bluuebunny/crossref_metadata_2025 huggingface dataset:
Less frequent follow‐up in routine care than in trials does not impact resistance selection in patients failing DRV/r or ATV/r first line treatment
Authors: Marcelin Anne‐Genevieve , Charpentier Charlotte , Wirden Marc , Descamps Diane , Calvez Vincent
Published: November 2014

Introduction

Selection of resistance mutations on antiretroviral therapy (ART) including darunavir (DRV/r) or atazanavir (ATV/r) has been reported infrequently but mainly in clinical trials where patients were followed very frequently (at least four to five clinical visits and viral load measurements per year). The aim of this study was to evaluate the rate of resistance at failure and mutational patterns emerging in patients receiving DRV/r or ATV/r based‐regimen as first line treatment and followed in standard clinical practice with less clinical visits and viral load measurements (median=2 per year).

Methods

We studied 1,518 patients starting their first line antiretroviral therapy and followed during at least two years (n=799 TVD+DRV/r, n=70 KVX+DRV/r, n=618 TVD+ATV/r, n=31 KVX+ATV/r). The median viral load at baseline was 76,000 copies/mL and the median CD4 cell count 384 cell/mm3. Virological failure was defined as two consecutive viral load=50 copies/mL after previous suppression <50 copies/mL, or failure to achieve <50 copies/mL. Predicted susceptibility was determined using the last ANRS algorithm.

Results

Among the 1,518 patients, 193 (12.7%) failed during the two years of follow‐up. Among patients failing TVD+DRV/r (n=95), the emerging mutations observed were RT M184V (n=8; 8%) and Pro V32I (n=1; 1%). Among patients failing KVX+DRV/r (n=8), the emerging mutations observed were RT M184V (n=3; 37%) and Pro I47V (n=1; 12%). Among patients failing TVD+ATV/r (n=86), the emerging mutations observed were RT M184V (n=9; 10%), Pro N88S (n=2; 2%) and Pro I50L (n=1; 1%). Among patients failing KVX+ATV/r (n=4), the emerging mutations observed were RT M184V (n=2; 50%) and no Pro mutation. Most of patients retained virus predicted to be susceptible to all antiretrovirals (22 virus became resistant to 3TC/FTC and three became resistant to ATV). None of them became resistant to DRV.

Conclusions

Among 1,518 patients in routine care who started their first line treatment with DRV/r or ATV/r, very few of them (1.4%) selected resistance mutations at failure with three patients selecting an ATV resistant virus. None of them became resistant to DRV. The less frequent follow‐up of patients in routine care compared to clinical trials does not impact the resistance selection rate in patients treated by boosted DRV or ATV based regimen.
Comparison of HIV‐1 drug resistance profiles generated from novel software applications for routine patient care
Authors: Gonzalez Dimitri , Digmann Benjamin , Barralon Matthieu , Boulme Ronan , Sayada Chalom , Yao Joseph
Published: November 2014

Introduction

Clinical laboratories performing routine HIV‐1 genotyping antiviral drug resistance (DR) testing need reliable and up‐to‐date information systems to provide accurate and timely test results to optimize antiretroviral treatment in HIV‐1‐infected patients.

Materials and Methods

Three software applications were used to compare DR profiles generated from the analysis of HIV‐1 protease (PR) and reverse transcriptase (RT) gene sequences obtained by Sanger sequencing assay in 100 selected clinical plasma samples from March 2013 through May 2014. Interpretative results obtained from the Trugene HIV‐1 Genotyping assay (TG; Guidelines v17.0) were compared with a newly FDA‐registered data processing module (DPM v1.0) and the research‐use‐only ViroScore‐HIV (VS) software, both of which use the latest versions of Stanford HIVdb (SD v7.0) and geno2pheno (G2P v3.3) interpretive algorithms (IA). Differences among the DR interpretive algorithms were compared according to drug class (NRTI, NNRTI, PI) and each drug. HIV‐1 tropism and integrase inhibitor resistance were not evaluated (not available in TG).

Results

Overall, only 17 of the 100 TG sequences obtained yielded equivalent DR profiles among all 3 software applications for every IA and for all drug classes. DPM and VS generated equivalent results with >99.9% agreement. Excluding AZT, DDI, D4T and rilpivirine (not available in G2P), ranges of agreement in DR profiles among the three IA (using the DPM) are shown in Table 1.

Conclusions

Substantial discrepancies (<75% agreement) exist among the three interpretive algorithms for ETR, while G2P differed from TG and SD for resistance to TDF and TPV/r. Use of more than one DR interpretive algorithm using well‐validated software applications, such as DPM v1.0 and VS, would enable clinical laboratories to provide clinically useful and accurate DR results for patient care needs.
Time trends in HIV‐1 transmitted drug resistance mutation frequency in Poland
Authors: Parczewski Milosz , Witak‐Jedra Magdalena , Maciejewska Katarzyna , Bociaga‐Jasik Monika , Skwara Pawel , Garlicki Aleksander , Grzeszczuk Anna , Rogalska Magdalena , Jankowska Maria , Lemanska Malgorzata , Hlebowicz Maria , Baralkiewicz Grazyna , Mozer‐Lisewska Iwona , Mazurek Renata , Lojewski Wladyslaw , Grabczewska Edyta , Olczak Anita , Jablonowska Elzbieta , Rymer Weronika , Szymczak Aleksandra , Szetela Bartosz , Gasiorowski Jacek , Knysz Brygida , Urbanska Anna , Leszczyszyn‐Pynka Magdalena
Published: November 2014

Introduction

In Poland, the HIV epidemic has shifted recently from being predominantly related to injection drug use (IDU) to being driven by transmissions among men‐who‐have‐sex‐with‐men (MSM). The number of new HIV cases has increased in the recent years, while no current data on the transmitted drug resistance associated mutations (tDRM) frequency trend over time are available from 2010. In this study, we analyze the temporal trends in the spread of tDRM from 2008 to 2013.

Materials and Methods

Partial pol sequences from 833 antiretroviral treatment‐naive individuals of European descent (Polish origin) linked to care in 9 of 17 Polish HIV treatment centres were analyzed. Drug resistance interpretation was performed according to WHO surveillance recommendations, subtyping with REGA genotyping 2.0 tool. Time trends were examined for the frequency of t‐DRM across subtypes and transmission groups using logistic regression (R statistical platform, v. 3.1.0).

