Suchergebnisse

IntroductionTDF/FTC/RPV has been shown effective in both naïve and PI‐pre‐treated patients. Less is known about a switch strategy in subjects receiving EFV.Materials and MethodsWe evaluated viro‐immunologic outcomes, Quality of Life (QoL) and costs of an unselected cohort of patients switching from a TDF/FTC/EFV STR (≥6 months duration) to a TDF/FTC/RPV STR. The considered outcome measures were quality‐adjusted life years (QALYs) as measured with the EQ5D questionnaire and the overall direct health costs. 64 patients with a baseline viral load<50 copies/mL were randomized to immediately switch therapy or to continue TDF/FTC/EFV for four months and then switch to TDF/FTC/RPV. Six patients in the deferred switch group did not actually change cART.ResultsPatients were mostly males (73.4%) with a mean age of 46 years, a baseline mean HIV‐RNA of 6.4 copies/mL and a mean baseline CD4 count of 588 cells/µL. For the considered follow‐up period, the mean cost per patient resulted 2,563 for TDF/FTC/RPV and 2,572 for TDF/FTC/EFV. Viremia remained undetectable and CD4 stable in all patients. Over time the mean QoL increased in the RPV arm ad slightly decreased in the EFV arm, after four months the mean per patient QALYs was 0.849 for RPV and 0.841 for EFV, respectively (Figure 1). A sharp increment of QoL was observed in the deferred‐switch arm after switch, too. VAS analysis of health status perception also increased overall from 82.78 to 83.79 due to the improvement in the RPV arm. Mean cholesterol levels improved in the RPV arm from 203 to 170 mg/dL, while an increment from 190 to 207 mg/dL was observed in the EFV arm. HDL levels lowered from 49 to 45 and rose from 53 to 54 mg/dL in the RPV and EFV arms, respectively. Triglycerides levels improved both in the RPV arm (from 138 to 112 mg/dL) and in the EFV arm (from 110 to 103 mg/dL).ConclusionsSwitching from TDF/FTC/EFV to TDF/FTC/RPV is a safe, well tolerated strategy that improves the overall health status of HIV‐treated patients. The switch does not expose patients to a risk of virologic failure due to possible PK interactions of the drugs. RPV compared to EFV proved to be cost‐effective showing lower cost and higher outcome measure values.

IntroductionProven resistance against HIV drugs, either by phenotyping or genotyping is a rare event in clinical trials. The overall assumption of drug resistance disappearing is additionally driven by the recommendations to screen for transmitted drug resistance, leading to large numbers of examinations with relatively low rates of resistance. Goal of our analysis was to assess if drug resistance in treatment failure is also decreasing outside of clinical trials.Materials and MethodsThe MIB database at timepoint of analysis consists of data from 2876 HIV infected patients. Besides various laboratory parameters, clinical data and treatment history is included. HIV‐1 protease and reverse transcriptase sequences were analyzed using the HIV‐GRADE drug resistance algorithm. As in only a small number of patients genotypic resistance testing for integrase inhibitors was performed, mainly due to reimbursement reasons, it was assumed that failing treatment on a previous integrase inhibitor containing regimen is equate to resistance.ResultsOf the 2876 patients in the database, 220 had a treatment change due to treatment failure between 2009 and 2012, a genotypic resistance testing at an appropriate timepoint of maximum four weeks before treatment change and a treatment duration of at least six months before treatment failure. In 2009, 61% of patients showed no drug resistance while 39% showed resistance against one or more drug classes (two or more drug classes: 19.5%; three or more drug classes: 2.4%, four drug classes 2.4%). In 2012, no resistance was found in 52% of patients while resistance against three or more drug classes was found in nearly 14% of patients (one or more: 48%; two or more 23%; four classes: 4.5%).ConclusionsTreatment failure with viral load sufficiently high for drug resistance testing was not frequently observed in our database. Nevertheless, treatment failure was often associated with drug resistance against at least one drug class. With more use of the newer drug classes, resistance against those new classes will become more common and rates of multiclass resistance will be increasing.

