that may mature in very different ways. © 2014 by John Wiley & Sons, Inc.
Genetic Manipulation of Acinetobacter baumannii
Authors: Jacobs Anna C. , Thompson Mitchell G. , Gebhardt Michael , Corey Brendan W. , Yildirim Suleyman , Shuman Howard A. , Zurawski Daniel V.
Published: November 2014

Acinetobacter baumannii is a Gram‐negative nosocomial pathogen of clinical importance. A lack of genetic tools has hindered the research of this organism in the past; however, recently, various methods have been designed, modified, and optimized to facilitate the genetic manipulation of A. baumannii. This unit describes some of the recent genetic advances and new recombinant tools developed for this pathogen, including standard transformation and conjugation techniques specifically developed for the bacteria. As the need to understand the basic biology of A. baumannii increases with the prospect of developing new therapeutics, the use of the basic genetic methods herein can provide the critical first step to identify genes required for infection. © 2014 by John Wiley & Sons, Inc.
Quantitative Analysis of HSV Gene Expression during Lytic Infection
Authors: Turner Anne‐Marie W. , Arbuckle Jesse H. , Kristie Thomas M.
Published: November 2014

Herpes Simplex Virus (HSV) is a human pathogen that establishes latency and undergoes periodic reactivation, resulting in chronic recurrent lytic infection. HSV lytic infection is characterized by an organized cascade of three gene classes; however, successful transcription and expression of the first, the immediate early class, is critical to the overall success of viral infection. This initial event of lytic infection is also highly dependent on host cell factors. This unit uses RNA interference and small molecule inhibitors to examine the role of host and viral proteins in HSV lytic infection. Methods detailing isolation of viral and host RNA and genomic DNA followed by quantitative real‐time PCR allow characterization of impacts on viral transcription and replication, respectively. Western blots can be used to confirm quantitative PCR results. This combination of protocols represents a starting point for researchers interested in virus‐host interactions during HSV lytic infection. © 2014 by John Wiley & Sons, Inc.