Results

Frequency of tDRM proved stable over time, with mutation frequency change from 11.3% in 2008 to 8.3% in 2013 [OR: 0.91 (95% CI 0.80–1,05), p=0.202] (Figure 1a). Also, no significant differences over time were noted for the subtype B (decrease from 8.4% 2008 to 6.2% in 2013 [OR: 0.94 (95% CI 0.79–1.11), p=0.45] and across non‐B variants [change from 22.6% 2008 to 23.1% in 2013, OR: 0.94 (95% CI 0.75–1.19), p=0.62]. When patient groups were stratified according to transmission route, in MSM there was a trend for a NNRTI t‐DRM decrease (from 6.8% 2008 to 1% in 2013, OR: 0.61 (95% CI 0.34–1.02), p=0.0655, slope −0.74%/year) (Figure 1b), related to the subtype B infected MSM (decrease from 7% 2008 to 1% in 2013, OR: 0.61 (95% CI 0.34–1.03), p=0.0662, slope −0.75%/year). Overall tDRM frequency decrease was also noted for the heterosexually infected patients [from 17.6% 2008 to 10.3% in 2013, OR: 0.83 (95% CI 0.67–1.02, p=0.077, slope −2.041%/year)] but did not associate with drug class (Figure 1c). In IDUs, the trends in t‐DRM frequency were not significant over time (change from 1.9% in 2008 to 0 in 2013 [OR:1.24 (95% CI 0.73–2.26), p=0.4)].

Conclusions

The frequency of t‐DRM in Poland is generally stable over time. Decrease in the overall tDRM frequency in heterosexual infected cases and NNRTI resistance in subtype B infected MSM may be related to the higher treatment efficacy of current cART.
Primary drug resistance at diagnosis of HIV‐1 infection: a Portuguese cohort
Authors: Rocha Pereira Nuno , Duro Raquel , Piñero Carmela , Figueiredo Cristóvão , Sofia Santos Ana , Soares Jorge , Serrão Rosário , Sarmento António
Published: November 2014

Introduction

Presence of viral mutations conferring resistance to antiretroviral drugs has potential impact on success of antiretroviral therapy (ART). The aim of this study was to describe the prevalence of resistance‐associated mutations in HIV‐infected patients without prior ART in a Portuguese cohort.

Materials and Methods

Retrospective single‐centre study of patients newly diagnosed with HIV‐1 infection between 2006 and 2012. Resistance genotyping was obtained with HIV TRUGENE® and Viroseq® tests and the analysis of drug resistance was based on the Stanford University HIV Drug Resistance Database. Epidemiological data was also gathered. Continuous variables were summarized by mean and standard deviation, whereas categorical variables were presented as proportions. Comparison of proportions was performed with Chi square and Fisher exact test while means were compared with Student test. Statistical significance was assumed when p<0.05. Statistical analysis was performed with SPSS 21.0®.

Results

Resistance testing was performed in 624 patients. General characteristics of the patients are summarized in Table 1. Mutations were found in 291 (46.6%) patients but resistance‐associated mutations were present in 79 (12.7%) patients. Resistances to different drug classes were the following: NNRTIs‐resistance in 42 (6.7%) patients; NRTIs‐resistance in 19 (3.0%) patients; PIs‐resistance in 30 (4.8%) patients. Only 10 (1.6%) patients presented simultaneous resistance‐associated mutations to more than one class of drugs. There were no statistical significant differences between the years at which HIV‐1 was diagnosed. Also no significant difference in the distribution of the parameters age, sex, CD4‐cell count, and viral load, between groups with and without resistance was identified. Resistance‐associated mutations were significantly more common in patients with non‐B HIV‐1 subtypes (15.4% vs 9.8%; p=0.048) and in those presenting with AIDS (18.2% vs 11.1%; p=0.03).

Conclusions

Prevalence of resistance‐associated mutations identified in this study was similar to those reported in similar studies from Western Europe. Knowledge about the epidemiology of primary resistance in our country is important in order to improve HIV care.
Increased risk of virological failure to the first antiretroviral regimen in HIV‐infected migrants compared to natives: data from the ICONA cohort
Authors: Saracino Annalisa , Lorenzini Patrizia , Lo Caputo Sergio , Girardi Enrico , Castelli Francesco , Bonfanti Paolo , Galli Massimo , Caramello Pietro , Abrescia Nicola , Mussini Cristina , Monno Laura , d'Arminio Monforte Antonella
Published: November 2014

Introduction

Aim of the study was to evaluate possible disparities in access and/or risk of virological failure (VF) to the first antiretroviral (ART) regimen for migrants compared to Italian‐born patients and to assess determinants of failure for the migrants living with HIV.

Methods

All native and migrant naïve patients enrolled in ICONA in 2004–2014 were included. Firstly, variables associated to ART initiation were analyzed. In a second analysis, the primary endpoint was time to failure after at least six months of ART, defined as: (a) VF (first of two consecutive viral load (VL) >50 and >200 copies/mL); (b) treatment discontinuation (TD) for any reason; and (c) treatment failure (TF: confirmed VL >200 cp/mL or TD). A Poisson multivariable analysis was performed to control for confounders.

Results

A total of 5777 HIV‐pos ART‐naïve patients (1179 migrants and 4598 natives) were evaluated. Most migrants were from sub‐Saharan Africa (35.3%) and South‐Central America/Caribbean (29%). Median duration of residency in Italy was five years (IQR 1–10). Baseline characteristics significantly differed between the two groups (Table 1); in particular, lower CD4 counts and higher frequency of AIDS events were observed in migrants vs natives. When adjusting for baseline confounders, migrants presented a lower chance to initiate ART compared to natives (OR 0.78, 95% CI 0.65–0.93, p=0.006). After ART initiation, the incidence rate of VF >50 cp/mL was 15.5 per 100 person‐years (95% CI 12.8–18.8) in migrants and 8.9 in natives (95% CI 7.9–9.9), respectively. By multivariable analysis, migrants had a significantly higher risk of VF, both >50 cp/mL (OR 1.50, 95% CI 1.17–1.193, p=0.001) and >200 cp/mL (OR 1.59, 95% CI 1.23–2.05, p<0.001), and of TF (OR 1.15, 95% CI 1.00–1.32, p=0.045), while no differences were observed in TD risk. Among migrants, variables associated with a higher VF risk were age (for 10‐year increase, OR 0.96, 95% CI 0.93–0.98, p=0.002), unemployment (OR 1.96, 95% CI 1.20–3.20, p=0.007) and use of a boosted PI based‐regimen (OR 2.04, 95% CI 1.25–3.34, p=0.005 vs NNRTI‐based), while pregnancy was associated with TD (OR 3.73, 95% CI 2.36–5.90, p<0.001) and TF (OR 3.13, 95% CI 02.00–4.89, p<0.001).