IntroductionWide inter‐patient variation of plasma efavirenz (EFV) concentrations has been observed, and a substantial proportion of HIV‐positive patients may have unnecessarily higher plasma EFV concentrations than recommended while receiving EFV‐containing combination antiretroviral therapy (cART) at the currently recommended daily dose of 600 mg. A lower daily dose (400 mg) of EFV has recently been demonstrated to be as efficacious as the recommended 600 mg when combined with tenofovir/mtricitabine in a multinational clinical trial, with a lower incidence of adverse effects. We aimed to use a therapeutic drug monitoring (TDM)‐guided strategy to optimize the EFV dose in HIV‐positive Taiwanese patients.Materials and MethodsThe plasma EFV concentrations at 12 hours (C12) after taking the previous dose were determined among HIV‐positive adults who had received EFV‐containing cART with viral suppression (plasma HIV RNA load (PVL) <200 copies/mL). For those with EFV C12 >2.0 mg/L, EFV (Stocrit, MSD) was reduced to half a tablet daily. Determinations of EFV C12 were repeated 4–12 weeks after switch using high‐performance liquid chromatography. CYP2B6 G516T polymorphisms were determined using polymerase‐chain‐reaction restriction fragment‐length polymorphism.ResultsBetween April 2013 and June 2014, 111 patients (95.5% male; mean age, 39 years; 96.4% with PVL <40 copies/ml; 26.4% HBsAg‐positive and 7.5% anti‐HCV‐positive) with plasma C12 efavirenz >2.0 mg/L were switched to a reduced dose (1/2# hs) of EFV; 45.5% of them had CYP2B6 G516T or TT genotypes; and 32.4% weighed 60 kg or less. The mean baseline EFV C12 before switch was 3.65 mg/L (interquartile range (IQR), 2.62–4.17) for 111 patients, which decreased to 1.96 mg/L (IQR, 1.53–2.33) for 64 patients who had completed follow‐up of C12 EFV 4 weeks after switch, with a reduction of 49.4% (IQR, 38.9–57.0%). As of 10 July, 2014, all of the 38 patients (100%) who had completed at least one follow‐up of PVL achieved undetectable PVL (<40 copies/ml) following switch to a reduced dose of EFV after a mean observation of 13 weeks (IQR, 7–15 weeks).ConclusionsSwitch to cART containing a half tablet of EFV (1/2#) in HIV‐positive Taiwanese patients with higher plasma EFV concentrations who had achieved viral suppression could maintain successful viral suppression with the guidance of TDM.

IntroductionDarunavir/r (DRV/r) is currently used at a dose of 800/100 mg once daily (OD) in a high proportion of patients. Pharmacokinetic data suggest that 600/100 OD may be effective, reducing toxicity and cost. However, drug concentrations in reservoirs such as cerebrospinal fluid (CSF) might not be adequate to inhibit viral replication. We aimed to evaluate concentrations of DRV and HIV‐1 viral load (VL) in CSF patients receiving DRV 600/100 mg OD.MethodsDRV600 is an ongoing randomized open study comparing DRV/r 800/100 mg (DRV800) vs 600/100 mg (DRV600) OD plus TDF/FTC or ABC/3TC in 100 virologically suppressed patients (eudraCT 2011‐006272‐39). Here we present the results of a CSF sub‐study. A lumbar puncture (LP) was performed in participating patients after at least six months of inclusion in the study, 20–28 hours after a dose of DRV/r. VL (PCR, LOD 40 copies/mL) was determined in CSF and in plasma. DRV concentrations were quantified in CSF by liquid chromatography mass spectrometry (LC/MS/MS) and in plasma using high‐performance liquid chromatography (HPLC).ResultsSixteen patients were included (eight in each arm). All DRV600 patients and four out of eight DRV800 patients received TDF/FTC, and the other four ABC/3TC. 75% were males, median (range) age was 48 (17–71) years, CD4 cell count 532 cells/mL (190–1,394). Median total time on DRV/r was 30 (11–57) months, and since the beginning of the study 8 (6–12) months in DRV800 and 10 (7–12) months in DRV600 patients. LP was performed a median of 26 (24–28) hours after the last DRV/r+TVD or KVX dose. In DRV600 patients the median DRV plasma levels were 1,674 (326–3,742) ng/mL, CSF levels 17.08 (5.79–30.19) ng/mL and DRV CSF:plasma ratio 0.0084 (0.0028–0.0388), while in the DRV800 arm, median DRV plasma levels were 1,707 (958–3,910) ng/mL, CSF levels 13.23 (3.47–32.98) ng/mL and DRV CSF:plasma ratio 0.0104 (0.0018–0.0262). All patients had VL<40 copies/mL in plasma and 14 patients VL<40 copies/mL in CSF. Two patients (1 in each arm, and taking TDF/FTC) had detectable VL in CSF (280 and 159 c/mL). These patients had the lowest CSF DRV concentrations (5.47 and 3.47 ng/mL), with plasma DRV concentrations of 802 and 958 ng/mL respectively.ConclusionsCSF DRV concentrations and CSF VL were similar between patients receiving DRV/r 800/100 mg or 600/100 mg OD. Low CSF DRV concentrations might be associated with viral escape in CNS. This may be taken into account in patients receiving OD DRV/r. Larger studies should confirm these findings.

IntroductionDolutegravir (DTG) 50 mg once daily was superior to darunavir/ritonavir (DRV/r) 800 mg/100 mg once daily through Week 48, with 90% vs. 83% of participants achieving HIV RNA 50 c/mL (p=0.025) [1]. We present data through Week 96.Material and MethodsFLAMINGO is a multicentre, randomized, open‐label, Phase IIIb non‐inferiority study, in which HIV‐1‐positive ART‐naïve adults with HIV‐1 RNA≥1000 c/mL and no evidence of viral resistance were randomized 1:1 to receive DTG or DRV/r, with investigator‐selected backbone NRTIs (TDF/FTC or ABC/3TC). Participants were stratified by screening HIV‐1 RNA (≤100K c/mL) and NRTI backbone.ResultsA total of 484 adults were randomized and treated; 25% had baseline HIV RNA 100K c/mL. At Week 96, the proportion of participants with HIV RNA 50 c/mL was 80% in the DTG arm vs. 68% in the DRV/r arm (adjusted difference 12.4%; 95% CI 4.7, 20.2%; p=0.002). Secondary analyses supported primary results: per‐protocol [(DTG 83% vs. DRV/r 70%), 95% CI 12.9 (5.3, 20.6)] and treatment‐related discontinuation = failure [(98% vs. 95%), 95% CI 3.2 (−0.3, 6.7)]. Overall virologic non‐response (DTG 8%; DRV/r 12%) and non‐response due to other reasons (DTG 12%; DRV/r 21%) occurred less frequently on DTG. As at Week 48, the difference between arms was most pronounced in participants with high baseline viral load (82% vs. 52% response through Week 96) and in the TDF/FTC stratum (79% vs. 64%); consistent responses were seen in the ABC/3TC stratum (82% vs. 75%). Six participants (DTG 2, none post‐Week 48; DRV/r 4, two post‐Week 48) experienced protocol‐defined virologic failure (PDVF; confirmed viral load 200 c/mL on or after Week 24); none had treatment‐emergent resistance to study drugs. Most frequent drug‐related adverse events (AEs) were diarrhoea, nausea and headache, with diarrhoea significantly more common on DRV/r (24%) than DTG (10%). Significantly more participants had Grade 2 fasting LDL toxicities on DRV/r (22%) vs. DTG (7%), p<0.001; mean changes in creatinine for DTG (~0.18 mg/dL) observed at Week 2 were stable through Week 96.ConclusionsOnce‐daily DTG was superior to once‐daily DRV/r in treatment‐naïve HIV‐1‐positive individuals, with no evidence of emergent resistance to DTG in virologic failure and relatively similar safety profiles for DTG and DRV/r through 96 Weeks.

Current drugs against HIV can suppress the progression to AIDS but cannot clear the patient from the virus. Because of potential side effects of these drugs and the possible development of drug resistance, finding a cure for HIV infection remains a high priority of HIV/AIDS research. We recently generated a recombinase (termed Tre) tailored to efficiently eradicate the provirus from the host genome of HIV‐1 infected cells by specifically targeting a sequence that is present in the long terminal repeats (LTRs) of the viral DNA [1]. In vivo analyses in HIV‐infected humanized mice demonstrated highly significant antiviral effects of Tre recombinase [2]. However, the fact that Tre recognizes a particular HIV‐1 subtype A strain may limit its broad therapeutic application. To advance our Tre‐based strategy towards a universally efficient cure, we have engineered a new, universal recombinase (uTre) applicable to the majority of HIV‐1 infections by the various virus strains and subtypes. We employed the search tool SeLOX [3] in order to find a well‐conserved HIV‐1 proviral sequence that could serve as target site for a universal Tre from sequences compiled in the Los Alamos HIV Sequence Database. We selected a candidate (termed loxLTRu) with a mean conservation rate of 94% throughout the major HIV‐1 subtype groups A, B and C. We applied loxLTRu as substrate in our established substrate‐linked protein evolution (SLiPE) process [4] and evolved the uTre recombinase in 142 evolution cycles. Highly specific enzymatic activity on loxLTRu is demonstrated for uTre in both Escherichia coli and human cells. Naturally occurring viral variants with single mutations within the loxLTRu sequence are also shown to be efficiently targeted by uTre, further increasing the range of applicability of the recombinase. Potential off‐target sites in the human genome are not recombined by uTre. Furthermore, uTre expression in primary human T cells shows no obvious Tre‐related cytopathic or genotoxic effects. Finally, uTre expressing mice show no undesired phenotypes during their normal lifespan. We have developed a broad‐range HIV‐1 LTR specific recombinase that has the potential to be effective against the vast majority of HIV‐1 strains and to cure HIV‐1 infected cells from the infection. These results strongly encouraged us in our confidence that a Tre recombinase‐mediated HIV eradication strategy may become a valuable component of a future therapy for HIV‐infected patients.