Conclusions

Despite the use of more potent and safer antiretroviral drugs in the last 10 years, and even in a setting of universal access to ART, migrants living with HIV still present barriers to ART initiation and increased risk of VF compared to natives.
Effectiveness and tolerability of abacavir‐lamivudine‐nevirapine (ABC/3TC/NVP) in a multicentre cohort of HIV‐infected, ARV‐naïve patients
Authors: Podzamczer Daniel , Fredy Rojas Jhon , Neves Isabel , Ferrer Elena , Llibre Josep M , Leal Manuel , Gorgolas Miguel , Jose Crusells M , Gatell Josep M , Correia Abreu Ricardo , Curto Jordi , Domingo Pere , Pilar Barrufet M , Rozas Nerea
Published: November 2014

Purpose

Very scarce information has been published to date with the combination of ABC/3TC/NVP but it is currently being used in clinical practice in Spain and Portugal. Our aim was to present the clinical experience with this regimen in a cohort of adult HIV‐infected antiretroviral (ARV)‐naïve patients.

Methods

Retrospective, multicentre, cohort study. Consecutive adult HIV‐infected ARV‐naïve HLA‐B*5701‐negative patients, who started ABC/3TC/NVP between 2005‐2013, with at least one follow‐up visit, were included. Demographic, clinical and laboratory variables were assessed at baseline, month 1, and every three–four months thereafter. The primary end point was HIV‐1 viral load (VL)<40 c/mL at 48 weeks. Data were analyzed by intent‐to‐treat (ITT) (switch=failure, and missing=failure) and on treatment (OT) analyses.

Results

78 patients were included. Median follow up was 26 (0.1‐84) months. 86% were male, median age 41 (23‐69) years, 9% had AIDS, 8% were HCV+, baseline CD4 was 275 (10‐724) cells/µL and median VL 4.58 (3.02‐6.92) log. After 48 weeks, VL was<40 c/mL in 89.8% (OT), 79.7% (M=F) and 65.4% (S=F) and at 96 weeks in 88.5%, 78.9% and 61.6%, respectively. CD4 increased +246 (p<0.001) and +292 (p<0.001) cells/uL after 48 and 96 weeks, respectively. One or more drugs of the regimen were discontinued in 33 (42.3%) patients. In 15 (19.2%) patients (13 NVP, 2 ABC/3TC) therapy was stopped due to toxicity after a median of one month (in only two cases after six months of follow up): 80% of them had rash/liver toxicity. Six (7.7%) patients discontinued ART due to virologic failure, five (6.4%) because of other reasons and seven (9%) were lost to follow‐up. ALT but not AST significantly increased (+0.07 ukat/L at 96 weeks, p=0.033). A significant increase of 25%, 26% and 42% in total cholesterol, LDLc and HDLc, respectively, and a significant decrease in TC/HDL ratio (6%, p=0.008) was observed after 96 weeks.

Conclusions

Despite a considerable proportion of patients had to stop therapy due to toxicity (most associated with NVP), those initially tolerating this regimen presented a high virologic and immunologic response after 96 weeks, as well as a favourable lipid profile. ABC/3TC/NVP may be a suitable alternative first regimen, mainly in countries with economic constraints.
Four‐drugs regimen containing raltegravir is highly effective in HIV patients starting therapy with >500,000 copies/mL viral load
Authors: Sterrantino Gaetana , Zaccarelli Mauro , Prati Francesca , Boschi Andrea , Sighinolfi Laura , Borghi Vanni
Published: November 2014

Introduction

Assessing virological response of four‐drugs antiretroviral regimen that include raltegravir (RAL) in naïve patients with high viral load (>500,000 copies/mL) selected from a multicentre Italian database.

Methods

Naïve patients with HIV RNA>500,000 copies/mL, who began standard antiretroviral regimens either based on non‐nucleoside reverse transcriptase inhibitors (NNRTI) or boosted‐PI (PI/r), or a standard regimen plus RAL between 2008 and 2013 were analyzed. Observation was censored at 12 months and the percentage of patients who achieved a viral load below the limit of detection (BLD) was calculated. Virological failure was defined as two consecutive viral loads>40 copies/mL.

Results

Overall, 179 patients were included (13% with primary HIV infection (PHI), and 42.5% with AIDS diagnosis). Of them, 156 started standard three‐drugs antiretroviral regimen (75.6% PI/r‐based, 24.4% NNRTI‐based. Among patients with PHI, 23 patients (12.8%), 6 (25%) started a four‐drugs antiretroviral regimen containing both RAL and PI/r. Patients’ characteristics were as follows: males 74%, median age 42 years (IQR 35–51), sexually transmission 75.1%, median CD4 count 156 cells/µL (IQR 47–368) and median HIV‐RNA 6.1 log10 copies/mL (IQR 5.8–6.4). 91 of 179 patients (50.8%) reached BLD viral load during the twelve months of observation. Three patients (1.7%) who began regimens PI/r‐based with three‐drugs had virological rebound after reaching BLD viral load. By use of survival analysis, we show that those patients who added RAL to the standard regimen have reached the primary end point faster (mean 8.4 months (95% CI 7.2–9.6) vs 11.4 (95% CI 11.0–11.8) in PI group and 10.3 (95% CI 9.4–11.1) in NNRTI group; p<0.001, Figure 1). In the adjusted analysis, the choice of a standard regimen versus a four‐drugs regimen was driven only by higher baseline viral load (OR. 9.05; 95% CI 2.41–37.41; p=0.001).

Conclusions

Only half of the naïve patients who began antiretroviral therapy having >500,000 copies/mL HIV‐RNA had virological success at 12 months. The success was reached faster using the RAL‐containing four‐drugs regimen, suggesting that strengthening the initial regimen could be an option in patients with very high viral load to improve virological response.
Long‐term effect of a four‐drugs induction regimen for patients with high baseline viral load
Authors: Maggiolo Franco , Masini Giulia , Astuti Noemi , Di Filippo Elisa , Benatti Simone , Valenti Daniela , Callegaro Anna Paola , Rizzi Marco
Published: November 2014

Introduction

The long‐term effects of an intensified induction regimen are unknown. In this pilot, randomized, prospective study we evaluate the effect of a short‐term four‐drugs induction regimen in patients with high baseline viral load.

Methods

Naive patients with HIV‐RNA>100.000 copies/ml receiving TDF+FTC+EFV+RAL (group ER) for 4 months and were then simplified to TDF+FTC+EFV. Two randomized control groups treated ab‐initio with TDF+FTC+EFV (E) or TDF+FTC+RAL (R) were used.

Results

19 patients with a mean age of 38 years and mean baseline CD4 count of 334 (SD 216) cells/mcL and HIV‐RNA of 5.47 log (SD 0.32) copies/mL were enrolled. No baseline significant difference was observed among groups. Early HIV‐RNA reduction was significantly higher in ER compared to the other groups from week 1 to week 4 (P from 0.026 to 0.003) (figure 1), thereafter HIV‐RNA values were comparable among the groups. At week 96, all patients had an HIV‐RNA < 50 copies/mL, however only patients in the ER group had in all cases an HIV‐RNA level < 3 copies/mL with a statistically significant difference compared to E (60%; P=0.038) and R (50%; P=0.020). At 96 weeks, CD4 cell median counts were 765 cells/mcL for ER, 600 cells/mcL for E and 771 for R (P=0.16), however patients in the ER group presented a lower proportion of activated CD4+CD38+HLADR+ cells (1.9% versus 3.9 and 3.8%) and CD8+CD38+HLADR+ cells (10.3% versus 16.8 and 16.5%) and a significantly better CD4/CD8 ratio (0.98 versus 0.53 and 0.61; P=0.03).

Conclusions

A four‐drug regimen in naive patients with high pre‐therapy viral load improves early virologic response. A quick drop of HIV‐RNA seems to correlate with a sustained virologic response. Although limited in time (four months), the four‐drug regimens correlates with an improved immunological response as measured by the CD4/CD8 ratio or the percentage of activated CD4+ and CD8+ cells. The reasons why this happens deserve further studies. This study highlights the importance of a personalised therapy especially in high risk patients.
Who gets single tablet regimens (STR), and why?
Authors: Tarrier Laura , Kegg Stephen
Published: November 2014

Introduction

The BHIVA guidelines now feature three single tablet regimens (STRs) as recommended treatments for HIV‐positive people new to therapy [1]. They are popular with patients and are attractive in a number of clinical scenarios. We sought to determine how our use of STRs had developed over a three‐year period, and how the decision to opt for an STR was made.

Methods

Retrospective case‐note review and database interrogation of all patients starting anti‐retroviral therapy (ART) from 1st March 2011 to 31st March 2014.

Results

215 patients started ART. 58% (125/215) were black‐African and 47% (100/215) were female. Median CD4 at baseline was 272 cells/µL (range 1‐1044 cells/µL). 69 (32%) had a viral load (VL) >100,000 copies/mL. 7 individuals had evidence of transmitted drug resistance. 88 patients started an STR. Two tested positive for HLAB5701. None had a 10 year CVS risk score of >20% and 36% had a baseline VL >100,000 copies/mL. 127 patients started a non‐STR regimen, 29% had a VL >100 000 copies/mL and none had an elevated CVS risk. Information regarding baseline renal function and HLAB5701 will be provided at the conference. The use of STRs increased over the three years (25% 2011–12; 57.1% 2012–13; 44% 2013–14). There was no difference in STR prescribing between men and women. In men, heterosexual male patients were more likely to be prescribed an STR than MSM males (54% versus 43%, p 0.005). In 43% (38/88) patients had indicated a preference for an STR and 32/88 expressed a preference for a particular drug. 2% (2/88) requested to be on the same treatment as a partner. In those patients who expressed an interest in a particular drug, four had received information from a friend or partner. In 33% (29/88) cases an STR was felt by the clinician to be the best option, largely based on concerns around pill‐burden and adherence (31%), viral load (16%) and renal or cardiac risk (7%).

Conclusions

Use of STRs is increasing. This is not driven on in our cohort by cardiovascular risk of HLAB5701 carriage but by patient and clinician preference, and to a lesser extent by higher baseline viral loads.
Week 48 results of a Phase IV trial of etravirine with antiretrovirals other than darunavir/ritonavir in HIV‐1‐infected treatment‐experienced adults
Authors: Arathoon Eduardo , Bhorat Asad , Silaghi Rodica , Crauwels Herta , Lavreys Ludo , Tambuyzer Lotke , Vanveggel Simon , Opsomer Magda
Published: November 2014

Introduction

In DUET, etravirine (ETR) 200 mg bid had durable efficacy and a favourable safety profile versus placebo, both arms with an optimised background regimen (BR) including darunavir/ritonavir (DRV/r). TMC125IFD3002 (VIOLIN; NCT01422330) investigated ETR plus ARVs other than DRV/r.

Materials and Methods

This was a 48 week, Phase IV, open‐label, single‐arm, multicentre study. HIV‐1‐infected treatment‐experienced adult patients on=8 weeks ARV therapy prior to screening, switching either for virologic failure (VF) (viral load [VL] =500 c/mL) or regimen simplification/AEs (RS/AE) (VL<50 c/mL), received active ETR 200 mg bid with an investigator‐selected BR of =1 active ARVs, but excluding DRV/r or NRTIs only. The primary objective was to evaluate safety, tolerability and pharmacokinetics (PK).