IntroductionSerious non‐AIDS events (SNAE) are frequent in HIV patients receiving cART. Current CD4 count was shown to be more strongly associated with infective compared to not‐infective SNAE and unable to predict cardiovascular events. We investigated the relationship between baseline and current CD4 count and the risk of both infective and non‐infective SNAE in HIV‐positive patients according to current ART use.MethodsWe included all HIV‐positive persons enrolled in the ICONA Foundation Study cohort who had at least one follow‐up visit. SNAE were grouped in infective (pneumonia, sepsis, endocarditis and meningitis) and non‐infective (malignancies, chronic kidney disease, cardiovascular events, hepatic events and pancreatitis) aetiology. Incidence of these event groups were calculated overall and according to baseline and current CD4 count (grouped as 0–200, 201–350, 351–500, 501–750, and >750 cells/mm3). Participants' follow‐up accrued from the date of enrolment (baseline) to a diagnosis of SNAE or their last visit. An event was defined the first time one of the considered SNAE occurred so that each person contributed a single event. A Poisson regression model for each of the two endpoints was used.ResultsA total of 10,822 patients were included (25.3% females, 38.2% heterosexuals) and 26.6% had hepatitis co‐infections. Median age was 36 (IQR 31–42) years. Overall, 423 not‐infective and 385 infective SNAE were included. The most frequent non‐infective SNAE were malignancies (n=202) and the most frequent infective SNAE were pneumonia (n=289). Crude rates of non‐infective SNAE were 0.78, 1.08 and 0.80/100 PYFU, and those of infective SNAE were 1.00, 0.51 and 0.66/100 PYFU in ART naive, currently off and currently on ART patients, respectively. Higher current CD4 count was associated with reduced risk of both infective and non‐infective SNAE in naives and in patients on ART (Table 1). The association was less strong in the group which suspended ART (for non‐infective SNAE the p value for interaction between current log‐CD4 and ART‐status, p=0.004). Conversely, we found no association between baseline CD4 count and risk of non‐infective SNAE in people treated with ART (p value for interaction = 0.0001). When CVD were considered separately, there was no association with CD4 count (not shown).ConclusionsOur findings show that, differently from ART naive, in ART‐treated patients, non‐infective SNAE are predicted by current but not by baseline CD4, suggesting that immune restoration is crucial to prevent these events.

IntroductionMost people achieve and maintain viral load (VL) suppression on first‐line antiretroviral therapy (ART) but for a minority this does not happen. It is unclear whether those who have maintained VL suppression for several years will be able to continue to do so, or if rates of VL failure – due to poor adherence, ART interruption and/or resistance – remain at appreciable levels.MethodsEligible participants were ART‐naïve and started treatment after 1st January 2000, with ≥3 antiretrovirals and ≥9 months follow‐up. VL failure was defined as failure to achieve VL suppression (≤50 copies/mL) by 9 months on ART or a single VL >200 copies/mL after 9 months after start of ART. Kaplan‐Meier estimates were used to examine the cumulative probability of experiencing a VL >200 copies/mL over time, irrespective of treatment interruption (Figure 1). Follow‐up was censored at last VL assessment but not at treatment interruption. In a sensitivity analysis, VL failure was instead defined as two consecutive VL >1000 copies/mL.ResultsA total of 13,556 participants were included. Median (IQR) age at start of ART was 37 (32–43), median follow‐up 4.1 (2.3–6.7) years, pre‐ART VL 71,400 (17,400–221,900) copies/mL and pre‐ART CD4 count 204 (110–290) cells/mm3. Fifty‐one percent were white, 71% male and 50% MSM. Of which, 5,351 (39%) participants experienced a VL >200 copies/mL. In sub‐groups of participants the proportion experiencing a VL >200 copies/mL by one year after start of ART were: <50 years 22%, ≥50 years 17%, men 20%, women 26%, MSM 19%, black heterosexuals 23%, white heterosexuals 26% and other 23%. The median time to VL >200 copies/ml was 8 years. In sensitivity analyses based on 12,811 participants, 4274 (33%) experienced two consecutive VL >1000 copies/mL. Table 1 presents the rate of experiencing a VL >200 copies/mL (two consecutive VL >1000 copies/mL) by time since start of ART. The rate of VL >200 copies/mL declines over time, from 30 per 100 person‐years after up to two years after ART, to two per 100 person‐years after up to 11.5 years after ART. A sum of 2,047 (15%) participants stopped ART at some point (10, 14 and 17% had stopped ART by 1, 3, and 5 years, respectively).ConclusionsAlthough resistance will often not be present and, even if present, several drug options will likely remain, first occurrence of VL > 200 copies/mL after having attained viral suppression continues to occur after 10 years on ART.

IntroductionBMS‐663068 is a prodrug of BMS‐626529, an attachment inhibitor that binds directly to HIV‐1 gp120, preventing initial viral attachment and entry into the host CD4+ T‐cell. AI438011 is a Phase IIb, randomized, active‐controlled trial investigating the safety, efficacy and dose–response of BMS‐663068 versus atazanavir/ritonavir (ATV/r) in treatment‐experienced (TE), HIV‐1‐positive subjects.Materials and MethodsAntiretroviral TE subjects (exposure to ≥1 antiretroviral for ≥1 week) with susceptibility to all study drugs (BMS‐626529 IC50 100 nM), were randomized equally to four BMS‐663068 arms (400 or 800 mg, BID; 600 or 1200 mg, QD) and a control group (ATV/r 300/100 mg QD) with tenofovir disoproxil fumarate (TDF) + raltegravir (RAL). A sub‐group analysis of viral efficacy and immunologic reconstitution is presented.ResultsA total of 251 subjects were treated. Median age was 39 years, 60% were male and 38% were white. Median baseline (BL) viral load (VL) was 4.85 log10 c/mL (43%; 100,000 c/mL) and median CD4+ T‐cell count was 230 cells/mm3 (38%; 200 CD4 cells/mm3). Through Week 24, response rates (HIV‐1 RNA 50 c/mL) were comparable across all BMS‐663068 arms and the ATV/r arm regardless of gender, age and race. Response rates for subjects with BL VL 100,000 c/mL (BMS‐663068, 82‐96%; ATV/r, 93%) were higher than those for subjects with BL VL ≥100,000 c/mL (BMS‐663068, 70‐87%; ATV/r, 73%); however, there were no substantial differences in response across the BMS‐663068 and ATV/r arms in either sub‐group. Response rates for subjects with BL CD4+ cell counts ≥200 cells/mm3 (87‐96%) were higher than those for subjects with BL CD4+ cell counts 200 cells/mm3 (62–82%); however, no substantial differences in response were seen across the BMS‐663068 and ATV/r arms in either sub‐group. Mean changes in CD4+ T‐cell counts from BL were similar across all arms regardless of gender, age and BL CD4+ T‐cell count.ConclusionVirologic response rates were similar across the BMS‐663068 and ATV/r arms in TE subjects, regardless of BL demographic characteristics (gender, race, age), BL HIV‐1 RNA, or BL CD4+ T‐cell count. Mean increases in CD4+ T‐cell counts across the BMS‐663068 arms were consistent with ATV/r, regardless of gender, age and BL CD4+ T‐cell count. These results support continued development of BMS‐663068.NotePreviously submitted at IDWeek, Philadelphia, PA, 8 October 2014.

IntroductionSuccessfully treated HIV‐infected patients may still have an increased risk for cardiovascular morbidity and mortality, which might be related not only to traditional risks, but also to inflammation and dyslipidemia induced by HIV and/or antiretroviral therapy [1, 2]. We examined the relationship of serum lipid levels with plasma biomarkers of inflammation using a composite inflammatory burden score (IBS) from the following seven markers of inflammation: CD40L, tPA, MCP‐1, IL‐8, IL‐6, hCRP and P‐selectin.Materials and MethodsSubjects were selected among consecutive HIV‐infected males ≥18 years of age with an undetectable viral load (<50 copies/mL of HIV1‐RNA), seen at the University Hospital for Infectious Diseases, Zagreb, Croatia, in the period from January 2012 to March 2013. Plasma inflammatory biomarkers (CD40L, tPA, MCP‐1, IL‐8, IL‐6, hCRP and P‐selectin, quantified by bead‐based cytometry) >75th percentile were considered elevated and an IBS was constructed as the presence of zero, one, two, or three or more elevated biomarkers. Correlations between the IBS and lipid parameters were examined using Spearman's Rho and by ordered logistic regression proportional odds model to estimate the odds of more elevated (>75th percentile) biomarkers.Results181 male patients were included into the study, the median age was 46.7 (Q1–Q3, 39.9–55.0) years and the median current CD4 cell count was 553.0 (Q1–Q3, 389–729) per microliter. The patients were mainly treated with two nucleoside reverse transcriptase inhibitor (NRTI) plus one non‐NRTI (NNRTI) (N=100, 60.8%) or two NRTI plus lopinavir (N=50, 27.6%). There was a significant correlation between the IBS and serum cholesterol (Rho=0.23, 95% CI, 0.09–0.37), triglycerides (Rho=0.30, 95% CI, 0.16–0.42) and cholesterol/HDL‐cholesterol ratio (Rho=0.25, 95% CI 0.11–0.38). In the multivariable model a one unit increase in cholesterol/HDL‐cholesterol ratio was associated with a 1.72‐fold (95% CI, 1.27–2.33) increased odds of having a greater IBS. One unit increase (mmol/L) of cholesterol and triglycerides was associated with a 1.41‐fold (95% CI, 1.13–1.76) and 1.37‐fold (95% CI, 1.18–1.60) increased odds of having a greater IBS, respectively.ConclusionsOur study suggests that in virologically suppressed patients there is a significant association between markers of inflammation and serum levels of cholesterol and triglycerides as well as the cholesterol/HDL‐cholesterol ratio.