Results

Of 211 treated patients, 55% were female, 61% black/African American. 155 patients (73%) had baseline (BL) VL=50 c/mL versus 56 (27%) with BL VL<50 c/mL. Between these two latter subgroups, median BL VL was 4.42 versus 1.28 log10 c/mL and CD4+ count 238 versus 410.5 cells/mm3. Overall, 96% previously used <2 NNRTIs and 99% used=5 PIs; median number of BL NNRTI RAMs was 2, PI RAMs 5 and NRTI RAMs 1. Overall, most common BR ARVs were PIs (83%), mostly lopinavir/r (62%) and mostly used alone (20%) or with 1 or 2 NRTIs (61%). Raltegravir was used in 9% of patients. Most frequent AEs (any cause/grade) were diarrhoea (17%) and URTI (8%). Incidence of grade 3–4 AEs was 13%, serious AEs 5% (no rashes; none ETR related), AEs leading to discontinuation 4%, AEs possibly related to ETR 23% and AEs of interest: rash (any type) 4%, hepatic 6% and neuropsychiatric 3%. At week 48, VF and RS/AE virologic responses (% patients with VL<50 c/mL; FDA Snapshot) were: 48% (74/155) and 75% (42/56), respectively. VF rates were 42% and 13%; 10% and 13% had no VL data in the week 48 window. The percentage of patients adherent to treatment (assessed based on PK sampling plus ETR pill count) was 47% (69/148) and 57% (30/53), in VF and RS/AE, respectively. Median CD4+ count (NC=F) increases were 0.0 and 24.0 cells/mm3. In 29/49 of VFs with genotypic data at failure, ETR RAMs emerging in =5 patients were Y181C, E138A and M230L. The geometric mean ETR AUC12h was 4877 ng.h/mL and C0h 293 ng/mL (N=199).

Conclusions

Results of this study were consistent with those for ETR in other similar populations and support the use of ETR 200 mg bid with a non‐DRV/r based BR.
Antiretroviral therapy (ART) management of Low‐Level Viremia in Taiwan (ALLEVIATE)
Authors: Cheng Chien‐Yu , Luo Yu‐Zhen , Wu Pei‐Ying , Liu Wen‐Chun , Yang Shan‐Ping , Zhang Jun‐Yu , Cheng Shu‐Hsing , Hung Chien‐Ching
Published: November 2014

Introduction

This retrospective study aimed to investigate that if switch of combination antiretroviral therapy (cART) would result in viral suppression (<40 copies/mL) at 48 weeks for patients with persistent low‐level viremia after having received cART for six months or more at two hospitals designated for HIV care in Taiwan.

Materials and Methods

Between January 2001 and January 2013, patients were enrolled if plasma HIV RNA load (PVL) were >20 to <1000 copies/mL detected for six months or more [1, 2]. Using a standardized data collection form, we recorded data of PVL and CD4 count before cART and at the detection of low‐level viremia, serologies for hepatitis B and C virus, risk factors, duration of cART exposure, years of HIV diagnosed and ever experiencing treatment failure. The strategy of switch is based on the clinical guidelines of BHIVA, which suggest change of cART from non‐nucleoside reverse‐transcriptase inhibitors (nNRTIs) or unboosted protease inhibitor (PI) to boosted PI, newer boosted PI or ARV of different mechanism [3].

Results

In this study, 165 patients were enrolled, 119 patients (72.1%) did not switch (Group 1), and 46 patients (27.9%) switched previous regimens to ARV of different mechanism (Group 2). The two groups differed significantly in the proportion of injecting drug users (IDU) (Group 1 vs Group 2, 10.9 vs 26.1%) and median PVL (67 vs 159 copies/mL), and the proportion of PVL<200 copies/mL (84.0% vs 58.7%) when low‐level viremia was first detected. In Group 1, 39 (32.8%) continued two nucleoside reverse‐transcriptase inhibitors (NRTIs) plus nNRTI; 29 (24.4%) 2 NRTIs plus PI, 47 (39.5%) 2 NRTIs plus boosted PI, and 4 (3.3%) 2 NRTIs plus integrase inhibitor (II). In Group 2, two (4.3%) switched to 2 NRTIs plus PI, 38 (82.6%) 2 NRTIs plus boosted PI, three (6.5%) 2 NRTIs plus II and three (6.5%) boosted PI plus II. In multivariate analysis, IDUs (adjusted odds ratio [AOR], 6.757; 95% CI 2.427–18.868) and PVL of 200–999 copies/mL at enrollment (AOR, 4.902; 95% CI 1.992–12.048) were more likely to be switched. At 48 weeks, patients in Group 2 were more likely to achieve PVL<40 copies/mL than Group 1 (82.6% vs 63.0%, p=0.016), while no difference was observed in achieving PVL <200 copies/mL between the two groups (95.7% vs 92.4%, p=0.729).

Conclusions

According to the clinical guidelines of BHIVA, patients with low‐level viremia who switched to cART consisting of 2 NRTIs plus boosted PI or newer mechanisms were more likely to re‐establish viral suppression to <40 copies/mL at week 48.
Effectiveness and durability of darunavir/ritonavir (DRV/r) in DRV/r‐experienced HIV‐1‐infected patients in routine clinical practice
Authors: Antinori Andrea , Galli Massimo , Gianotti Nicola , Mussini Cristina , Quirino Tiziana , Sterrantino Katia , Mancusi Daniela , Termini Roberta
Published: November 2014

Introduction

This was a descriptive non‐interventional study in HIV‐1‐infected patients treated with DRV/r conducted in the clinical setting, with a single‐arm prospective design. The primary objective was to collect data on utilization of darunavir/ritonavir (DRV/r) under the conditions described in the marketing authorization. Efficacy (measured as viral load [VL] <50 copies/mL and CD4+ cell count) was evaluated for DRV/r in combination with other antiretroviral (ARV) agents in routine clinical practice in Italy.

Materials and Methods

Here we describe an analysis of effectiveness and durability data from two cohorts of DRV/r‐experienced patients with HIV‐1 infection, already receiving DRV/r according to usual clinical practice, collected prospectively from June 2009 to December 2012: Cohort 1, data from patients from the DRV/r Early Access Program (TMC114‐C226 study; N=235 patients) and Cohort 2, a separate cohort of ARV‐DRV/r‐experienced patients (N=407 patients), treated with DRV/r in the market. Patient characteristics are shown in Table 1.