IntroductionThis descriptive, non‐interventional study on HIV‐1‐infected patients treated with DRV/r in the usual clinical setting, with a single‐arm prospective observational design, collected data on utilization of darunavir/ritonavir (DRV/r) under the conditions described in marketing authorization in usual clinical practice in Italy to evaluate efficacy and safety of DRV/r‐based antiretroviral (ARV) treatment. This analysis focussed on the safety profile of DRV/r in HIV‐1 infected patients.Materials and MethodsData were analyzed from four cohorts of HIV‐1‐infected patients treated with DRV/r in the real‐world setting, including an ARV‐naïve‐DRV/r‐naïve cohort (Cohort 1), an ARV‐experienced‐DRV/r‐naïve cohort (Cohort 2) and two ARV‐DRV/r‐experienced cohorts (Cohorts 3 and 4), one of which (Cohort 3) was from the DRV/r Early Access Program. The objective of this analysis was to examine the safety data obtained in these four cohorts in patients enrolled from June 2009 to November 2011 and observed until December 2012 or DRV/r discontinuation.ResultsSafety data from 875 patients were analyzed. DRV/r‐based treatment was well tolerated, with 36.2% of patients reporting ≥1 adverse event (AE) and very few discontinuations due to study drug‐related AEs (3.0% overall). The most frequent AEs were diarrhoea (2.7%), reduced bone density (2.6%) and hypercholesterolaemia (2.1%) (Table 1). Regarding metabolic parameters, levels of liver enzymes alanine aminotransferase (ALT) and aspartate aminotransferase (AST) remained stable from baseline to the last study visit (LSV) in DRV‐experienced patients and decreased in DRV‐naïve patients. Blood glucose concentrations remained stable in all cohorts. Serum triglyceride and cholesterol concentrations remained stable in DRV‐experienced patients but increased in naïve patients, yet were still within normal range.ConclusionsIn HIV‐1‐infected patients treated with DRV/r in these settings, the tolerability profile was favourable and similar to (or better than) that reported in controlled clinical trials. These data confirm DRV/r to be a safe treatment choice in DRV/r‐experienced and naïve patients.

IntroductionConcomitant use of combination antiretroviral regimen (cART) and cancer chemotherapy is difficult due to complex interactions and increased toxicity. Raltegravir could be an adequate option through its favourable drug‐drug interaction profile.MethodsProspective longitudinal study of HIV patients with cancer, AIDS related or not, undergoing chemotherapy. Patients without resistance or previous failure were switched or initiated raltegravir plus two nucleoside analogues. Plasma trough levels of raltegravir were measured.ResultsOverall, 28 patients receiving a raltegravir‐based regimen (4 naive) with tenofovir‐emtricitabine (18 cases) or abacavir‐lamivudine (10 cases) were included. Mean age was 46.2 years (IQR, 39–52.7), and 79% were male. Median time of HIV was 201.7 months, CD4+ nadir was 268 cells/mm3, and 75% had previous AIDS. At the diagnosis of neoplasia, 17 were on protease inhibitors and 4 with efavirenz. Ten patients had a non‐HIV‐related cancer (three breast, two pancreatic, one Ewing sarcoma, one myeloblastic leukemia, one melanoma, one parotid adenocarcinoma, one lung), and 18 had an HIV‐related cancer (nine non‐Hodgkin lymphoma, seven Hodgkin disease, two anal). Overall, 43% of patients received more than one line of chemotherapy, including antimetabolites in 12 patients (5‐FU, capecitabine, methotrexate, gemcitabine), alkylating agents in 12 cases (ciclophosphamide, iphosphamide), vinca alkaloids in 20 patients (vincristine, vinblastine, vindesine), antitumor antibiotics in 16 cases (adriamycin), cisplatin o carboplatin in six and monoclonal antibodies in six patients (rituximab, trastuzumab, cetuximab). Six patients modified the doses of antineoplastic agents due to toxicity (four neutropenia), not related to raltegravir. During a median follow up of 12.7 patients‐year in concomitant therapy, there was only 1 case of virological failure and no patient discontinued raltegravir. Plasma concentrations of raltegravir in eight patients showed a median concentration of 143 ng/mL (79–455). Four patients (14%) died during the study, not related to AIDS progression. Raltegravir was continued after chemotherapy in all the cases.ConclusionsA raltegravir‐based therapy is safe and effective in HIV patients undergoing antineoplastic chemotherapy, regardless of the type of tumour, and type and duration of chemotherapy. Pharmacokinetic data show adequate raltegravir levels.

IntroductionSexually transmitted diseases (STDs) data collected in HIV+ patients could be used as indicator of risky sexual behaviour possibly linked to HIV transmission. We described the STDs incidence over time and identified higher incidence factors.MethodologyAll patients in the ICONA Foundation Study enrolled after 1998 were included. STDs considered: any‐stage syphilis, human papilloma virus (HPV) diseases, gonococcal and non‐gonococcal urethritis, herpes simplex virus (HSV) genital ulcers, vaginitis and acute hepatitis B virus (HBV), hepatitis A virus (HAV), and hepatitis C virus (HCV) infections (only for non‐IVDU (intravenous drug user) patients). STDs incidence rate (IR): number of STDs divided by person years of follow‐up (PYFU). Calendar periods: 1998–2002, 2003–2007 and 2008–2012. Predictors of STDs occurrence were identified using Poisson regression and sandwich estimates for the standard errors were used for multiple STD events.ResultsData of 9,168 patients were analyzed (median age 37.3 (SD=9.3), 74% male, 30% MSM). Over 46,736 PYFU, 996 episodes of STDs were observed (crude IR 17.3/1,000 PYFU). Median (IQR) CD4/mmc and HIV‐RNA/mL at STD: 433 (251–600) and 10,900 (200–63,000). Highest crude IRs were observed for any‐stage syphilis (3.95, 95% CI 3.59–4.35), HPV diseases (1.96, 1.71–2.24) and acute hepatitis (1.72, 1.49–1.99). At multivariable analysis (variables of adjustment shown in Figure 1), age (IRR 0.82 per 10 years younger, 95% CI 0.77–0.89), MSM contacts (IRR 3.03, 95% CI 2.52–3.64 vs heterosexual) and calendar period (IRR 1.67, 95% CI 1.42–1.96, comparing 2008–2012 with 1998–2002) significantly increased the risk of acquiring STDs. Moreover, having a HIV‐RNA >50 c/mL (IRR 1.44, 95% CI 1.19–1.74 vs HIV‐RNA <50 c/mL) and current CD4+ cell count <100/mmc (IRR 4.66, 95% CI 3.69–5.89, p<0.001 vs CD4+ cell count >500) showed an increased risk of STDs. Being on ARV treatment significantly reduced the risk of developing an STD (IRR 0.37, 95% CI 0.32–0.43) compared to ART‐naïve people, even in the situation of temporary interruption of treatment (IRR 0.51, 95% CI 0.39–0.43) (see Figure 1).ConclusionsThe overall incidence of STDs has been increasing in the recent years. Interventions to prevent STDs and potential further spread of HIV infection should target the recently HIV diagnosed, the young population and MSM. Being on ARV treatment (potentially an indicator of whether a person is regularly seen for care) seems to reduce the risk of acquiring STDs independently of its viro‐immunological effect.