Results

The median length of DRV/r exposure during the study was 925 days (interquartile range [IQR] 692–1006) in Cohort 1, and 581 (IQR 508–734) days in Cohort 2. Of those patients that completed the study, 94% and 87% of patients were virologically suppressed in Cohort 1 and 2, respectively, at last study visit (LSV). As expected, the virological suppression rate was higher in patients with baseline VL <50 copies/mL (Table 2). Mean CD4+ cell counts improved from baseline to LSV in both cohorts (Cohort 1: +54 cells/µL [95% CI 31, 77] and Cohort 2: +59 cells/µL [95% CI 44, 73]). High persistence rates were seen in both cohorts, with 75.3% of patients in Cohort 1 and 82.6% in Cohort 2 remaining on treatment at LSV; very few patients discontinued due to virologic failure (Table 1). Other reasons for study discontinuation are shown in Table 1. Very few patients changed DRV/r dosing during the study, 15 from 1200 to 800 mg o.d.

Conclusions

In patients already treated with DRV/r, DRV/r‐based ARV treatment provided effective viral suppression with long‐lasting durability, low virological response failure, low discontinuation rates and good tolerability. These data confirm DRV/r to be an effective treatment choice in previously treated patients.
Switch to raltegravir‐based regimens and HIV DNA decrease in patients with suppressed HIV RNA
Authors: Bianco Claudia , Meini Genny , Rossetti Barbara , Lamonica Silvia , Mondi Annalisa , Belmonti Simone , Fanti Luri , Ciccarelli Nicoletta , Di Giambenedetto Simona , Zazzi Maurizio , De Luca Andrea
Published: November 2014

Introduction

Raltegravir intensification is associated with an increase in 2‐LTR episomal HIV DNA= circles, indicating a persistent low‐level replication, in some individuals in ART with suppressed HIV RNA. We aimed at monitoring residual plasma HIV RNA and cellular HIV DNA in virologically suppressed patients switching to a raltegravir‐based regimen.

Materials and Methods

Forty‐six HIV‐infected subjects on PI or NNRTI based‐regimens, with plasma HIV RNA level <40 copies/mL for ≥6 months and CD4 >200 cells/µL for ≥12 months were enrolled. Thirty‐four patients switched to raltegravir‐based regimen (RASTA study group) and 12 continued a PI or NNRTI based‐regimen (control group). Ultrasensitive HIV residual viremia and total PBMC HIV DNA were assessed at baseline (W0), 24 (W24) and 48 (W48) weeks. HIV RNA levels were determined by an ultrasensitive test derived from a commercial real time PCR (limit of detection 5 copies/ml). A real time PCR was used to quantify HIV DNA copy numbers in PBMCs.

Results

At W0, HIV DNA was detected in all patients while at W48 it was detectable in 82.3% of RASTA group vs 100% of controls (p=0.01). The difference between the average values of HIV DNA log10 copies/10°6 CD4 at W0 (median 3.11, IQR 2.70–3.45) and W48 (median 2.87, IQR 2.24–3.38) was statistically significant for RASTA group (p=0.035). Male gender (mean difference −0.37 log10 copies/10°6 PBMC, p=0.023) and previous PI based‐ART (mean difference +0.39 log10 copies/10°6 PBMC, p=0.036) were predictive of HIV DNA level at W0. After adjusting for previous PI based‐ART, male gender was the only variable independently associated with HIV DNA size at W0 (mean difference −0.326 log10 copies/10°6 PBMC, 95% CI −0.641, −0.011 p=0.043). Ultrasensitive HIV‐1 RNA was detectable at W0 in 50% of RASTA group versus 66.7% of controls and at W48 in 32.4% versus 45.5%, respectively. No differences were found between HIV RNA levels at W0 and W48 within and between the two groups.

Conclusions

Switching to raltegravir‐based regimens may be associated with a decrease of HIV reservoir, as measured by total PBMC HIV DNA. A larger sample size is required to confirm this finding.
Boosted lopinavir vs boosted atazanavir in patients failing a NNRTI first line regimen in an urban clinic in Kampala
Authors: Laker Eva , Mambule Ivan , Nalwanga Damalie , Musaazi Joseph , Kiragga Agnes , Parkes‐Ratanshi Rosalind
Published: November 2014

Introduction

In 2011 Uganda recommended boosted atazanavir (ATV/r) as the preferred PI for second line due to once daily dosing, replacing aluvia (LPV/r) [1, 2]. The evidence was based on the BMS O45 trial, of LPV/r vs ATV/r was performed in a high‐income setting, on patients with prior PI use and resistance testing [2, 3]. There are no RCTs or observational studies comparing use of ATV/r with LPV/r in patients failing NNRTI first line antiretroviral therapy in sub‐Saharan Africa [3, 4]. The Infectious Diseases Institute (IDI) has a large second line cohort (>1838). This aims to compare clinical, immunologic and virologic response of LPV/r versus ATV/r at IDI.

Methods

Retrospective cohort analysis on routinely collected data of patients switched to second line with NRTI backbones TDF/3TC or FTC, AZT/3TC, ABC/3TC from January 2009 to December 2013. Students T‐tests and Chi‐square tests were used in this analysis.

Results

A total of 1286 (73.5% female) patients were switched to LPV/r 991 (77%) and ATV/r 295 (23%) (p<0.001). NRTI backbones were 760 on TDF/3TC (66.8% LPV/r vs 33.2% on ATV/r), 504 on AZT/3TC (93.3% vs 6.7%), and 22 on ABC/3TC (59% vs 41%). Median (IQR) time on first line for LPV/r was 21 (1–44) months and for ATV/r was 41 months (22–68). Median CD4 (IQR) at switch to LPV/r was 181 cells/uL (66–424) and to ATV/r was 122 (57–238) (p≤0.001). A total of 366 patients had CD4 done at six months after switch and the mean (IQR) CD4 increase was 153 (54–241) for LPV/r versus 116 (52–171) for ATV/r (p=0.232). Additionally, 304 had a CD4 at 12 months and the means were 172 (45–272) for LPV/r vs 179 (60–271) for ATV/r (p=0.426). There was no significant difference in the mean increment by NRTI backbone or by stratifying to viral load (VL) at time of switch to VL <100,000 and ≥100,000. Median (IQR) VL at switch was 61,000 (13,000–2,030,000) LPV/r and 51,000 (14,000_151,000) ATV/r. 269 had a VL done in the first 12 months and 178/250 (71.2%) on LPV/r versus 16/19 (84.2%) on ATV/r were undetectable (p=0.228). 259 (26%) LPV/r versus 33(11%) ATV/r had ≥1 opportunistic infections on second line (p<0.001).