IntroductionDue to their low CNS penetrance, there are concerns about the capacity of non‐conventional PI‐based ART (monotherapy and dual therapies) to preserve neurocognitive performance (NP).MethodsWe evaluated the NP change of aviremic participants of the SALT clinical trial [1] switching therapy to dual therapy (DT: ATV/r+3TC) or triple therapy (TT: ATV/r+2NRTI) who agreed to perform an NP assessment (NPZ‐5) at baseline and W48. Neurocognitive impairment and NP were assessed using AAN‐2007 criteria [2] and global deficit scores (GDS) [3]. Neurocognitive change (GDS change: W48 – baseline) and the effect of DT on NP evolution crude and adjusted by significant confounders were determined using ANCOVA.ResultsA total of 158 patients were included (Table 1). They had shorter times because HIV diagnosis, ART initiation and HIV‐suppression and their virologic outcome at W48 by snapshot was higher (79.1% vs 72.7%; p=0.04) compared to the 128 patients not included in the sub‐study. By AAN‐2007 criteria, 51 patients in each ART group (68% vs 63%) were neurocognitively impaired at baseline (p=0.61). Forty‐seven patients were not reassessed at W48: 30 lost of follow‐up (16 DT‐14 TT) and 17 had non‐evaluable data (6 DT‐11 TT). Patients retested were more likely to be men (78.9% vs 61.4%) and had neurological cofounders (9.6% vs 0%) than patients non‐retested. At W48, 3 out of 16 (5.7%) patients on DT and 6 out of 21 (10.5%) on TT who were non‐impaired at baseline became impaired (p=0.49) while 10 out of 37 (18.9%) on DT and 7 out of 36 (12.3%) on TT who were neurocognitively impaired at baseline became non‐impaired (p=0.44). Mean GDS changes (95% CI) were: Overall −0.2 (−0.3 to −0.04): DT −0.26 (−0.4 to −0.07) and TT −0.08 (−0.2 to 0.07). NP was similar between DT and TT (0.15). This absence of differences was also observed in all cognitive tests. Effect of DT: −0.16 [−0.38 to 0.06]) (r2=0.16) on NP evolution was similar to TT (reference), even after adjusting (DT: −0.11 [−0.33 to 0.1], TT: reference) by significant confounders (geographical origin, previous ATV use and CD4 cell count) (r2=0.25).ConclusionsNP stability was observed after 48 weeks of follow up in the majority of patients whether DT or TT was used to maintain HIV‐suppression. Incidence rates of NP impairment or NP impairment recovery were also similar between DT and TT.

IntroductionDarunavir (DRV) is a preferred agent in treatment guidelines for ART‐naïve and experienced patients [1]. It is considered to have a high genetic barrier to resistance and 11 resistance‐associated mutations (RAMs) are recognized by IAS‐USA [2]. These have largely been identified by analyses examining the correlation between baseline genotype and virological response [3]. However, there is little information on RAMs that are directly selected by DRV, outside of short‐term clinical trials. We aimed to identify emerging mutations by comparing the genotypes of individuals before and after DRV exposure.Materials and MethodsThe UK HIV Drug Resistance Database was used to identify patients aged over 16 who had received at least 30 days of a DRV‐containing regimen. Patients were included if they had a "baseline" resistance test, prior to DRV exposure, and a "repeat" test, either on DRV or within 30 days of stopping this agent. To avoid attributing the effects of other PIs on emerging RAMs to DRV, patients were excluded if they had received another PI for greater than 90 days between the baseline genotype and the start of DRV. The baseline and repeat tests were compared to determine the nature of mutations stratified by PI history.ResultsA total of 5623 patients had DRV, of whom 306 met the inclusion criteria. A total of 228 (74.5%) were male, median age at the start of DRV was 42 years (IQR 37–47), and half had subtype B infection. The mode of transmission was homosexual contact for 50%, heterosexual for 38%, and 3% were injection drug users. The median CD4 count at the start of DRV was 257 cells/mm3 (IQR 94–453). A total of 149 patients (49%) had a history of PI use prior to DRV, and 157 (51%) were PI‐naïve. The most common previous PIs were lopinavir, atazanavir, and saquinavir. Baseline DRV RAMs were present in 1 (0.6%) PI‐naïve and 20 (13.4%) PI‐experienced patients. Mutations emerged under DRV pressure in a further 3 (1.9%) PI‐naïve patients, and in 7 (4.7%) PI‐experienced patients, 5 of whom had other DRV RAMs present at baseline (Table 1). The median time from the start of DRV to the repeat test was 196 days for PI‐naïve patients and 296 days for PI‐experienced.ConclusionsPI‐experienced patients had a greater prevalence of DRV RAMs at baseline than PI‐naïve individuals, probably due to the fact that some DRV RAMs can be selected by other PIs. This group also accumulated more RAMs during DRV exposure, possibly because previous PIs had caused minority variants which then emerged on DRV therapy. Overall, only 10 patients accumulated 16 RAMs, which supports the perception that DRV has a high genetic barrier to resistance. Repeat genotyping in the case of virological failure on DRV may still be warranted to detect emerging resistance and guide management decisions.