Conclusions

This is an observational study based on our experience at IDI. Like elsewhere in Africa, there is no routine viral load testing, making it difficult to get sensitive analysis of data on ART efficacy within routine clinical practice. Nevertheless, this observational study is reassuring in terms of efficacy of both ATV/r and LPV/r for patients failing first line therapy in our setting.
Switching to nevirapine‐based regimens after undetectable viral load is not associated with increased risk of discontinuation due to toxicity
Authors: Patterson Patricia , Socías Eugenia , Pryluka Daniel , Lapadula Pablo , Pérez Héctor , Cahn Pedro
Published: November 2014

Introduction

Due to its good tolerability, favourable cardiovascular risk‐profile, low‐pill burden and cost, nevirapine‐based regimens are an attractive simplification strategy for patients with suppressed viral load (VL). However, current guidelines recommend caution if nevirapine (NVP) is prescribed in males and females with CD4 counts above 400 or 250 cells/µL, respectively. The aim of this study is to determine the prevalence and risk factors associated with development of toxicity or treatment discontinuation in patients switching to NVP‐based regimens.

Materials and Methods

Retrospective chart review of HIV‐infected patients with suppressed VL who switched from a PI‐based regimen to a NVP‐based regimen in four HIV clinics in Argentina, between 1997 and 2013. Bivariate and multivariate analyses were performed to explore factors associated with treatment discontinuation. High CD4 count was defined as CD4‐cell count ≥400 or 250 cells/µL in males and females, respectively.

Results

Of 218 patients included, 165 (75.7%) were male; 21 (9.6%) were co‐infected with HCV and/or HBV. Median baseline (BSL) CD4 count: 138 cells/µL (IQR: 64–276). At switch, patients had a median age of 38 years (IQR: 33.4–43.8) and had been suppressed for a median of 1.4 years (IQR: 0.6–2.2); 138 patients (63.3%) had high CD4‐cell counts: among females, median CD4 count at switch was 462 (IQR: 330–709) cells/µL; among males, 433 (IQR: 305–595) cells/µL. Thirty‐six patients (13.5%) presented NVP‐related toxicity (30 skin toxicity, 6 hepatic toxicity), 29 (13.3%) discontinued NVP. Median time to development to toxicity: 32 days (IQR: 15–75). In bivariate analysis, chronic hepatitis was the only variable associated with development of toxicity (OR: 2.90, 95% CI 1.08–7.78). In multivariate analysis, no statistical significant associations were observed between either development of toxicity or treatment discontinuation and gender, chronic hepatitis, age or CD4‐cell count at BSL or at switch (all p>0.05).

Conclusions

In our study, switching to a NVP‐based regimen in patients with undetectable VL was associated with a low incidence of skin or liver toxicity, and treatment discontinuation. Moreover, these were unrelated to the CD4‐cell count. Our findings suggest that, in contrast with ART‐naïve patients, switching to NVP‐based regimens could be a safe strategy for patients with suppressed viremia regardless of the CD4‐cell count.
Lipid changes in HIV‐patients switching to the coformulated single tablet FTC/RPV/TDF (Eviplera®). Efficacy and safety analysis. GeSida Study 8114
Authors: Pérez‐Hernández Isabel A , Palacios Rosario , Mayorga Marisa , González‐Doménech Carmen M , Castaño Manuel , Rivero Antonio , del Arco Alfonso , Lozano Fernando , Santos Jesús
Published: November 2014

Introduction

Rilpivirine (RPV) has a better lipid profile than efavirenz (EFV) in naïve patients [1]. Switching to RPV may be convenient for many patients, while maintaining a good immunovirological control [2]. The aim of this study was to analyze lipid changes in HIV‐patients at 24 weeks after switching to Eviplera® (emtricitabine/RPV/tenofovir disoproxil fumarate [FTC/RPV/TDF]).

Materials and Methods

Retrospective, multicentre study of a cohort of asymptomatic HIV‐patients who switched from a regimen based on 2 nucleoside reverse transcriptase inhibitors (NRTI)+protease inhibitor (PI)/non nucleoside reverse transcriptase inhibitor (NNRTI) or ritonavir boosted PI monotherapy to Eviplera® during February‐December, 2013; all had undetectable HIV viral load for ≥3 months prior to switching. Patients with previous failures on antiretroviral therapy (ART) including TDF and/or FTC/3TC, with genotype tests showing resistance to components of Eviplera®, or who had changed the third drug of the ART during the study period were excluded. Changes in lipid profile and cardiovascular risk (CVR), and efficacy and safety at 24 weeks were analyzed.

Results

Among 305 patients included in the study, 298 were analyzed (7 cases were excluded due to lack of data). Men 81.2%, mean age 44.5 years, 75.8% of HIV sexually transmitted. 233 (78.2%) patients switched from a regimen based on 2 NRTI+NNRTI (90.5% EFV/FTC/TDF). The most frequent reasons for switching were central nervous system (CNS) adverse events (31.0%), convenience (27.6%) and metabolic disorders (23.2%). At this time, 293 patients have reached 24 weeks: 281 (95.9%) have continued Eviplera®, 6 stopped it (3 adverse events, 2 virologic failures, 1 discontinuation) and 6 have been lost to follow up. Lipid profiles of 283 cases were available at 24 weeks and mean (mg/dL) baseline vs 24 weeks are: total cholesterol (193 vs 169; p=0.0001), HDL‐c (49 vs 45; p=0.0001), LDL‐c (114 vs 103; p=0.001), tryglycerides (158 vs 115; p=0.0001), total cholesterol to HDL‐c ratio (4.2 vs 4.1; p=0.3). CVR decreased (8.7 vs 7.5%; p= 0.0001). CD4 counts were similar to baseline (653 vs 674 cells/µL; p=0.08), and 274 (96.8%) patients maintained viral suppression.

Conclusions

At 24 weeks after switching to Eviplera®, lipid profile and CVR improved while maintaining a good immunovirological control. Most subjects switched to Eviplera® from a regimen based on NNRTI, mainly EFV/FTC/TDF. CNS adverse events, convenience and metabolic disorders were the most frequent reasons for switching.
Switching to boosted protease inhibitor plus a second antiretroviral drug (dual therapy) for treatment simplification: a multicenter analysis
Authors: Zaccarelli Mauro , Fabbiani Massimiliano , Pinnetti Carmela , Borghi Vanni , Giannetti Alberto , Sterrantino Gaetana , Lorenzini Patrizia , Latini Alessandra , Loiacono Laura , Colafigli Manuela , Ammassari Adriana , D'Ettorre Gabriella , Plazzi Maddalena , Di Giambenedetto Simona , Antinori Andrea
Published: November 2014

Background

To assess the role of drugs used in dual therapy (DT), as cART simplification, over the risk of treatment failure.

Materials and Methods

Patients starting DT regimen composed by a boosted protease inhibitor (PI/r): darunavir (DRV/r), lopinavir (LPVr) or atazanavir (ATV/r) plus a second drug: raltegravir (RAL), maraviroc (MRV) etravirine (ETR), lamivudine (3TC) or tenofovir (TDF), this one generally used in HBV co‐infected patients, were included. The effect of each drug as well as other clinical and virological cofactors over treatment failure was assessed using survival analysis.

Results

Overall, 480 patients from six reference Italian centres were included: all switched to DT with HIV‐RNA <500 cp/µL, 376 of them at <50 cp/µL. Patients who switched at <50 cp/µL showed a significant lower risk of treatment failure (13.3% versus 23.3% at 1 year and 28.0% versus 44.6% at 3 years, p=0.005), thus the analysis was focused on this subgroup. Among the patients who switched at <50 cp/µL, the proportion of drug used in DT was: DRV/r 63.0%, RAL 53.7%, ETR 19.4%, ATV/r 18.4%, MRV 17.3%, LPV/r 12.8%, TDF 6.4% and 3TC 5.9%; DRV/r‐RAL was the most widely used combination: 32.5%. Treatment failure was observed in 78 patients, of whom 38 virological and 35 for toxicity/intolerance, one patient died during follow‐up and four patients interrupted for personal decision with undetectable HIV‐RNA. At Cox Model, adjusted by gender, age, non‐Italian origin, AIDS diagnosis, time on cART, number of regimens, CD4 nadir, baseline CD4, all the drugs had a positive effect on probability of failure (Figure), however the effect was significant for DRV/r (HR:0.21, 95% CI 0.07–0.59, p=0.03), ATV/r (0.30, 0.09–0.97, p=0.044) and RAL (0.37, 0.15–0.93, p=0.034); higher CD4 count at baseline was also associated with lower risk of failure while number of previous regimens with a higher risk. Moreover, ATV/r was found significant associated with significant higher risk of failure by toxicity (as well as LPV/r) but lower risk of virological failure, while both 3TC and RAL with significant lower risk of toxicity.

Conclusions

Our analysis suggest that using PI/r‐based DL is highly effective if switching from HIV‐RNA <50 cp/µL; DL should be used with caution in patients with low CD4 count and longer history of treatment; DRV/r is the best compromise among PI/r, ATV/r is effective but is associate with frequent interruption by toxicity; RAL showed high tolerability so that its use is related to the lowest risk of failure as second drug.
Simplification to Stribild vs continuation of RTV‐boosted DRV with FTC and TDF in virologically suppressed HIV adults: a STRATEGY‐PI subgroup analysis
Authors: Arribas Jose , Rizzardini Giuliano , Arasteh Keikawus , Zurawski Christine , Dietz Craig , Pontani Dennis , Garner Will , Nguyen Thai
Published: November 2014

Introduction

Simplification to Stribild (STB) was statistically superior to continuation of a ritonavir‐boosted protease inhibitor (PI+RTV) with emtricitabine and tenofovir DF (FTC/TDF) at week (W) 48 in virologically suppressed HIV adults (1). We report the W48 efficacy and safety of STB versus RTV‐boosted darunavir (DRV) with FTC/TDF in suppressed subjects.

Material and Methods

Virologically suppressed subjects on PI+RTV with FTC/TDF regimens for ≥6 months were randomized (2:1) to switch to STB vs continue their PI regimen. Eligibility criteria included no documented resistance to FTC and TDF, no history of virologic failure and eGFR ≥70 mL/min. The primary endpoint was the proportion of subjects in the modified ITT population who maintained HIV‐1 RNA <50 copies(c)/mL at W48 by FDA snapshot algorithm (12% non‐inferiority margin). Subgroup analysis by PI use (DRV [173], atazanavir [174], lopinavir [72], Other PI [13]) at screening was pre‐specified.

Results

Four hundred twenty‐nine subjects were randomized and treated (mITT set). In the DRV subgroup, 113 switched to STB; 60 continued a RTV‐boosted DRV with FTC/TDF. At W48, 95% STB versus 92% DRV maintained HIV‐1 RNA <50 c/mL. No emergent resistance was detected in either group. Median increases from baseline in CD4 count at week 48 (cells/µL): 28 STB versus 29 DRV (p=0.81). Discontinuations due to adverse events were 3% STB versus 2% DRV; one case of isolated decrease in eGFR in the DRV group and no cases of proximal renal tubulopathy in either group. There were statistically significant decreases in the frequency of diarrhoea reported on the HIV Symptom Index at week 4 to week 48 compared to baseline after switching to STB. There was a greater but non‐progressive decrease from baseline in eGFR in the STB vs DRV group; median changes (mL/min) at week 48: −8.5 vs −0.6, consistent with the known cobicistat inhibition of renal creatinine secretion. Switch to STB was associated with a higher treatment ease (convenience, flexibility, demand, lifestyle, understanding) score (range: −15 to 15) at week 4 (median: 12 vs 9; p=0.006) and week 24 (median: 13 vs 8; p=0.001).

Conclusions

In this small group of virologically suppressed subjects, simplification to STB versus continuation of a RTV‐boosted DRV with FTC/TDF was safe, well‐tolerated, and associated with a high rate of virologic suppression at week 48. There was more treatment ease with STB use.